==== Front Signal Transduct Target Ther Signal Transduct Target Ther Signal Transduction and Targeted Therapy 2095-9907 2059-3635 Nature Publishing Group UK London 37386015 1484 10.1038/s41392-023-01484-7 Review Article Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future Zhang Yun zhangyun@xwhosp.org 1 Chen Huaqiu 1 Li Ran 2 Sterling Keenan 3 http://orcid.org/0000-0001-9928-889X Song Weihong weihong@wmu.edu.cn 1234 1 grid.24696.3f 0000 0004 0369 153X National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital, Capital Medical University, Beijing, China 2 grid.268099.c 0000 0001 0348 3990 The Second Affiliated Hospital and Yuying Children’s Hospital, Institute of Aging, Key Laboratory of Alzheimer’s Disease of Zhejiang Province, Wenzhou Medical University, Wenzhou, Zhejiang China 3 grid.17091.3e 0000 0001 2288 9830 Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, Vancouver, BC V6T 1Z3 Canada 4 grid.268099.c 0000 0001 0348 3990 Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang China 30 6 2023 30 6 2023 2023 8 2485 2 2023 5 5 2023 9 5 2023 © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Amyloid β protein (Aβ) is the main component of neuritic plaques in Alzheimer’s disease (AD), and its accumulation has been considered as the molecular driver of Alzheimer’s pathogenesis and progression. Aβ has been the prime target for the development of AD therapy. However, the repeated failures of Aβ-targeted clinical trials have cast considerable doubt on the amyloid cascade hypothesis and whether the development of Alzheimer’s drug has followed the correct course. However, the recent successes of Aβ targeted trials have assuaged those doubts. In this review, we discussed the evolution of the amyloid cascade hypothesis over the last 30 years and summarized its application in Alzheimer’s diagnosis and modification. In particular, we extensively discussed the pitfalls, promises and important unanswered questions regarding the current anti-Aβ therapy, as well as strategies for further study and development of more feasible Aβ-targeted approaches in the optimization of AD prevention and treatment. Subject terms Neurological disorders Drug discovery https://doi.org/10.13039/501100001809 National Natural Science Foundation of China (National Science Foundation of China) 82150710557 82201576 Zhang Yun Song Weihong issue-copyright-statement© West China Hospital, Sichuan University 2023 ==== Body pmcIntroduction Alzheimer’s disease (AD) is the most common neurodegenerative disorder leading to progressive cognitive decline with pathological hallmarks of senile plaque and neurofibrillary tangle formation in the brain. In 1984, Glenner & Wong discovered that the amyloid β protein (Aβ) is the central component of extracellular amyloid plaques in AD.1 Since then, Aβ has been considered as a driver of Alzheimer’s pathological processes and the “amyloid cascade hypothesis” has become a leading theory of AD pathogenesis.2 Over the past decades, targeting Aβ has been the main direction of developing AD treatment.3–6 However, the repetitive failures of Aβ-targeted clinical trials have cast considerable doubt on this hypothesis. Anti-Aβ therapy has now become a significant controversy in AD drug development and treatment. Aβ is generated from the amyloid precursor protein (APP) by sequential cleavage of β- and γ-secretase. However, the non-amyloidogenic pathway is the predominant pathway in vivo.7 APP is mostly cleaved first by α-secretase within Aβ domain at the Aβ Leu17 site in the non-amyloidogenic pathway, generating a secreted form of APP (sAPPα) and an 83-amino acid membrane-bound C-terminal fragment (CTF) C83, thus precluding Aβ production. The beta site APP cleaving enzyme 1 (BACE1), the β-secretase, and its homolog BACE2, the θ-secretase, also contribute to the non-amyloidogenic pathway.7,8 Under physiological conditions, BACE1 predominantly processes APP at the Aβ Glu11 β-secretase site to generate C89, and γ-secretase cleaves C89 to produce a truncated Aβ11-40.7,8 BACE2 cleaves APP at the Aβ Phe20 θ-secretase site to generate C80 and precludes Aβ generation.9–11 Two enzymatic cleavages of APP by BACE1 and γ-secretase are required to produce Aβ in the amyloidogenic pathway. BACE1 first cleaves APP at the Asp1 site to generate sAPPβ and C99. Subsequently, γ-secretase cleaves C99 to release Aβ and CTFγ. γ-secretase is a presenilins 1 (PS1)-containing macromolecular complex12–16 and this high molecular weight complex also requires nicastrin, anterior pharynx-defective 1, and PEN-2 for its enzymatic activity17,18 (Fig. 1).Fig. 1 Amyloidogenic and non-amyloidogenic processing pathways of APP. In the amyloidogenic pathway, BACE1 first cleaves APP at the Asp1 site to generate sAPPβ and a 99-amino acid membrane-bound C-terminal fragment (CTF) C99. Subsequently, γ-secretase cleaves C99 to release Aβ and CTFγ. Under physiological conditions (non-amyloidogenic pathways), APP is mostly cleaved first by α-secretase within Aβ domain at the Aβ Leu17 site, generating a secreted form of APP (sAPPα) and an 83-amino acid membrane-bound C-terminal fragment (CTF) C83, thus precluding Aβ production; BACE1 predominantly processes APP at the Aβ Glu11 β-secretase site to generate C89, and γ-secretase cleaves C89 to produce a truncated Aβ11-40; BACE2 cleaves APP at the Aβ Phe20 θ-secretase site to generate C80 and precludes Aβ generation. APP amyloid precursor protein, BACE1 β-site APP-cleaving enzyme 1, sAPP secreted APP, CTF C-terminal fragment, Aβ amyloid-β, tAβ truncated amyloid-β, BACE2 β-site APP-cleaving enzyme 2 The balance between continual Aβ generation and efficient clearance is important for Aβ homeostasis to prevent its toxic aggregation into misfolded assemblies.19 Similar to other brain metabolites, Aβ clearance depends on different pathways including enzyme degradation, crossing the blood–brain barrier (BBB), interstitial fluid (ISF) bulk-flow and CSF absorption.19,20 The BBB is composed of endothelial cells connected by tight junctions to form a selectively permeable system.21 The transport of soluble Aβ across brain endothelial cells to the peripheral circulation is mainly via low density lipoprotein receptor-related protein 1(LRP-1) and ABC transporter sub-family A and B member 1 (ABCA1 and ABCB1),22,23 while receptors for advanced glycosylation end-products (RAGE) is responsible for circulating Aβ entering into the brain.24 It has been identified that the expressions of the two blood efflux transporters LRP1 and ABCB1 were reduced during AD, whereas the expression of the blood influx transporter RAGE is elevated.21,25 The perivascular drainage pathway plays a vital role in ISF bulk-flow clearance of Aβ.26 Failure of perivascular drainage of Aβ altered Aβ homeostasis associated with synaptic dysfunction and cognitive impairment, leading to the development of AD.27 CSF absorption clearance of Aβ depends on factors including CSF production by the choroid plexus, integrity of the blood-CSF barrier, relevant transporters and CSF lymphatic absorption.28 In AD, the structural integrity of the blood-CSF barrier is destroyed, resulting in aberrant Aβ clearance.29 Enzymatic pathways for Aβ degradation include the zinc metalloendopeptidases, insulin-degrading enzyme (IDE), matrix metalloproteinase (MMPs), angiotensin converting enzyme (ACE), and endothelin-converting enzyme (ECE), serine proteases, cystein proteases, and kallikrein-related peptidase 7.30,31 In the hippocampus of AD patients, the enzymes IDE, ACE and NEP had decreased activity.30 AD model mice also showed the impaired Aβ degradation system.21,32 In GWAS, many genetic risk factors for AD (e.g. RIN3, CLU and PTK2B) are linked to Aβ degradation.33,34 Extensive genetic studies have supported the causative role of Aβ accumulation in AD pathogenesis. Down syndrome (DS) patients with trisomy-21 having extra copy of APP gene develop typical Alzheimer’s neuropathology including amyloid plaques and neurofibrillary tangles.35–37 Mutations in APP, presenilin 1 (PSEN1) and PSEN2 genes that increase Aβ production, elevate Aβ42/Aβ40 ratio and promote plaque formation cause autosomal dominant early-onset familial AD (FAD), implicating a role of altering APP processing in AD pathogenesis.7,38,39 In contrast, an APP mutation identified in the Icelandic population reduces Aβ production, leading to protection against cognitive decline in the elderly.40 Both genetic (e.g., ApoE4, TREM2) and non-genetic (e.g. diabetes, obesity, stroke, or physical inactivity) risk factors for late-onset sporadic Alzheimer’s disease (SAD) have also been identified to increase Aβ generation and/or reduce Aβ clearance for its accumulation.4,41–45 These studies suggest that Aβ accumulation drives disease progression in both FAD and SAD and thus illustrates why clinical trials involving anti-Aβ therapies have garnered so much attention in the Alzheimer’s community. Recently, Aβ-based therapy has received encouraging results. Aducanumab, a monoclonal antibody against Aβ aggregates, has obtained the FDA’s approval as an Alzheimer’s drug for its ability to reduce the level of Aβ plaques in patients with early AD or mild cognitive impairment (MCI).46–48 On Nov 30 2022, Eli Lilly and Company (https://investor.lilly.com/news-releases/news-release-details/lilly-shares-positive-donanemab-data-first-active-comparator) announced the result of the first active comparator study (TRAILBLAZER-ALZ 4), which showed that donanemab, another monoclonal antibody targeting deposited plaques had outperformed aducanumab-avwa treatment in terms of brain amyloid clearance in patients with early symptomatic AD.49 At the same time, results from the highly anticipated CLARITY AD study were published, showing that 18 months of treatment with lecanemab, a humanized IgG1 monoclonal antibody targeting Aβ soluble protofibrils, reduced markers of amyloid and moderately improved cognitive decline in patients with early AD.50 Recently, the FDA approved lecanemab as the second-ever monoclonal antibody to treat AD. ANAVEX®2-73 (Blarcamesine), which targets sigma-1 and M1 muscarinic receptors, has also demonstrated its disease-modifying activity in AD transgenic mice (3xTg-AD), including reducing amyloid and tau pathologies as well as improving cognitive deficits.51,52 The results of its Phase 2B/3 study, presented at the Clinical Trials on Alzheimer’s Disease (CTAD) Congress 2022, showed that 48 weeks of blarcamesine treatment significantly reduced cognitive decline in patients with early AD. This series of positive results offers a fresh hope and indicates that Aβ-based therapy may be indeed the right direction to be followed. In this review, we summarized the history and current understanding of the “amyloid cascade hypothesis”. In particular, we discussed the pitfalls, promise and important unanswered questions about the current anti-Aβ therapy, which will provide a foundation for further studying and developing more feasible Aβ-targeted strategies to optimize AD prevention and treatment. The history of amyloid cascade hypothesis (Fig. 2) In 1984, Aβ was identified as the primary component of extracellular amyloid plaques in AD,1 which is the unique pathological hallmark of the disease.53 Hardy and Higgins then proposed “the amyloid cascade hypothesis” in 1992, positing that Aβ deposits in the brain are the initiating event of AD pathogenesis, resulting in subsequent tau tangle formation, neuronal loss and dysfunction as well as cognitive decline.2 Since then, many genetic and non-genetic studies have supported this hypothesis. Down syndrome with APP gene triplication or APP locus duplications produces an increase in Aβ production and the Aβ42/40 ratio, leading to plaque formation and cognitive decline. APP mutations increase total Aβ and the ratio of Aβ42/Aβ40, leading to early-onset Alzheimer’s disease (EOAD). The apolipoprotein E (APOE) and clusterin (CLU), the strongest genetic risk factors for late-onset Alzheimer’s disease (LOAD), has also been identified to influence Aβ seeding and clearance.4,41Fig. 2 Milestone of the amyloid cascade hypothesis and its applications. Yellow box: key research findings; blue box: the Aβ-related toxicity; green box: the diagnostic application; pink box: important drug and non-drug anti-Aβ therapies. AD Alzheimer’s disease, CSF cerebrospinal fluid, FDA food and Drug Administration, LTP long-term potentiation Morphology of Aβ aggregates After secretion, Aβ first aggregates into different soluble species that then change their conformation into cross-β-sheet fibrils to form plaques. There are two types of amyloid plaques: classical and diffuse ones. The classical plaques have a compact core of Aβ surrounded by an optically clear area and an outer corona.54 The corona consists of both neuronal and glial elements, including degenerative neuronal processes (neurites) along with reactive astrocytes and microglia.55,56 Diffuse plaques comprise very small, often stellate assemblies scattered about the parenchyma. It refers to the fact that the Aβ accumulation is widely spread or scattered, but not concentrated.57–59 Without consideration of the nature of the Aβ deposits (e.g. thread-like or punctate), “diffuse” thus denotes only the characteristics of the Aβ deposits, and not the dysmorphic neuritis or any other component of the plaques. A recent study showed that it is the classical plaques with inflammatory cells rather than diffuse plaques that correlate with the cognitive impairment during AD.60 Pathological role of Aβ aggregates (Fig. 3) The amyloid cascade hypothesis has been the leading model of AD pathogenesis since it was proposed, and the hypothesis has being revised over time. The original hypothesis focuses on large insoluble Aβ fibrils as the key offender of neuronal damage, while growing evidence supports that the Aβ oligomers exist and exert their neurotoxicity independently of mature fibrils.61 The amyloid-β oligomer (AβO) hypothesis suggests that AD pathogenesis was instigated by soluble, ligand-like Aβ oligomers.Fig. 3 The generation, aggregation and pathological functions of Aβ. Aβ is generated from APP by sequential cleavage of β-secretase (beta-site APP cleaving enzyme 1, BACE1) and γ-secretase. BACE1 first cleaves APP at the Asp1 site to generate sAPPβ and C99. Subsequently, γ-secretase cleaves C99 to release Aβ (Aβ1-40/42 are the most common isoforms) and CTFγ. After secretion, Aβ peptides first oligomerize into different soluble species then convert their conformation into profibrils and cross-β-sheet fibrils, forming amyloid plaques. Aβ aggregates interact with tau proteins to exert the toxic effects. In addition, they contribute to other AD pathological features including neuroinflammation, oxidative stress and mitochondrial dysfunction, leading to neuronal death and dysfunction. Aβ amyloid β, APP amyloid precursor protein Interact with cell membrane Aβ aggregates can directly interact with the lipid and cholesterol components of the cell membrane, forming channels and destroying membrane integrity and permeability, which allows Ca2+ entering into the cell, leading to LTP inhibition and neuronal death.62,63 For example, AβOs bind to sialic acid-containing GM1 ganglioside on cell membrane to induce LTP impairment.64 On the other hand, cholesterol-rich lipid rafts provide an optimal environment for Aβ synthesis and enhance the interaction of Aβ with the membrane.65 Both β- and γ-secretases show increased enzymatic activity in the lipid rafts with higher cholesterol level, while non-amyloidogenic α-secretase activity is inhibited by cholesterol.66–69 In addition, It is well established that cholesteral-containing lipid membrane can influence Aβ seeding and aggregation.70,71 As a nucleation process, cholesterol and GM1-rich lipid rafts accelerate Aβ aggregation by binding with Aβ to stabilize its structure.72,73 Thus, reduction of cholesterol in endosomes or lysosomes ameliorates Aβ aggregation and its toxicity in mouse models.74 Interfere with synaptic plasticity Impaired synaptic function is considered to be an early and key pathology of AD. Synaptic loss is also closely correlated with cognitive decline in Alzheimer’s patients.75 Aβ oligomers change the morphology and density of synapses, leading to the impairment of synaptic plasticity.76,77 As a glutamate receptor, functional NMDARs regulate the formation of synapes and synaptic plasticity.78 AβOs directly disturb the activity of NMDARs and impair NMDAR-mediated signaling pathways (e.g. Wnt/β-catenin signaling pathway), leading to synaptic loss and the reduction of spinal density.79 Furthermore, AβOs destroy Glu-recycling at the synapse by increasing glutamate release, reducing glutamate uptake and impairing glutamate transporters, which causes the overactivation of extrasyaptic NMDARs, ultimately leading to LTP suppression, LTD enhancement, and synaptic loss.80 α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) is another glutamate receptor containing four subunits GluA1-4, which makes up to 80% of the excitatory synapses in the CA1 region of hippocampus.81,82 Many studies have shown that AMPARs also take part in the modulation of synaptic plasticity.83,84 However, AβOs induce AMPAR ubiquitination and degradation, leading to the loss of AMPARs followed by the suppression of synaptic transmission.85,86 Recently, two parallel studies have further investigated the underlying mechanism of the Aβ’s detrimental effect over synaptic transmission.87,88 They found that intracellular administration of the AβOs rather than administration of the AβOs at the extracellular level altered the synaptic transmission and fast axonal transport via the casein kinase 2 (CK-2) activation. In addition, the LTP inhibtion and LTD enhancement mediated by Aβ aggregates further result in the shrinkage of dendritic spines by remodeling actin.89,90 Furthermore, Aβ aggregates and hyperphosphorylated tau protein exert synergistic effect on impairing synapse function.91–93 AβOs induce tau hyperphosphorylation and accumulation in dendritic spine, which further lead to synaptic loss and dysfunction.94,95 The level of pathological tau in AD patients is correlated with the severity of impaired synaptic plasticity and cognitive dysfunction.96 The pathological tau interacts with the presynaptic compartments including synapsin-1, synaptophysin, to inhibit the mobility and release of synaptic vesicles, leading to the development of AD.97–99 Missorted tau proteins at postsynaptic terminals interacts with the subunits of AMPARs and NMDARs, leading to the excessive activation of glutamate receptors, Ca2+ influx, impaired LTP and enhanced LTD.92,100,101 It has been demonstrated that the absence of tau proteins prevent Aβ-induced LTP impairment mouse hippocampal slices.102 Another study also indentified that reduction of tau could ameliorate Aβ-induced Ca2+ influx into neurons and AD-related excitotoxicity in vivo.103 These findings suggest that the synaptic toxicity induced by Aβ was dependent on pathological tau proteins to some extent. Aβ-induced tauopathy Beside Aβ plaques, neurofibrillary tangles (NFTs) containing hyperphosphorylated tau are also a hallmark of Alzheimer’s pathology.104–107 Over past dozen years, a growing number of evidence has indicated the importance of Aβ-tau interaction in Alzheimer’s pathogenesis. In the tripple transgenic mice (3xTg-AD), extracellular Aβ accumulates in the neocortex and hippocampus followed by tau seeding into fibrillar tangles.108 Injection of Aβ aggregates into brain of P301L mutant tau transgenic mice triggers a five-fold elevation in NFTs in the amygdala.109 In the clinical setting, neuroimaging of sporadic Alzheimer’s patients show the increased cortical tau-PET ligand retention only in the presence of Aβ accumulation, which is also associated with cortical atrophy in AD.110 In addition, longitudinal studies idenfied that antecedent Aβ aggregates could successfully predict the subsequent tau changes in the inferior temporal cortex.111 As the upstream factor, Aβ triggered the hyperphosphorylation of tau protiens,112–114 which synergistically induced neuronal impairment and cognitive deficits.111,115 Aβ accelerated the tau hyperphosphorylation by the activation of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3 (GSK-3).116–118 GSK-3β, which is inextricably associated with Aβ production and accumulation,119 is a key trigger of tau phosphorylation and aggravates Aβ-induced tau toxicity.120 CDK5-P25 phosphorylates tau at sites of Thr181, Ser199, Ser202, Thr205, Thr212, Ser214, Ser217, Thr231, Ser235, Ser396, and Ser404.121 Thus, inhibitors of GSK-3β or CDK-5 such as AZD1080 and roscovitine, markedly reduced the levels of tau phosphorylation and prevented further tau aggregation.122,123 Further studies have found that mitogen-activated protein kinases (MAPKs) including ERK1/2, SAPKs and p38 are also involved in Aβ-induced formation of PHF-tau during AD.124,125 Cellular prion protein (PrPC) has been found as a receptor for toxic Aβ oligomers to induce LTP loss and cognitive impairment in AD model mice.126,127 PrPC has been also detected in Aβ plaques in Alzheimer’s patients,128–130 which activates Fyn kinase and phosphorylates tau by the GluN2B subunit of NMDARs.100,131–133 In addition to its stimulatory effect on tau phosphorylation, Aβ also affected tau oligomerization and tangle formation.134 Aβ triggered caspase-3 (CASP3)-induced cleavage of tau at Asp421 to yield an N-terminal product, which self-aggregated and further assembled into neurotoxic oligomers.134,135 Tau oligomers not only led to neuronal damage but also bound to astrocytes and microglia to induce neuroinflammation.136 In hippocampal neurons, Aβ also induced the activation of calpain-1 and generated a 17-kDa tau fragment, resulting in neurite degeneration and neuronal death.137 Meanwhile, the toxic state of tau proteins also influence Aβ production. Thus, knocking out the tau genes in the APP/PS1 mice inhibited the amyloidogenic pathway of APP processing, Aβ production and the amyloid plaque formation.138 Furthermore, the neurotoxicity of Aβ is tau-dependent. Absence of tau on NMDARs of spines successfully prevented the toxic effect induced by the binding of Aβ to NMDARs.92 A recent study proposed that the phosphorylation of tau at Tyr18 by Fyn kinase also blocked Aβ toxicity.139,140 Aβ promoted the phosphorylation and activation of Fyn kinase, which further migrated into dendritic spines, leading to synaptic impariment.141,142 Tau protein mediated Aβ toxicity by interacting with Fyn kinase via its amino-terminal projection domain (PD).143 Accordingly, inhibition of Fyn improved the cognitive deficits in transgenic mice with Aβ and tau depositions.144,145 PET and CSF tests also indicate the synergy between Aβ and tau, which leads to brain dysfunction and cognitive impairment.146–148 In contrast, Aβ and tau have antagonistic effects on neural circuit.149 Tau induces the profound silencing of circuits by blocking Aβ-dependent hyperactivity in the cortex.150 Induce inflammation Neuroinflammation is chronic inflammation in the CNS, which is attributed to activated microglia and astrocytes to produce numerous pro-inflammatory cytokines.151 Growing evidence demonstrates that neuroinflammation plays a vital role in the neuropathological changes in AD.152–154 In addition, patients who are with long-term nonsteroidal anti-inflammatory drugs (NSAIDs) for treating other diseases such as rheumatoid arthritis, showed a 50% reduction in the risk for developing AD.155 It has been reported that the inflammation-associated proteins and cells were localized closely to Aβ plaques in AD brain.156 However, the possible underlying mechanisms are still unclear. One potential explanation for the activated glia cells in AD brain could be the response to Aβ produced largely by neurons.157,158 Aβ shares structural similarities with antimicrobial peptides (AMPs) and viral fusion domains, which stimulates glia cells to secrete a mass of pro-inflammatory cytokines.159 Similar to AMPs, Aβ aggregates can also induce pores in cell membranes, which allow a variety of stimuli to activate glia cells.160 Microglia comprise around 10–15% of all glial cells, which are the resident macrophages within the CNS.161 In a healthy adult brain, microglia are in a resting state and highly ramified morphology with small somas.162 These cells communicate with surrounding environments including neurons, astrocytes and blood vessels to maintain the development and homeostasis of the CNS.163,164 When microglia recognize the insults of the CNS, they respond to the injury or invasion by a morphological change, resulting in cell enlargement and migration.165 In the development of AD, it has been suggested that Aβ aggregates are the primary driver to activate microglia and set them into motion. Activated microglia migrated to the Aβ deposition and stimulated the phagocytosis of Aβ.166–168 Thus, factors such as CD33, which impedes Aβ phagocytosis by microglia, has been considered to increase the risk for suffering from AD.169 However, the prolonged activation of microglia become enlarged and are no longer able to exert their phagocytic function. In contrast, their capacity of pro-inflammatory cytokine production is unaffected, contributing to an exacerbation of AD pathology including Aβ accumulation and neuronal damage.170,171 To compensate the impaired clearance of Aβ, peripheral macrophages are recruited to the brain in an effort to clear Aβ plaques, which likely worsens the sustained inflammation and thus AD pathologies.172,173 Compared with microglia distal to the amyloid in AD brain tissues, there is an increased expression of TREM2 in the cells close to Aβ plaques.174,175 Increased TERM2 experession has been found in human AD blood, indicating the important role of peripheral TREM2 in Alzheimer’s pathogenesis.176,177 Using flow cytometry identified that these cells also contained high levels of CD45, Ly6c, and CD11b, which highly express in peripheral macrophages as well.174 Partial or completed deletion of TREM2 markedly reduced the number of Aβ-associated macrophages and increased cerebral Aβ plaques in AD model mice.174,175,178 The reduction of TREM2 in Aβ-associated macrophages also altered astrocytosis detected by glial fibrillary acidic protein (GFAP) and S100β.178 As the most abundant glial cells in the CNS, astrocytes play an essential role in the communication with neurons and regulation of synapse formation and function.179 Under pathological conditions, astrocytes become reactive, which are characterized by cell hypertrophy with GFAP and vimentin expressions as well as the release of cytotoxins.180–182 The reactive astrocytes are close to Aβ plaques in brains from AD patients and rodent models.183,184 Astrocytes response to Aβ aggregates in a TLR-dependent manner, which further activates the target genes to produce proinflammatory factors.185,186 The excessive production of proinflammatory cytokines such as TNF-α or IFN-γ modulated the APP processing in astrocytes, leading to the increased Aβ levels and toxicity.187 These studies have revealed a significant role of reactive astrocytes in the loop between inflammatory cytokines and Aβ load.188 Disturbed this cross-talk has been considered to underlay Alzheimer’s pathogenesis. Impaired astrocyte activity also increased the number of microglia surrounding Aβ plaques and altered the microglia status.189 In turn, microglia could alter the status of astrocytes. The activated microglia secreted IL-1α, TNF and C1q cytokines to further induce A1 reactive astrocytes, which are neurotoxic and increased in human AD post-mortem tissues.190 In addition, Aβ produced by neurons induced the complement protein C3a released by astrocytes via NFκB signaling, which interacted with the receptors (C3aRs) on microglia and neurons to aggravate Aβ aggregate loads and cognitive impairment.191 Mitochondrial dysfuntion and oxidative stress Mitochondria are the major powerhouses for cells, where oxidative phosphorylation (OXPHOS) occurs to generate ATP for maintaining the optimal neuronal activities.192 Mitochondria are essential for the glutamate synthesis, synaptic transmission and calcium regulation.193,194 Disrupted energy metabolism has been found in early AD and precedes the disease development, suggesting the core role of mitochondria dysfunction in Alzheimer’s pathogenesis.195,196 Soluble Aβ oligomers disrupted the balance between mitochondrial fission and fusion, leading to significant mitochondrial dysfunction.197,198 Excessive mitocondrial fission is a key modulator of Aβ toxicity.199 Thus, restoration of mitochondrial fission rescued APP- or Aβ-induced mitochondrial abnormality and neuronal damage.200,201 Only 1% of mitochondrial proteins are synthesized in the mitochondria itself. Instead, most proteins of the mitochondria are synthesized by cytosolic ribosomes then imported into the organelle.202 APP- or Aβ-induced impairment of mitochondrial import pathway has been considered as a hallmark of AD.203–205 It has been demonstrated that APP blocked mitochondrial import machinery and impaired mitochondrial function in AD brain by forming a complex with translocases of the inner and outer mitochondrial membranes.204 In addition, endoplasmic reticulum (ER)-mitochondria contact sites provide a platform to regulate important cellular activities, including synthesis of phospholipids, calcium transport between ER and mitochondria, regulation of mitochondrial homeostasis, activation of inflammasome, and induction of apoptosis.206,207 Alteration of mitochondria-associated endoplasmic reticulum membrane (MAM) signaling has been implicated in neurodegenerative diseases such as AD.208,209 Overexpression of APP mutants or Aβ aggregates increased ER-mitochondria connectivity, resulting in the elevation of mitochondrial calcium.208,210,211 C99, a C-terminal fragment of APP cleaved by β-secretase, also activated sphingolipid turnover and increased ceramide to impact the ER-mitochondria contacts, leading to impaired mitochondrial respiration and metabolic disturbance.212 Mitochondria are also the major source of oxidative stress because the inevitable leakage of electrons at complex I and complex III of the electron-transport chain to produce reactive oxygen species (ROS).213,214 Mitochondria generate approximately 90% of the cellular ROS.215 The damaged mitochondria are less efficient to generate ATP but more efficient to produce ROS.216 The vulnerability of the brain to ROS is now emerging as a key detrimental factor driving AD pathogenesis. Neurons exposed to ROS stimuli are more susceptible to developing age-related neurodegenerative pathologies, as seen in AD brains. Redox active metal ions, such as Cu and Fe bind to Aβ to produce the ROS, which contributes to the oxidative damage on proteins and lipids leading to impaired membrane integrity, neuronal dysfunction and DNA damage.217–220 In addition, mitochondrion-derived ROS modulated the APP processing and triggered Aβ production to form a vicous cycle.221 Change neurochemical systems Aβ aggregates interact with glutamatergic neurotransmission, which impairs excitatory synaptic plasticity, leading to cognitive decline.222–225 Excessive Aβ peptides induced LTD by inhibiting LTP and making a shift of the NMDAR-dependent signaling cascades.226 Thus, Aβ accumulation inhibited the synaptic transmission, resulting in early cognitive impairment.224 Aβ-induced LTD is also caused by inhibiting glutamate uptake and stimulating glutamate releasing, which evently elevates glutamate levels in the synapse cleft.222,225,227,228 An increase of glutamate activated GluN2B-bearing NMDARs, which further led to calcium-induced LTD and synaptic depression.85 Aβ oligomers also regulated the trafficking of NMDARs to change dendritic spine density.222,227,229 As with NMDARs, AMPARs are also the principal receptors mediating excitatory synaptic transmission.230 It has been identified that APP overexpression and increase of soluble Aβ oligomers are related with the downregulation of GluA1/2 subunits of AMPARs, leading to the inhibition of synaptic plasticity, spine loss, and memory deficits.231,232 The basal forebrain cholinergic system is one of the earliest brain regions vulnerable to degeneration during AD.233 The correlations between enhanced BACE1 activity, Aβ accumulation with atrophy of basal forebrain and loss of functional connectivity have been found in neuropathological and neuroimaging studies.234–237 Furthermore, such an inverse correlation seems to be intensified with the ε4 allele of the apolipoprotein E (APOE) gene, which is one of the strongest risk factors for LOAD.238 Impair brain networks Decrease of default-mode network (DMN) functional connectivity has been found in prodromal stages of AD, which is associated with loss of gray matter volume in neocortex and hippocampus.239,240 Reduced DMN connectivity only occurs in individuals with elevated baseline Aβ-PET indexes, accelerating cortical atrophy.241 Consistent with the findings in humans, aging and AD animal models also show disruptions of functional connectivity in the DMN.242 The salience network (SN) identifies salient stimuli and plays an important role in the coordination of the central executive (CEN) and the DMN, whose functional impairment is related to learning and episodic memory deficits in both amnestic mild cognitive impairment (aMCI) and AD.243 There is an increased Aβ-PET signal within the CEN and the SN in the progression of AD.244,245 A spatial covariance between Aβ aggregates with reduced connectivity and metabolism in the CEN and SN has also been found in AD.246,247 Discovery and development of Aβ-based biomarkers Based on the amyloid cascade hypothesis, Aβ measurement has been considered as a valuable indicator to assist the diagnosis of AD. In clinical settings, Aβ peptides are most frequently measured in the cerebrospinal fluid (CSF) or through brain imaging of Aβ fibrils with positron emission tomography (PET).248 CSF analysis offers a quantitative result of the net effect of Aβ peptides, while.249,250 There are four tracers used to detected levels of amyloid in the human brain, including 11C-Pittsburgh compound B (11C-PiB),251 AmyvidTM (flobetapir F18),252 NeuraceqTM (florbetaben F18)253 and VizamylTM (flutemetamol F18).254 In practice, reduced concentrations of Aβ42 in CSF and increased retention of Aβ tracers in the brain have been considered as early biomarkers of AD.255–258 Both biomarkers have been demonstrated to have high diagnostic and prognostic value as they start changing decades before the onset of dementia symptoms.259–266 However, CSF- and PET-based measures are not suitable for large-scale screening due to their invasiveness, high cost and low accessibility. Considering the greater availability of blood sampling, blood-based biomarkers become the primary goal in screening for and diagnosing AD in the population and many studies now focus on examining the role of peripheral Aβ and APP in AD development.267–269 One such study found that plasma concentrations of soluble β-secretase cleaved n-terminal APP (sAPPβ) were significantly reduced in AD patients compared with age-matched cognitively healthy individuals or patients with behavioral variant frontotemporal dementia (bvFTD), indicating the potential role of sAPPβ as a promising new biomarker of AD.270 In addition, there is increasing evidence to support that plasma Aβ acts as an endophenotype of AD, which simultaneously changes with Aβ status in the brain.271–273 The blood levels of APP669-711/Aβ42 and Aβ40/Aβ42 ratios, as well as peripheral Aβ-bound extracellular vesicles (EVs), have been shown to predict brain Aβ burden.274,275 Our group has also identified that circulating Aβ could pass the blood brain barrier (BBB) and enter the brain, contributing to the development of AD.276 In contrast, Aβ peptides in the CNS can also move into the circulatory system, where the peptides are phagocytosed by the monocytes or neutrophils, directly degraded by the enzymes, or further transported to the peripheral organs or tissues for degradation or excretion.28,277 Recently, the development of single molecular assay (Simoa), an ultra-sensitive immunoassay technology, allows the measurement of Aβ40 and Aβ42 levels at sub-femtomolar concentration. The availability of reliable and sensitive detection of Aβ peptides in blood makes a promise for early diagnosis and better prognosis of AD. The progression of Anti-Aβ therapy To date, five drugs have been approved for the treatment of AD. Four of these medications are classified as cholinesterase inhibitors (CIs), including tacrine, donepezil, rivastigmine, and galantamine. Most of them are approved to treat Alzheimer’s type in the mild-to-moderate stages, except for donepezil which is administered to patients with severe or late-stage AD. Tacrine has been discontinued in the US due to severe liver toxicity. Unlike these four medications, memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist, which exerts its neuronal protective effects by inhibiting glutamate activity. However, these drugs can only help alleviate the symptoms instead of modifying the disease. Thus, development of effective disease-modifying therapies for AD is urgent and necessary. According to ALZFORUM (March 2023, www.alzforum.org), 298 AD therapies have been under clinical trials. 76 of them target the Aβ peptide or its aggregates, including small molecules (Table 1) and immunotherapies (Table 2), which can be classified into four categories: (1) to reduce Aβ generation;278–282 (2) to enhance the degradation and clearance of Aβ and its aggregates;283–285 (3) to neutralize soluble Aβ monomers or its toxicity;286–294 (4) to directly inhibit Aβ aggregation.295–299 So far, two antibody-based drugs aducanumab and lecanemab have been approved by the FDA and 38 of them have been discontinued due to ineffectiveness or toxic side effects.Table 1 Aβ-related small molecules for AD treatment Agent Route Mechanism of action Reference Reduce Aβ generation  Acitretin Oral Increases the expression of α-secretase (ADAM10) to boost the non-amyloidogenic processing of APP and reduce Aβ levels 278  Lenalidomide Oral Inhibits BACE1 expressions 280  Levetiracetam Oral N/A 281  NIC5-15 Oral γ-secretase modulator ALZFORUM  Posiphen Oral Blocks the translation of APP 282 Enhance the clearance of Aβ or its aggregates  ALZT-OP1 Oral Promotes the microglia-mediated phagocytosis of Aβ ALZFORUM  Bexarotene Oral Acts as an agonist of retinoid X receptor to increase brain ApoE concentration 283 Destabilize or inhibit Aβ aggregates  ALZ-801 Oral Prodrug of the modified amino acid homotaurine that inhibits the aggregation of Aβ42 into toxic oligomers by stabilizing Aβ42 monomers. 295  Contraloid Oral Stabilizes Aβ42 monomers to inhibit its aggregation 296  PBT2 Oral Lowers extracellular levels of bioactive metals, and thus reduce metal-mediated Aβ aggregation 298  Varoglutamstat Oral Inhibits the generation of a highly toxic and aggregation-prone form of Aβ (pGlu-Aβ). 299 Ameliorate the toxic effects of Aβ aggregates  ALX-001 Oral It prevents Aβ-induced synapse loss by competing with metabotropic glutamate receptor type 5 (mGluR5) for binding with Aβ oligomers 286,287  CT1812 Oral Blocks the binding of oligomeric Aβ with its receptors, and thus reduce Aβ-induced synaptic toxicity 289  Nasal insulin Intranasal delivery Synaptic remodeling and glucose utilization 290–292  Simufilam Oral Prevents and reverses the binding of Aβ42 to α7nAChR, which reduces tau deposition, neuroinflammation and synaptic dysfunction 293,294 Aβ amyloid β, AD Alzheimer’s disease, APP amyloid precursor protein, BACE1 beta site APP cleaving enzyme 1, CSF cerebrospinal fluid, DS down syndrome, FDA Food and Drug Administration, NfL neurofilament light, PET positron emission tomography Table 2 Immunotherapy targeting Aβ (clinicaltrials.gov accessed March 19, 2023) Agent Route Mechanism of action Ongoing clinical trials Clinical outcome Reference Targeting Aβ monomers  ABBV-916 Intravenous infusion A monoclonal antibody recognizing truncated Aβ modified with pyroglutamate at position 3 (N3), which is aggregated in amyloid plaques NCT05291234 (Phase 2) Unpublished ALZFORUM  ABvac 40 Subcutaneous injection An active vaccine targeting the C terminus of Aβ40 NCT03461276 (Phase 2) Safe, well tolerated, and consistently elicited a specific immune response in patients with mild to moderate AD 326  AV-1959D Intradermal injection A DNA vaccine fuses coding sequences of three copies of Aβ1-11 to 12 to elicit antibodies to Aβ peptides NCT05642429 (Phase 2) Unpublished 328  Aduhelm (Approved by the FDA) Intravenous infusion A human IgG1 mAb against a conformational epitope found on the N-terminus of Aβ (residues 3–6) NCT05310071 (Phase 4) The highest dose of aducanumab treatment significantly improved cognitive deficit in the participants. In June 2021, aducanumab was approved by the FDA for medical use. As required by the FDA, a Phase 4 confirmatory trial called ENVISION was planned in May 2022. The study will recruit 1500 patients with early AD including participants from black and Hispanic communities in the US 46–48,347–349  Donanemab Intravenous infusion A humanized IgG1 monoclonal antibody against a pyroglutamate form of Aβ to inhibit its aggregation NCT05026866 (Phase 3) NCT04437511 (Phase 3) NCT05108922 (Phase 3) NCT04640077 (Phase 3) NCT05508789 (Phase 3) Slowed cognitive and functional decline as well as reduced plaque loads and tau accumulation in patients with early symptomatic AD but might cause ARIA-E and reduce brain volume. Two Phase 3 trials, including those for prevention and treatment ones are currently underway 49,344  MEDI1814 Subcutaneous or intravenous injection An antibody specific for the C-terminus of Aβ42 N/A Increased CSF Aβ42 levels and decreased NfL levels in the plasma. No significant changes in plasma or CSF pTau181, total Tau, or neurogranin were found ALZFORUM  PRX012 Subcutaneous injection A humanized monoclonal IgG1 antibody to an N-terminal epitope on Aβ, which stimulates microglia-mediated phagocytosis N/A A phase 1 study is ongoing to determine the safety, tolerability, immunogenicity and pharmacokinetics Press release and company presentation  Remternetug Subcutaneous or intravenous injection A monoclonal antibody recognizing truncagted Aβ modified with pyroglutamate at position 3 (N3), which is aggregated in amyloid plaques NCT04451408 (Phase 1) NCT05463731 (Phase 3) A phase 1 study is ongoing to determine the safety, tolerability, immunogenicity and pharmacokinetics. A phase 3 trial called TRAILRUNNER-ALZ1 is currently underway. The study plans to recruit 400 patients with early symptomatic AD ALZFORUM  Solanezumab Intravenous infusion A humanized monoclonal IgG1 antibody directed against the mid-domain of the Aβ peptide to reduce Aβ-induced synaptic toxicity NCT01760005 (Phase 2/3) Increased in plasma Aβ levels and decreased in CSF Aβ40 levels in a dose-dependent way, and may slightly improve cognition in participants with mild but not moderate AD. Phase 2/3 clinical trials are ongoing to assess its effect in participants genetically at risk for early onset AD 345,346  UB-311 Intramuscular route A synthetic peptide vaccine, which neutralizes Aβ toxicity and promotes plaque clearance. N/A UB-311 was safe and generated Aβ antibodies in 96% of patients with mild AD. Participants receiving four boosters showed a modest reduction in brain amyloid 327 Targeting Aβ aggregates  ACI-24 Subcutaneous injection A liposome vaccine designed to elicit an immune response against Aβ aggregates NCT05462106 (Phase 1 and 2) Safe, well tolerated, and immunogenic in people with mild AD, but may have no clinical effect as there was no change on amyloid-PET; A Phase 1/2 clinical trial is ongoing to assess its safety, tolerability, immunogenicity, and clinical efficacy in AD in Down’s syndrome (DS) patients 324  ACU193 Intravenous infusion A humanized IgG2 monoclonal antibody to selectively bind with soluble Aβ oligomers NCT04931459 (Phase 1) Unpublished 288  ALZ-101 Intramuscular injection Stimulates an immune response specific to soluble Aβ oligomers NCT05328115 (Phase 1) A Phase1b study is ongoing 325  Crenezumab Subcutaneous injection or intravenous infusion Has high affinity with the oligomeric and fibrillar Aβ species, which stimulates the phagocytosis of amyloid plaques Discontinued Safe and well tolerated but had no effect on disease biomarkers or clinical decline in participants with prodromal to mild AD. The prevention trial was also negative on the primary outcomes 339–343  DNL919 Oral A TREM2 agonist antibody to stimulate microglia for amyloid phagocytosis NCT05450549 (Phase 1) Unpublished 331  Gantenerumab Subcutaneous injection Human IgG1 antibody designed to bind with a conformational epitope on Aβ fibrils, which recruits microglia to activate phagocytosis Discontinued Reduced plaque load and normalized CSF levels of disease biomarkers in AD participants but did not improve cognition (symptomatic) or prevent cognitive decline (asymptomatic). Phase 2/3 clinical trials showed that gantenerumab reduced only half as much as plaque as expected. The results showed the trends of clinical improvement, but fell short of statistical significance 336–338  IBC-Ab002 Intravenous infusion Recruits regulatory T cells and monocytes to stimulate amyloid clearance and alleviate inflammation NCT05551741 (Phase 1) A Phase 1, first-in-human study has begun to evaluate the safety, tolerability, pharmacokinetics, and immunogenicity of intravenous IBC-Ab002 in AD patients 285  Lecanemab (Approved by the FDA) Subcutaneous or intravenous injection A humanized IgG1 version of the mouse mAb158, which specifically binds to large, soluble Aβ protofibrils NCT03887455 (Phase 3) NCT04468659 (Phase 3) NCT01767311 (Phase 2) NCT05269394 (Phase 2/3) Reduced brain amyloid and improved cognitive decline in the highest-dose group (twice-monthly 10 mg/kg). The results of the Phase 3 study showed that patients with lecanemab treatment had lower brain amyloid levels and reduced cognitive and functional decline as measured by the Clinical Dementia Rating-Sum of Boxes (CDR-SB), by 27% compared with placebo. Routine MRI scans showed around 21% of individuals on lecanemab experienced side effects such as ARIA, compared with just over 9% in placebo-treated controls 50,350–353  Trontinemab Intravenous infusion A new version of gantenerumab with Roche’s “brain shuttle” technology to have a better ability of crossing the BBB NCT04639050 (Phase 1/2) No safety events were observed in the phase 1 study. Another phase 1 study was begun in March 2021, which includes 120 people with prodromal or mild to moderate AD and a positive amyloid PET scan https://www.alzforum.org/news/conference-coverage/shuttle-unloads-more-gantenerumab-brain Aβ amyloid β, AD Alzheimer’s disease, ARIA amyloid-related imaging abnormality, BBB blood-brain barrier, CSF cerebrospinal fluid, DS down syndrome, FDA Food and Drug Administration, MRI magnetic resonance imaging, NfL neurofilament light, PET positron emission tomography BACE1 inhibitors In 1999, BACE1 was identified as an enzyme required for Aβ production.300–303 Since then, inhibiting BACE1 activity has been pursued as a key method of halting the amyloid cascade and the development of effective BACE1 inhibitors has become a focus of many drug trials. LY2886721 was the first BACE inhibitor to reach Phase 2 clinical trials.304 Compared to the previous compound, it has better brain penetrance. In 2012, Eli Lilly announced that the application of LY2886721 produced the expected results in Phase 1 studies with reduced CSF levels of Aβ40 and Aβ42 as well as increased sAPPα levels (P3-359, Alzheimer’s Association International Conference, 2012). However, it was halted in the Phase 2 study due to abnormal liver biochemistry values in four participants. Its toxicity was considered to be an off-target effect of the compound, which was not related to BACE1 inhibition (The 11th International Conference on Alzheimer’s & Parkinson’s Disease, 2013). Besides LY2886721, many other candidates have also reached late stages of clinical trials, including atabecestat (Phase 2/3),305 elenbecestat (Phase 3),306 lanabecestat (Phase 2/3)307,308 and umibecestat (Phase 2/3).309 However, all of them have failed to receive final approval to reach the market. Several obstacles have been found in the development of effective BACE1 inhibitors. BACE1 possesses structural similarities with many other aspartyl proteases, such as BACE2, pepsin, renin, cathepsin D and cathepsin E, a significant challenge to achieve the selectivity in BACE1 inhibition without affecting other proteases that cause off-target side effects.310 In addition, the size of the BACE1 active site is relatively large, including catalytic aspartic acid residues, flap, and 10 S loop.311 Since all the developed BACE1 inhibitors are small molecules, it may be difficult to occupy this large active site to efficiently block BACE1 activity. Low penetrance of blood-brain barrier (BBB) is also another concern.312 γ-secretase inhibitors/modulators γ-secretase inhibitors (GSIs) have been widely investigated as potential therapeutic approaches for AD due to their ability to inhibit Aβ production. However, the existing GSIs act too generally, which causes serious side effects through inhibiting the processing of other proteins, such as Notch, a transmembrane receptor involved in regulating cell-fate decisions.15,313 Thus, researchers have tried to develop a much more specific γ-secretase inhibitor, which only disrupts the production of Aβ but not others. Avagacestat is a recently developed arylsulfonamide γ-secretase inhibitor with high selectivity for APP over Notch, which successfully reduces CSF Aβ levels in the animal models without any Notch-related toxicity.314 Avagacestat was considered as a promising AD treatment with the ability to selectively inhibit the APP processing without affecting the Notch pathway. However, it was terminated in Phase 2 trials due to gastrointestinal and dermatological side effects.315 These failures popularized the development of γ-secretase modulators (GSMs) as an alternative approach. GSMs aim to regulate but not totally block the enzyme’s activity. A recent study found that treatment with one potential candidate, SGSM-36, which successfully reduced the level of toxic Aβ42 peptides, without changing the proteolytic processing of Notch or α- and β-secretase processing of APP.316 EVP-0962 is another GSM that was shown to reduce Aβ42 levels and increase Aβ38 levels without affecting Notch signaling in vitro. It also improved the memory deficits in AD model mice.317 Unfortunately, all of them have been discontinued in the clinical trials. Active and passive immunotherapy Immunotherapy has been considered as one of the most promising strategies aimed at the modification of AD development. This approach involves designing synthetic peptides or monoclonal antibodies (mAbs) to decrease brain Aβ load and slow the disease progression. The first AD vaccine tested in a clinical study was AN1792, a synthetic full-length Aβ42 peptide.318 Although the vaccine showed some therapeutic effects, including slowed cognitive decline, the clinical trials were terminated due to the occurrence of aseptic meningoencephalitis in 6% of the participants.319–321 A possible explanation for this side effect is the induction of T helper 2 (Th2) cell responses by the excipients applied to produce C-terminus region of Aβ peptides.321 Accordingly, the subsequent vaccines do not include this region of Aβ peptides. Vanutide cridificar (ACC-001) is a conjugate of multiple short Aβ fragments to avoid the safety concerns associated with AN1792.322 Preclinical data showed that vanutide cridificar induced the generation of N-terminal anti-Aβ antibodies and successfully improved cognitive impairment in AD animal models. However, all clinical trials using vanutide cridificar were also discontinued following a serious adverse event.323 Another example is Lu AF20513, which is a mixed peptide containing three repeats of the first 12 amino acids of Aβ peptide interspersed with tetanus toxin sequences. The peptide was designed to activate a B cell response to produce polyclonal antibodies against Aβ. While Lu AF20513 was shown to successfully remove brain amyloid deposits in the initial preclinical study, clinical trials were terminated due to a lack of efficacy.324 Currently, four vaccines are under the clinical trials, including ALZ-101 (Phase 1), ACI-24 (Phase 2), ABvac 40 (Phase 2) and UB311 (Phase 3). ALZ-101 is a vaccine specific to soluble Aβ oligomers rather than Aβ monomers or fibrils.325 It is undergoing a Phase 1B study. ACI-24 is a liposome vaccine based on the Aβ1-15 sequences. It is designed to generate antibodies specifically against the β-sheet folding of Aβ. In the preclinical studies, ACI-24 was shown to generate high titers of anti-Aβ IgG1 and IgG2b antibodies and improve novel object recognition in AD mice.324 Its Phase 2 trials have been started, in which ACI-24 becomes the first anti-Aβ vaccine to be evaluated for treating AD in Down’s syndrome patients. Another vaccine called ABvac40 targets the C-terminus of Aβ peptides and is also currently being evaluated in Phase 2 clinical studies.326 UB-311 consists of the Aβ1-14 peptides in combination with a Th-cell epitope, which was designed to specifically stimulate Th2 cells regulatory immune responses over Th1-mediated autoimmune responses. UB-311 was shown to neutralize Aβ toxicity and enhance plaque clearance in preclinical studies.327 In the Phase 2 studies, UB-311 also showed its safety and generated Aβ antibodies in 96% of the patients with mild AD (14th International Conference on Alzheimer’s and Parkinson’s Disease, 2019). In 2020, it was announced that UB-311 would begin a Phase 3 clinical testing, in which two double-blind, placebo-controlled studies will be conducted. However, the data related to this clinical trial have not been released. In May 2022, UB-311 was granted fast-track designation by the FDA for Alzheimer’s treatment. Passive immunotherapy prevents some issues of the active immunization by using monoclonal antibodies (mAbs) directly targeting different forms of Aβ peptides, including monomers, oligomers and fibrils to inhibit the formation of toxic aggregates.328–331 The Fc domain of mAbs binds to the Fc-γ receptors on the microglia, leading to the phagocytosis of the Aβ-mAb complex.332 In addition, the Aβ-mAb complex induces the complement-dependent cytotoxicity, resulting in the lysis of the target cells. In the blood, the mAbs interact with Aβ to reduce Aβ concentration, resulting in a concentration gradient that stimulates the efflux of Aβ from the brain.333 Bapineuzumab is the first antibody to be tested in clinical trials. It is a humanized version of the mouse anti-Aβ monoclonal 3D6 antibody specifically targeting the N-terminal region of Aβ (residues 1–5). Humanized antibodies are generated by modifying protein sequences from non-human species to increase their similarity to natural antibody variants produced in humans, which reduce the immunogenicity of the antibodies, enhance human effector functions, and increase the serum half-life of the antibodies in humans.330 In the preclinical studies, 3D6 binds to monomeric, oligomeric and fibril forms of Aβ, leading to the reduced levels of Aβ and improved cognitive deficits in AD model mice.334 However, the Phase 3 clinical trials revealed that bapineuzumab could not improve clinical outcomes in mild to moderate AD patients.335 There are also other candidates under the Phase 3 trials, including gantenerumab, crenezumab, donanemab, solaneuzumab and lecanemab (BAN2401). Gantenerumab is a human mAb designed to bind with a conformational epitope on Aβ aggregates. It reduces the plaques by stimulating the microglia-mediated phagocytosis. The antibody was found to be safe and well tolerated during the Phase 1 clinical trials, except that transient amyloid-related imaging abnormalities (ARIA) appeared in some patients given a high dosage.336 The initial results of phase 2 studies suggested gantenerumab may have no efficacy in the enrolled cohort. However, subsequent post-hoc analyses showed a slight benefit in patients with fast disease progression. It was also tested in a Phase 2/3 study called the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) aimed at preventing dementia in 210 people who were in the progression to Alzheimer’s disease due to an inherited autosomal-dominant mutation in APP, PSEN1, or PSEN2.337 Gantenerumab treatment significantly reduced the amyloid loads and normalized CSF Aβ42 levels.338 However, cognitive data revealed that gantenerumab did not reach its therapeutic point. In addition, two Phase 3 trials were conducted in prodromal or mild AD patients with amyloid deposition. Just several months ago (Nov 14, 2022), Roche and Genentech announced that the outcome of the Phase 3 trials were disappointing, in which the drugs failed to slow cognitive impairment. A new version of ganterumab, called trontinemab is currently under Phase 1 trial, which contains a Fab fragment for better penetration to the BBB. Compared with unmodified ganterumab, 50 folds more trontinemab entered the brain and bound to Aβ plaques. Similar to gantenerumab, crenezumab also recognizes multiple forms of Aβ aggregates. It has high affinity with the oligomeric and fibril species and amyloid plaques.339,340 Crenezumab is being tested in both prevention and treatment paradigms.341–343 Unfortunately, most of the initial trials including the prevention trial failed to achieve their primary endpoints, and crenezumab is now discontinued. Donanemab is a humanized IgG1 monoclonal antibody targeting the existing amyloid plaques and clearing them from the brain.344 Early results from the Phase 1 and 2 clinical studies offered some compelling evidence that donanemab could slow down the amyloid and tau burden. As a result, donanemab has been granted the Breakthrough Therapy designation by the FDA and two Phase 3 trials, including those for prevention and treatment ones, are currently underway. In early of this month (May 3, 2023), Eli Lilly announced partial results of the Phase 3 study showing that donanemab significantly slowed cognitive and functional decline by 35% in patients with early symptomatic AD. In addition, 47% of the participants with donanemab for 1 year showed no clinical progression compared with 29% participants on placebo. The drug achieved its best effect in patients with moderate levels of tau proteins. However, its side effects of bleeding and seizures caused by ARIA also raise big concerns. Solaneuzumab is the humanized version of the murine m266 IgG1 mAbs that target the central region of Aβ. It has more affinity to Aβ monomers than the toxic aggregates. Although solanezumab was well tolerated in the participants, it was not able to show the significant therapeutic benefits to AD patients.345,346 The failure may be due to the too low concentrations of the antibody reaching to the brain. Aducanumab is the first FDA-approved therapy for Alzheimer’s.47,48 It is a human IgG1 mAb against a conformational epitope found on the N-terminus of Aβ (residues 3–6), and thus specifically targeting aggregates rather than monomers. It has been shown to reduce plaques in imaging studies.347 However, in 2019, Biogen and Eisai announced they would not start an anticipated Phase 3 secondary prevention program and would terminate all ongoing trials as aducanumab treatment was predicted to miss its primary endpoint based on the interim analysis (Mar 2019 news, www.eisai.com). Later, Biogen announced that the interim futility analysis was wrong and the highest dose of aducanumab treatment significantly improved cognitive deficit in the participants (Oct 2019 news, investors.biogen.com). In June 2021, aducanumab was approved by the FDA for medical use.47,48 However, it is considered controversial due to the lack of sufficient evidence to support its efficacy.348,349 As required by the FDA, a Phase 4 confirmatory trial called ENVISION was planned in May 2022. The study will recruit 1500 patients with early AD including at least 18% of participants from black and Hispanic communities in the US (Jan 2022 news, investors.biogen.com). Lecanemab (BAN2401) is the humanized IgG1 version of the mouse mAb158, which specifically binds to large, soluble Aβ protofibrils. The antibody has been proved to be safe without serious adverse events in the Phase 1 trials.350 In the Phase 2 trial, it had been identified to successfully reduce brain amyloid and improved cognitive decline in the highest-dose group (twice-monthly 10 mg/kg).351 A Phase 3 study called Clarity AD was initiated in March 2019 to determine the therapeutic efficacy of lecanemab on 1795 people with mild cognitive impairment (MCI) or early Alzheimer’s disease. The results were just published and showed that patients with lecanemab treatment had lower brain amyloid levels and reduced cognitive and functional decline as measured by the Clinical Dementia Rating-Sum of Boxes (CDR-SB), which quantifies symptom severity across a range of cognitive and function domains, by 27% compared with placebo.50 The positive results made lecanemab become another FDA-approved treatment of Alzheimer patients with mild cognitive impairment. However, routine MRI scans showed around 21% of individuals on lecanemab experienced side effects such as ARIA, compared with just over 9% in placebo-treated controls.352 ARIA may further cause brain atrophy showing as the increased size of the ventricle. In Feb 2020, it was announced that a large lecanemab study called AHEAD3-45 would run from July 2020 to October 2027 to measure the preventive effect of lecanemab treatment on amyloid and tau tangle formation.353 The stumbling block of anti-Aβ therapy Disturbed physiological functions of soluble Aβ Aβ peptides exist in both the brain and blood throughout an individual’s life.354 Although the aggregates have been considered to be toxic, soluble Aβ at physiological levels have been identified to have biological functions, including enhancement of long-term potentiation (LTP),355–358 stimulation of neuronal differentiation,359 improvement of the brain’s ability to recover from injuries,360–363 inhibition of oxidative stress,364 antimicrobial activity365 and tumor suppression366,367 (Fig. 4). These physiological functions must be taken into consideration when strategies are developed to lower Aβ levels in AD. Ideally, such strategies should have more precise targeting of conformations, which are fibrils protofibrils or oligomers, and maintain normal physiological level of Aβ monomers.Fig. 4 The physiological functions of soluble Aβ. Soluble Aβ at physiological levels has been identified to have some important functions, including induction of long-term potentiation (LTP), stimulation of neuronal differentiation, improvement of brain recover from injuries, inhibition of oxidative stress, antimicrobial activity and tumor suppression Modulation of synaptic function Although Aβ aggregates, especially the soluble oligomeric species impair synaptic plasticity by inhibition of LTP and induction of LTD, growing evidence indicates that a normal level of Aβ peptides may play a key role in the maintenance of synaptic function and cognition.368,369 It has been shown that the KLVFF (16~20 amino acid sequence) of Aβ peptides has a protective effect against excitotoxicity, which prevents neuronal death.370 In addition, both synthetic and endogenous Aβ42 monomers in nanomolar concentrations stimulated the activity of cyclic adenosine monophosphate (cAMP) responsive element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF), which possessed key roles in the regulation of gene expressions related to neuronal functions and survival in normal brains.371,372 In contrast, removal of endogenous Aβ by injection of anti-Aβ antibodies or genetic manipulation greatly decreased LTP and impaired memory, which could be rescued by the addition of human Aβ42.357,373–376 Together, the possible role of Aβ peptide in the modulation of synaptic function as well as learning and memory has been suggested. Aβ monomers stimulated astrocytes to increase the clearance of synaptic glutamate and therefore protect neurons from glutamate excitotoxicity.377,378 Aβ can also be released into the synaptic cleft, where it acts on presynaptic neurons to induce the release of neurotransmitters (e.g. acetylcholine) or directly activates α7-nicotinic acetylcholine receptors (α7-nAChRs) to enhance long-term potentiation (LTP).355–358 In the CNS, the nicotinic acetylcholine receptors (nAChRs) are expressed in both neurons and non-neuronal cells.379,380 As ligand-gated ion channels, nAChRs opened in response to the depolarization of the membrane, allowing Na+, K+ and Ca2+ to enter the cells.381,382 Among the isofroms, the α7-nAChRs had the highest Ca2+ permeability.381 The mechanism behind Aβ-induced α7-nAChR activation could be due to the disruption of intracellular signal transduction to stimulate the calcium influx.383 α7-nAChRs are involved in a variety of biological functions, including neurotransmitter release, synaptic plasticity and neurogenesis.384,385 In AD brain, nAChRs have been detected in Aβ42-positive neurons and their reduction is associated with disease progression.386 Furthermore, there was an increase of Aβ/nAChR-like complexes in carriers of APOE ε4, a strong risk factor for LOAD.387 In fact, Aβ might interact with specific subtypes of nAChRs with different structures to mediate its physiological effects or toxicity to cholinergic neurons. Under physiological conditions, low level of Aβ particularly interacted with the α7 isoform via the nitric oxide/cGMP/protein kinase G pathway to activate the channels.388,389 Thus, α7-nAChR KO mice at 12-month-old showed Aβ elevation as a compensatory response of α7-nAChRs and exhibited AD-like pathologies.390 Inhibition of APP changed the expressions of post-synaptic proteins such as GluA1subunit of AMPA receptors, suggesting the involvement of APP in synaptic formation.391 An obvious reduction of LTP was found in cultured hippocampal neurons with knockdown of APP expression.392 Similarly, conditional KO of PSEN1 and PSEN2 to inhibit Aβ production also led to impaired synaptic plasticity and cognitive deficits in animal models.393 In contrast, application of nanomolar synthetic Aβ successfully enhanced the cognitive and memory performance of the mice.357 However, the nanomolar concentrations of Aβ used in the study deviate too far from the physiological level of Aβ in picomolar concentrations. To address this concern, other studies injected picomolar concentrations of Aβ peptides into the mice, which also significantly enhanced synaptic plasticity and memory formation.394 These findings suggest that physiological levels of Aβ monomers are crucial to maintain a normal synaptic function while only Aβ aggregates have the inhibitory and toxic effects. Promotion of injury recovery Evidence from patients and animal models also shows rapidly increased Aβ expressions after being injured are beneficial,360–363 indicating the role of Aβ in stimulating the brain to recover from traumatic and ischemic injuries. There is an elevation of Aβ peptides during traumatic brain injury (TBI), indicating that Aβ may belong to the pathological cascade of TBI or be an agent for improving recovery.395,396 To answer this question, Aβ40 peptides were intracerebroventricularly injected into TBI-impacted BACE1–/– mice, which significantly improved motor memory deficits in these injured mice, suggesting the protective effect of Aβ.362 In contrast, reduction of endogenous Aβ levels by using γ-secretase inhibitor DAPT or deleting the enzyme BACE1 attenuated the functional recovery in mice with spinal cord injury (SCI).396 Aside from TBI, Aβ may also have a protective role against other types of brain injury such as cerebral ischemia, which blocks the blood flow in brain. It has been demonstrated that overexpression of human APP (hAPP695) leads to an obvious lower infarct volume in the cortex of mice suffering from cerebral ischemia.363 Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated autoimmune disease with inflammation in brain. Aβ treatment was found to effectively inhibit the production of proinflammatory T helper cells (TH1 and TH17) and the related cytokines including IL-6, IFN-γ and IL-17, which improved motor paralysis in EAE animal models. In constrast, genetic deletion of APP significantly aggravated the severity of the disease, suggesting the protective role of Aβ against autoimmune inflammation in CNS.397 Anti-microbial activity Recently, Aβ’s role as an anti-microbial peptide has been demonstrated. Animal models with the expression of human Aβ showed stronger resistance to bacterial and viral infections.365 Moreover, brain tissues from AD patients show higher anti-microbial activity than samples from age-matched non-AD individuals, which was correlated with Aβ levels in brain.398 It is hypothesized that the anti-microbial activity of Aβ is associated with its capacity to bind with microorganisms and form a net to trap the infectious agents.399 This idea fits with the findings that HSV1 and Borrelia DNA have been found in plaque cores of AD brains.400,401 Aβ peptides are able to interact and entrap various bacterial strains and viruses, such as HSV1 and HSV6, block their entry into the host cells to replicate.402–404 Interestly, Aβ42 cannot prevent the replication of non-enveloped human adenovirus, suggesting that it probably interacts with viral coat proteins.404 Aβ stimulated the aggregation of viral particles, which facilitated leukocyte-mediated uptake of viruses.405 In addition, the damaged host cells released nucleic acids containing Aβ aggregates, which were immunogenic and elicited the secretion of type I interferons (IFNs) by adjacent microglia to accomplish the antiviral response.406 The produced interferon-γ (IFN-γ) further facilitated Aβ generation to form a positive feedback loop.407 Similar to anti-viral activity, Aβ peptides also bound to fungal cells and stimulated the phagocytosis of microglia.408 Thus, familial AD mutations accelerated the clearance of C. albicans from brains in mice.408 Together, the underlying mechanisms of Aβ peptides exerting their anti-microbial activity including interation with membranes and disruption of membrane integrity; stimulation of phagocytosis by inducing cytokines or altering microorganisms’ conformation. Suppression of tumor growth In addition, recent studies show that AD patients have significantly lower incidences of several types of cancers, including skin cancer, lung cancer, breast cancer and bladder cancer.366,367 Aβ has been demonstrated to inhibit tumor cell growth. In vitro, application of media containing Aβ successfully inhibits the proliferation of cells, including human glioblastoma, human breast adenocarcinoma, and mouse melanoma cells.409 In vivo, injection of Aβ into mice transplanted with human glioblastoma and lung adenocarcinoma suppresses the tumor growth.410 In transgenic mice with the expression of human Aβ, the growth rates of implanted glioma tumor masses are inhibited by 40–50% compared to tumor masses in age-matched wild-type mice.411 A hypothesis has been proposed that Aβ may promote apoptosis, which contributes to its anti-tumor effects. Aβ42 peptides enhanced the transcription of p53, which is responsible for controlling cell apoptosis.412,413 In addition, Aβ42 induced oxidative stress and decreased the expression of X-linked inhibitor of apoptosis (XIAP), which directly inhibited key proteases of the apoptosis pathway including caspase 3, 7 and 9.414,415 Bcl-2, another key anti-apoptotic protein, was also shown to be blocked by Aβ42 peptides.416 In contrast, Aβ42 stimulated the expression of Bax, which induced cell apoptosis and was commonly observed in many cancers.416,417 Inhibition of oxidative stress A large amount of studies have shown the anti-oxidant properties of Aβ peptides.418–420 Both Aβ40 and Aβ42 in physiological concentrations prevented lipoprotein oxidation in CSF and plasma.364,421 In addition, the increased generation of Aβ by cells from Alzheimer’s patients with mutant PSEN1 was accompanied by a reduction of ROS levels.422 Conversely, application of Aβ to primary hippocampal neurons from PSEN1 mutant knock-in mice significantly increased superoxide production.423 Physiological amounts (picomolar concentrations) of Aβ peptides could function as anti-oxidants by inhibiting redox metals, such as Cu, Fe and Zn to bind with ligands in redox cycling.364 The absence of Aβ in neurons may inhibit adequate chelation of metal ions and appropriate removal of O2-, resulting in an increased rather than a reduced oxidative stress.424 Thus, the physiological anti-oxidant activity of Aβ peptides should be taken into account when designing therapeutic drugs to lower Aβ levels. Stimulation of neurogenesis Adult neurogenesis in humans was first reported in 1998, in which bromodeoxyuridine (BrdU)-positive cells were found in the post-mortem brain tissue of cancer patients.425 Adult brains contain resident neural stem/progenitor cells (NSPCs), which have multipotency and show great potential for self-renewal.426,427 Adult neurogenesis in AD brains was also widely investigated. Compared with brain tissues from non-demented individuals, AD brains had increased expressions of DCX, PSA-NCAM, TOAD-64/Ulip/CRMP (TUC-4) and NeuroD, indicating the enhanced neurogenesis.428 However, some contradictory results have also been reported. It has been demonstrated that the expression of microtubule-associated protein (MAP) isoforms MAP2a, a marker of the mature neuron, was dramatically decreased in the dentate gyrus of human AD brains, indicating a reduction of neuronal maturation in the hippocampus.429 Another study also found a reduced number of DCX- and Sox2-positive cells in the AD hippocampus as compared with non-demented controls.430 Furthermore, a study including 45 Alzheimer’s patients between 52 and 97 years of age identified that the number of DCX-positive cells declined with the neuropathological progression.431 Growing evidence has shown the effects of Aβ on neurogenic process using NSPCs.359,432 Both Aβ40 and Aβ42 peptides have been identified to induce the proliferation and differentiation of neural progenitor cells (NPCs).359,432 Aβ40 mainly drived differentiation of NPCs into neurons, differing from Aβ42, which increased glia markers in NPCs.359 It has been identified that Aβ peptides stimulate neurogenesis in the subventricular zone (SVZ) through interacting with the p75 neurotrophin receptors in adult mice.433 Maintenance of BBB integrity The blood-brain barrier (BBB) contributes to a stable brain microenvironment and normal neuronal function. Although neurotoxic Aβ aggregates play a key pathological role in the damage of the BBB, a low level of Aβ peptides may act as a seal to maintain the integrity of the BBB.434 This hypothesis is supported by the role of Aβ as a metal chelating antioxidant to maintain structural integrity under stress conditions.435 The ability of binding with copper ion or extracellular matrix molecules allows Aβ with its small size to be an excellent candidate molecule, which could form a “scab” in the brain. Thus, a rapid generation and deposition of Aβ in stroke and after head trauma, which could benefit to maintain the BBB integrity and inhibit the leakage of serum components into the brain, leading to neuroinflammation.436 Insufficient specificity γ-secretase has dozens of substrates. Previous clinical trials of γ-secretase inhibitors have failed, in large part due to the toxicity induced by lack of substrate-specific inhibition. Particularly notable is toxicity resulting from inhibition of Notch-1 cleavage, which disrupts essential signaling from this receptor.15,313 Thus, we should discover compounds that act as substrate-selective γ-secretase inhibitors, which block the cleavage of C99, the immediate precursor of Aβ, while allowing Notch cleavage to proceed unimpeded. Recently, a study showed that verteporfin only bound with the APP transmembrane domain rather than the transmembrane domain of the Notch-1 receptor, indicating its inhibitory effect is in a C99-specific manner.437 Our study also showed that PSEN1S169del (a deletion mutation in PSEN1 gene exon 6) has distinct effects on APP processing and Notch1 cleavage.39 This AD pathogenic mutation altered APP processing and Aβ generation without affecting Notch-1 cleavage and Notch signaling in vitro and in vivo. The results indicate that serine169 in PS1 could be a critical site as a potential target for the development of novel γ-secretase modulators without affecting Notch-1 cleavage to treat AD. A lack of selectivity is also a significant barrier to the therapeutic application of BACE1 inhibitors in AD. For instance, BACE2 is a close homolog of BACE1 but plays a neuroprotective role by inhibiting the amyloidogenic pathway of APP processing7,8,10 and reducing potassium channel Kv2.1-induced neuronal apoptosis.438 Thus, a non-selective BACE1 inhibitor also inhibits BACE2’s protective functions, leading to off target side effects. Although the aspartyl protease family (e.g. BACE2, pepsin, renin, cathepsin D and cathepsin E) has conserved catalytic aspartic acid residues, the subsites in the active sites may be unique.439 Targeting these subsites to develop BACE1 inhibitors may increase their specificity. Aβ-targeting antibodies also show off-target effects. A recent study identified that antibodies with Fc fragment reduced Aβ burden but also induced the engulgment of neuronal synapses by activating complement receptor 3 (CR3) or Fcγ receptor IIB (FcγRIIB), which exacerbates cognitive impairment in AD mice.440 Lack of accurate animal models AD can be classified into a genetic and sporadic form of the disease.441 More than 99% of AD cases occur at an age >60 years in a sporadic manner, potentiated by various risk factors related to lifestyle.442 Less than 1% of all AD cases are early-onset with symptoms developed at an age of 50 s and earlier, and caused by gene mutations in APP, PSEN1 or PSEN2.7,38,39 In order to study Alzheimer’s pathogenesis and therapeutic strategies, better animal models to recapitulate the natural process of the disease are required.443,444 Many transgenic mouse models have been developed and commonly used, including the mice containing mutations in the APP (e.g. Tg2576,445 APP SweDI,446 APP23,447 J20448 and TgCRND8449 mice), PSEN1 (e.g. PS1A246E,450 PS1M146L451), PSEN2 (PS2N141I452,453 mice) or combinations (e.g. APP23xPS1-R278I,454 APP/PS1,455 APPSwe/PSEN1dE9,456,457 APP23/PS45 (APPSwe/PS1G384A),119,458,459 5xFAD (APP SwFILon, PSEN1 M146L, L286V)460 and ARTE10461 mice). Although the human tau gene MAPT mutations per se only cause frontotemporal dementia (FTD) rather than AD,462 tau mediates Aβ toxicity to promote the pathological process of AD.92,137 The interaction between Aβ and tau is under investigation by the generation of transgenic mouse models expressing human tau and APP, including APP/PS1/rTg21221,463 3xTg-AD (APP Swedish, MAPT P301L and PSEN1 M146V)464 and PLB1-triple465 mice. To avoid the “random integration” problem occurring in the transgenic mice, knock-in mice are generated in place to precisely target a specific locus. AD knock-in/out mice have been employed, including APP knock-in/out,466,467 APPNL-F knock-in,468 APPNL-G-F knock-in468 and APPNL-G-F/MAPT double knock-in469,470 mice. However, such mouse models only mimic the familial AD with an early onset of the disease. The late-onset sporadic AD is induced by a combination of genetic (e.g. Apolipoprotein E4 and TREM-2),101,102 lifestyle and environmental factors.471–473 Unfortunately, the current animal models are unable to exactly reflect this complexity, such as aging, which is the major risk factor of sporadic AD. The immune system has long been implicated as an important factor in Alzheimer’s development.474 However, murine immune system is notably different from humans.475 Furthermore, the extensive neuronal loss in AD patients has not been replicated in the murine models.476 Thus, a lack of accurate disease models leads to a translational gap between animal research and the clinical setting. Design and exploration of patient-based research models will be required, which will be further discussed in Section “Perspective and Future Direction”. Late application PET imaging allows us to visualize Aβ fibrils in patients, which accumulate in an Alzheimer’s brain as early as 15 years before the onset of symptoms.477 A change in CSF Aβ levels can be detected even up to 25 years before a patient begins to show symptoms.478 Thus, the current application of Aβ therapies may be too late for symptomatic patients, whose therapeutic window has already closed. Compared with curing the disease, prevention by reducing the risk of Alzheimer’s development is believed to be more practical. Prevention trials stand a chance to prevent or slow the progression of cognitive decline and dementia in AD. In 2012, DIAN-TU launched the first prevention trial focusing on two drugs: gantenerumab (against Aβ aggregates) and solanezumab (against soluble Aβ monomers).337 The data showed that gantenerumab had a positive impact on the reduction of cortical amyloid, leading to its further study by an exploratory open-label extension (OLE).338 Crenezumab is the first immunotherapy to be evaluated in the Alzheimer’s Prevention Initiative.343 The participants in this trial were carriers of the autosomal-dominant gene mutation (e.g. PSEN1 E280A) but did not meet the criteria for mild cognitive impairment at the time of enrollment.341 Although crenezumab did not significantly improve cognitive impairment in the participants, it showed some favorable effects (Alzheimer’s Association International Conference, 2022). Discovery of new biomarkers to discriminate the very early stage of sporadic AD is essential for the success of AD prevention. Perspective and future direction Although the failed trials have fueled debate on the amyloid hypothesis and raised concerns as to if efforts have been properly directed, it has provided valuable lessons to learn from and information that may improve our understanding of Alzheimer’s pathogenesis and drug development. The following are some principle and practical approaches we believe could be beneficial for future Aβ-targeted drug development and therapy. Combination therapy and mechanism-based therapy Some current therapeutic approaches, such as BACE inhibitors and γ-secretase inhibitors/modulators, aim to target Aβ production, which is the early stage of the amyloid cascade.304–306 Although these inhibitors have been identified to slow down the plaque formation in patients, they were unable to clear the existing Aβ plaques and ameliorate toxic events already initiated by these Aβ aggregates. Accordingly, combination therapy should be considered for the clinical phase of the disease, which is already the standard of care for many diseases, including rheumatoid arthritis and HIV/AIDS.479,480 Growing evidence indicates that Aβ accumulation stimulates tau phosphorylation and fibrillary tangle formation, leading to the process of neurodegeneration.112–114 Thus, additional application of tau-phosphorylating kinase inhibitors or compounds that inhibit tau aggregation and/or promote aggregate disassembly should be beneficial. APP and Aβ can be imported into mitochondria, where they can interact with mitochondrial components, impair ATP production, and increase oxidative damage.481,482 Antioxidants such as lipoic acid,483 vitamin E,484,485 vitamin C486 and β-carotene487 may also be the promising combination approaches for AD. In addition, Aβ’s role in the modulation of synapse function has attracted great attention. The neurotoxic soluble Aβ oligomers have been identified to affect synaptic plasticity and synaptic transmission in various AD animal models.488 Targeting synapse loss and dysfunction may be an effective AD treatment strategy.489 Once the pathological cascade has begun, combination therapy targeting multiple AD pathologies will be more effective than a single therapy, which only addresses one abnormal factor. Growing evidence shows that elevation of brain Aβ levels in AD could be the consequence of upstream problems including neurovascular dysfunction, disturbed glucose homeostasis, failed control of cell cycle and inflammation.490–492 Autophagy, a part of the lysosomal system, is crucial for clearance of toxic accumulated proteins and damage organelles. The autophagic process consists of several steps including sequestration, elongation, maturation, fusion and degradation, aiming to deliver unwanted proteins, organelles and cellular debris to the lysosome for degration. It starts with the formation of phagophore, which then elongates and encloses the cargo to form an autophagosome. The autophagosome either directly fuses with the lysosome form an autolysosome or firstly fuses with late endosomes to form amphisomes, which subsequently fuse with lysosomes. Impairment of the autophagy-lysosomal system has been considered as one of the fundamental causes for many neurodegenerative diseases that feature the deposition of toxic amyloid proteins. Growing evidence shows that dysfunction of autophagy is closely linked with Aβ metabolism and accmulation in AD progression. Autophagy is implicated in Aβ metabolism likely via modulation of its production, secretion and clearance. Aβ originates from the cleavage of its precursor protein APP by β-secretase (BACE1) and γ-secretase. It has been identified that ATG5-dependent autophagy regulates APP degradation.493 In addition, the complex of APP and γ-secretases was found in autophagosomes, suggesting the role of authophgic pathway in the generation of Aβ peptides.494 Autophagy is also required for Aβ secretion. ATG7 is an essential molecule for the autophagosome formation. AD model mice with ATG7 KO showed deficient autophagy associated with drastically reduced extracellular Aβ plaques and markedly accumulated intraneuronal Aβ, suggesting that Aβ secretion was compromised due to the impaired autophagy.495,496 In addition, autophagy regulates the clearance of Aβ peptides. The cysteine protease cathepsin B (CatB) is a key lysosomal protease required for degrading autophagic substrates. It has been demonstrated that genetic deletion of CatB significantly increased Aβ42 burden and worsened amyloid deposition in AD mice, whereas overexpression of CatB reduced amyloid plaques.497 Accumulation of immature autophagosome in dystrophic neurites has been observed in the brain of Alzheimer’s patients due to the defective axonal transportation of autophagosomes.498 Thus, autophagy modulation becomes a promising stategy for Alzheimer’s treatment.499,500 Rapamycin is a commonly used autophagy activator, which inhibits the mTOR pathway by binding with immunophilin FK506-binding protein (FKBP12).501 Recent studies identified that 3xTg-AD mice had enhanced mTOR activity in the hippocampus and neocortex, two areas known to have high concentrations of Aβ plaques.502 Treatment with rapamycin significantly stimulated autophagy associated with markedly reduced both intracellular Aβ and extracellular amyloid deposition in brains as well as improved cognitive deficits in AD mice.503,504 Mechanism-based therapies to target these pathological processes will have optimal benefit when initiated in the asymptomatic stage. Traditional Chinese medicine (TCM) has been established in the Chinese health care system for thousands of years. Most TCM treatment are derived from natural products with multi-target, multi-pathway capacity and mild adverse events. It has preventive and therapeutic effects on many chronic diseases such as cancer, allergy, diabetes and infections by the regulation of cell growth and differentiation, reduction of inflammation, or increase of carbohydrate utilization.505–508 TCM treatment such as morroniside, rutin, resveratrol, triptolide and berberine have already shown their beneficial effects for AD509–527 (Table 3).Table 3 Multi-target traditional Chinese medicine for Alzheimer’s modification Agent Mechanism of action Reference Berberine Activates the PI3K/Akt/GSK3 pathway to reduce Aβ generation; Inhibits the ER stress by blocking the PERK/eIF2α signaling pathway 509,510 Gardenia jasminoides J.Ellis Protects the neurovascular unit (NVU) and inhibits the neuroinflammation; Decreases Aβ levels by inhibiting Aβ production and accelerating Aβ degradation 511,512 Icariin Modulates the differentiation of Th1, Th17 and Tregs cells; Inhibits the ER stress by blocking the PERK/eIF2α signaling pathway 513,514 Lonicera japonica Thunb Inhibits Aβ aggregation and the subsequent cytotoxicity; Promotes neuritogenesis 515,516 Morroniside Reduces the oxidative stress and tau phosphorylation 517 Platycodon grandiflorum Inhibits the oxidative stress by upregulating the antioxidant enzymes; Increases the expressions of Bcl-2 family proteins to inhibit apoptosis 518,519 Resveratrol Reduces Aβ generation by inhibiting the activity of β- and γ-secretases; Stimulates Aβ clearance by activating ADEs and increasing the permeability of the BBB; Increases the levels of estradiol and neprilysin 520,521 Rutin Recruits microglia to promote Aβ clearance; Inhibits the activity of β-secretase and Aβ-induced neuronal depolarization; Reduces the neuroinflammation by downregulating the proinflammatory cytokines 522–524 Tanshinone Reduces the ER stress by blocking the PERK/eIF2α, IRE1α/XBP1 and ATF6 pathways; Inhibits the CHOP or JNK pathways to reduce apoptosis; Inhibits the neuroinflammation by the downregulation of the RAGE/NF-κB signaling pathways 525,526 Aβ amyloid β, BBB blood-brain barrier, ER endoplasmic reticulum Patient-based research models Three-dimensional brain organoids derived from human pluripotent stem cells (hPSCs) have shown significant advantages in modeling neurological disorders including autism, microcephaly and Parkinson’s disease.528–530 Three methods have been established to recapitulate Alzheimer’s phenotype in brain organoids: application of Aftin-5 (an Aβ42 agonist) to induce Aβ42 production in brain organoids;531 generation of brain organoids from induced pluripotent stem cells (iPSCs) of familial AD patients;532,533 and creation of differentiated sporadic Alzheimer’s brain organoids by converting APOE3 to APOE4 in patient-derived iPSCs.534 Unlike cell models, AD brain organoids are capable of generating the blood-brain barrier (BBB) as well as connections with other organs.535 This enables them to potentially function as a superior approach in the understanding Alzheimer’s pathogenesis, as well as a better tool for exploration of Alzheimer’s modification. In addition, transplantation of brain organoids may be a novel way to recover neuronal function and neural network after neuronal death during AD.536 However, some limitations still exist and will need to be improved upon. So far, brain organoids can only be cultured within six months, otherwise volume shrinkage and cellular apoptosis occur as neither the oxygen nor nutrients will be able to reach the innermost organoid regions. This limitation leads to the concern that brain organoids are unable to grow “old” enough to mimic the aging human brain. To address this issue, obtaining brain organoids with a vascular system becomes a critical issue.537,538 Identification of early Alzheimer’s biomarkers Biomarkers that can identify patients at very early stages of AD will greatly benefit the development of disease-modifying therapies.539 In addition to the typical pathologies (e.g. Aβ and tau), other molecules associated with inflammation, synaptic plasticity, may also serve as the accurate and specific biomarkers for early diagnosing AD.540–542 Progranulin is a growth factor expressed in neurons and microglia, which modulates neuroinflammatory to reduce microgliosis and astrogliosis.543 It has been observed that the CSF level of progranulin elevates as early as ten years before the presentation of symptoms in patients with familial or sporadic AD.544 Neurogranin is expressed in the cortex and hippocampus, the brain areas most affected by AD.545 As a synaptic marker, it is involved in the modulation of synaptic strength and plasticity.546 Several studies have revealed an elevation of CSF neurogranin in AD and MCI individuals compared to healthy controls.547,548 The CSF neurogranin levels correlated with the brain amyloid load in patients with preclinical AD. It can also successfully predict the rates of cognitive decline in both early Alzheimer’s patients and cognitively healthy controls. In contrast, there is a significant reduction of plasma neuronal-derived exosomal neurogranin in AD patients compared with the healthy controls.549 More importantly, the CSF neurogranin increases exclusively in AD patients and has not been observed in other neurodegenerative disorders, such as frontotemporal dementia or Parkinson’s disease.550 MicroRNA (miRNA) are noncoding RNA molecules of 20–25 nucleotides that can manipulate gene expression post-transcriptionally by binding to the 3ʹ-untranslated region (3ʹUTR) of mRNA to block protein translation or accelerating the degradation of target mRNAs. It has been found that miRNAs are involved in Alzheimer’s pathogenesis and are easily detected in body fluids, including CSF, plasma and serum. Therefore, they become an attractive target for developing AD biomarkers.551,552 In addition to body fluids, ocular markers also gain increasing interest. Abundant evidence from animal and clinical studies shows a correlation between ocular pathology and AD development.553–555 A recent study also suggests that depressive symptoms in middle-aged individuals correlates with time to onset of cognitive decline, suggesting the role of psychiatric disorders as early markers of Alzheimer’s disease.556 Conclusions Since Aβ aggregates act as the unique specific pathological hallmark of AD and play a causative role in the disease development, they are believed as a promising target for Alzheimer’s modification. Most Aβ-targeting drug trials have failed as a consequence by lack of sufficient specificity and accurate translational models, loss of Aβ physiological homeostasis, and failure to be administered during the best therapeutic window. Nevertheless, learning from these failures will be beneficial to the design of better therapeutic approaches. Biomarkers are needed for identifying patients with preclinical Alzheimer’s disease so that treatment such as mechanism-based therapy could prevent or slow down the disease. Translational models and tools to mimic the nature of AD more closely are also required to bridge the gap between basic research and the clinical practice. Combination therapy that targets different mechanisms and pathologies would be directed by biomarkers and customized to the individual. We hope that these solutions could pave the way for exploration and development of more refined Aβ-based therapy for AD. Acknowledgements We thank Brian J. Song’s editing and comments. This work was supported by the National Natural Science Foundation of China (82201576), Beijing Hospitals Authority Youth Programme (QML20210804) and Beijng Medical Research 2021-8 (YZ), and the National Natural Science Foundation of China (82150710557, 82230043 and 82293642) to WS. WS was the Canada Research Chair in Alzhaimer’s Disease. Author contributions Y.Z. and W.S. conceived and designed this project. Y.Z. wrote the draft of the manuscript. Y.Z., Q.C., R.L. and K.S. did the literature search and review. Y.Z., K.S. and W.S. revised the manuscript, and Y.Z. and W.S. supervised the project. All authors have read and approved the article. Competing interests The authors declare no competing interests. ==== Refs References 1. Glenner GG Wong CW Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein Biochem Biophys. Res Commun. 1984 120 885 890 10.1016/S0006-291X(84)80190-4 6375662 2. Hardy JA Higgins GA Alzheimer’s disease: the amyloid cascade hypothesis Science 1992 256 184 185 10.1126/science.1566067 1566067 3. Lemere CA Masliah E Can Alzheimer disease be prevented by amyloid-beta immunotherapy? Nat. Rev. Neurol. 2010 6 108 119 10.1038/nrneurol.2009.219 20140000 4. Liu X Clusterin transduces Alzheimer-risk signals to amyloidogenesis Signal Transduct. Target Ther. 2022 7 325 10.1038/s41392-022-01157-x 36138003 5. Sun BL Critical thinking on amyloid-beta-targeted therapy: challenges and perspectives Sci. China Life Sci. 2021 64 926 937 10.1007/s11427-020-1810-y 33106917 6. Karran E Hardy J A critique of the drug discovery and phase 3 clinical programs targeting the amyloid hypothesis for Alzheimer disease Ann. Neurol. 2014 76 185 205 10.1002/ana.24188 24853080 7. Deng Y Amyloid-beta protein (Abeta) Glu11 is the major beta-secretase site of beta-site amyloid-beta precursor protein-cleaving enzyme 1(BACE1), and shifting the cleavage site to Abeta Asp1 contributes to Alzheimer pathogenesis Eur. J. Neurosci. 2013 37 1962 1969 10.1111/ejn.12235 23773065 8. Zhang S BACE1 cleavage site selection critical for amyloidogenesis and Alzheimer’s pathogenesis J. Neurosci. 2017 37 6915 6925 10.1523/JNEUROSCI.0340-17.2017 28626014 9. Sun X Distinct transcriptional regulation and function of the human BACE2 and BACE1 genes FASEB J. 2005 19 739 749 10.1096/fj.04-3426com 15857888 10. Sun X He G Song W BACE2, as a novel APP theta-secretase, is not responsible for the pathogenesis of Alzheimer’s disease in Down syndrome FASEB J. 2006 20 1369 1376 10.1096/fj.05-5632com 16816112 11. Liu X Wang Z Wu Y Wang J Song W BACE2 degradation mediated by the macroautophagy-lysosome pathway Eur. J. Neurosci. 2013 37 1970 1977 10.1111/ejn.12204 23773066 12. Li YM Presenilin 1 is linked with gamma-secretase activity in the detergent solubilized state Proc. Natl Acad. Sci. USA 2000 97 6138 6143 10.1073/pnas.110126897 10801983 13. De Strooper B A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain Nature 1999 398 518 522 10.1038/19083 10206645 14. De Strooper B Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein Nature 1998 391 387 390 10.1038/34910 9450754 15. Song W Proteolytic release and nuclear translocation of Notch-1 are induced by presenilin-1 and impaired by pathogenic presenilin-1 mutations Proc. Natl Acad. Sci. USA 1999 96 6959 6963 10.1073/pnas.96.12.6959 10359821 16. Zhang Z Presenilins are required for gamma-secretase cleavage of beta-APP and transmembrane cleavage of Notch-1 Nat. Cell Biol. 2000 2 463 465 10.1038/35017108 10878814 17. Takasugi N The role of presenilin cofactors in the gamma-secretase complex Nature 2003 422 438 441 10.1038/nature01506 12660785 18. Zhang S Zhang M Cai F Song W Biological function of Presenilin and its role in AD pathogenesis Transl. Neurodegener. 2013 2 15 10.1186/2047-9158-2-15 23866842 19. Bateman RJ Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo Nat. Med. 2006 12 856 861 10.1038/nm1438 16799555 20. Engelhardt B Vascular, glial, and lymphatic immune gateways of the central nervous system Acta Neuropathol. 2016 132 317 338 10.1007/s00401-016-1606-5 27522506 21. Sweeney MD Sagare AP Zlokovic BV Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders Nat. Rev. Neurol. 2018 14 133 150 10.1038/nrneurol.2017.188 29377008 22. Yamada K The low density lipoprotein receptor-related protein 1 mediates uptake of amyloid beta peptides in an in vitro model of the blood-brain barrier cells J. Biol. Chem. 2008 283 34554 34562 10.1074/jbc.M801487200 18940800 23. Elali A Rivest S The role of ABCB1 and ABCA1 in beta-amyloid clearance at the neurovascular unit in Alzheimer’s disease Front Physiol. 2013 4 45 10.3389/fphys.2013.00045 23494712 24. Deane R RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain Nat. Med 2003 9 907 913 10.1038/nm890 12808450 25. Zlokovic BV The blood-brain barrier in health and chronic neurodegenerative disorders Neuron 2008 57 178 201 10.1016/j.neuron.2008.01.003 18215617 26. Mawuenyega KG Decreased clearance of CNS beta-amyloid in Alzheimer’s disease Science 2010 330 1774 10.1126/science.1197623 21148344 27. Hampel H The amyloid-beta pathway in Alzheimer’s Disease Mol. Psychiatry 2021 26 5481 5503 10.1038/s41380-021-01249-0 34456336 28. Tarasoff-Conway JM Clearance systems in the brain-implications for Alzheimer disease Nat. Rev. Neurol. 2015 11 457 470 10.1038/nrneurol.2015.119 26195256 29. Silverberg GD Mayo M Saul T Rubenstein E McGuire D Alzheimer’s disease, normal-pressure hydrocephalus, and senescent changes in CSF circulatory physiology: a hypothesis Lancet Neurol. 2003 2 506 511 10.1016/S1474-4422(03)00487-3 12878439 30. Baranello RJ Amyloid-beta protein clearance and degradation (ABCD) pathways and their role in Alzheimer’s disease Curr. Alzheimer Res 2015 12 32 46 10.2174/1567205012666141218140953 25523424 31. Eckman EA Regulation of steady-state beta-amyloid levels in the brain by neprilysin and endothelin-converting enzyme but not angiotensin-converting enzyme J. Biol. Chem. 2006 281 30471 30478 10.1074/jbc.M605827200 16912050 32. Iwata N Metabolic regulation of brain Abeta by neprilysin Science 2001 292 1550 1552 10.1126/science.1059946 11375493 33. Sims R Hill M Williams J The multiplex model of the genetics of Alzheimer’s disease Nat. Neurosci. 2020 23 311 322 10.1038/s41593-020-0599-5 32112059 34. Lambert JC Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease Nat. Genet 2013 45 1452 1458 10.1038/ng.2802 24162737 35. Glenner GG Wong CW Alzheimer’s disease and Down’s syndrome: sharing of a unique cerebrovascular amyloid fibril protein Biochem Biophys. Res Commun. 1984 122 1131 1135 10.1016/0006-291X(84)91209-9 6236805 36. Burger PC Vogel FS The development of the pathologic changes of Alzheimer’s disease and senile dementia in patients with Down’s syndrome Am. J. Pathol. 1973 73 457 476 4271339 37. Lemere CA Sequence of deposition of heterogeneous amyloid beta-peptides and APO E in Down syndrome: implications for initial events in amyloid plaque formation Neurobiol. Dis. 1996 3 16 32 10.1006/nbdi.1996.0003 9173910 38. Goate A Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease Nature 1991 349 704 706 10.1038/349704a0 1671712 39. Zhang S A presenilin-1 mutation causes Alzheimer disease without affecting Notch signaling Mol. Psychiatry 2020 25 603 613 10.1038/s41380-018-0101-x 29915376 40. Jonsson T A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline Nature 2012 488 96 99 10.1038/nature11283 22801501 41. DeMattos RB ApoE and clusterin cooperatively suppress Abeta levels and deposition: evidence that ApoE regulates extracellular Abeta metabolism in vivo Neuron 2004 41 193 202 10.1016/S0896-6273(03)00850-X 14741101 42. Ridler C Alzheimer Disease: Misfolded diabetes-mellitus peptide seeds amyloid-beta aggregation Nat. Rev. Neurol. 2017 13 128 10.1038/nrneurol.2017.5 28106068 43. Fewlass DC Obesity-related leptin regulates Alzheimer’s Abeta FASEB J. 2004 18 1870 1878 10.1096/fj.04-2572com 15576490 44. Ashok A Rai NK Tripathi S Bandyopadhyay S Exposure to As-, Cd-, and Pb-mixture induces Abeta, amyloidogenic APP processing and cognitive impairments via oxidative stress-dependent neuroinflammation in young rats Toxicol. Sci. 2015 143 64 80 10.1093/toxsci/kfu208 25288670 45. Brown BM Physical activity and amyloid-beta plasma and brain levels: results from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing Mol. Psychiatry 2013 18 875 881 10.1038/mp.2012.107 22889922 46. Sevigny J The antibody aducanumab reduces Abeta plaques in Alzheimer’s disease Nature 2016 537 50 56 10.1038/nature19323 27582220 47. Alexander GC Emerson S Kesselheim AS Evaluation of aducanumab for Alzheimer disease: scientific evidence and regulatory review involving efficacy, safety, and futility JAMA 2021 325 1717 1718 10.1001/jama.2021.3854 33783469 48. Dunn B Stein P Cavazzoni P Approval of aducanumab for Alzheimer disease-The FDA’s perspective JAMA Intern Med 2021 181 1276 1278 10.1001/jamainternmed.2021.4607 34254984 49. Mintun MA Wessels AM Sims JR Donanemab in early Alzheimer’s disease. Reply N. Engl. J. Med 2021 385 667 34379934 50. van Dyck CH Lecanemab in early Alzheimer’s disease N. Engl. J. Med 2023 388 9 21 10.1056/NEJMoa2212948 36449413 51. Lahmy V Blockade of Tau hyperphosphorylation and Abeta(1)(-)(4)(2) generation by the aminotetrahydrofuran derivative ANAVEX2-73, a mixed muscarinic and sigma(1) receptor agonist, in a nontransgenic mouse model of Alzheimer’s disease Neuropsychopharmacology 2013 38 1706 1723 10.1038/npp.2013.70 23493042 52. Hampel H A precision medicine framework using artificial intelligence for the identification and confirmation of genomic biomarkers of response to an Alzheimer’s disease therapy: Analysis of the blarcamesine (ANAVEX2-73) Phase 2a clinical study Alzheimers Dement (N. Y.) 2020 6 e12013 32318621 53. Zhang Y Song W Islet amyloid polypeptide: Another key molecule in Alzheimer’s pathogenesis? Prog. Neurobiol. 2017 153 100 120 10.1016/j.pneurobio.2017.03.001 28274676 54. Masters CL Beyreuther K Henryk M. Wisniewski and the amyloid theory of Alzheimer’s disease J. Alzheimers Dis. 2001 3 83 86 10.3233/JAD-2001-3112 12214076 55. Mott RT Hulette CM Neuropathology of Alzheimer’s disease Neuroimaging Clin. N. Am. 2005 15 755 765 10.1016/j.nic.2005.09.003 16443488 56. Walker LC Abeta plaques Free Neuropathol 2020 1 31 33345256 57. Serrano-Pozo A Frosch MP Masliah E Hyman BT Neuropathological alterations in Alzheimer disease Cold Spring Harb. Perspect. Med 2011 1 a006189 10.1101/cshperspect.a006189 22229116 58. Iwatsubo T Saido TC Mann DM Lee VM Trojanowski JQ Full-length amyloid-beta (1-42(43)) and amino-terminally modified and truncated amyloid-beta 42(43) deposit in diffuse plaques Am. J. Pathol. 1996 149 1823 1830 8952519 59. Duyckaerts C Delatour B Potier MC Classification and basic pathology of Alzheimer disease Acta Neuropathol. 2009 118 5 36 10.1007/s00401-009-0532-1 19381658 60. Liu F Focal-type, but not diffuse-type, amyloid beta plaques are correlated with alzheimer’s neuropathology, cognitive dysfunction, and neuroinflammation in the human hippocampus Neurosci. Bull. 2022 38 1125 1138 10.1007/s12264-022-00927-5 36028642 61. Lambert MP Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins Proc. Natl Acad. Sci. USA 1998 95 6448 6453 10.1073/pnas.95.11.6448 9600986 62. Bode DC Freeley M Nield J Palma M Viles JH Amyloid-beta oligomers have a profound detergent-like effect on lipid membrane bilayers, imaged by atomic force and electron microscopy J. Biol. Chem. 2019 294 7566 7572 10.1074/jbc.AC118.007195 30948512 63. Yasumoto T High molecular weight amyloid beta(1-42) oligomers induce neurotoxicity via plasma membrane damage FASEB J. 2019 33 9220 9234 10.1096/fj.201900604R 31084283 64. Hong S Soluble Abeta oligomers are rapidly sequestered from brain ISF in vivo and bind GM1 ganglioside on cellular membranes Neuron 2014 82 308 319 10.1016/j.neuron.2014.02.027 24685176 65. DelBove CE Reciprocal modulation between amyloid precursor protein and synaptic membrane cholesterol revealed by live cell imaging Neurobiol. Dis. 2019 127 449 461 10.1016/j.nbd.2019.03.009 30885793 66. Sathya M Resveratrol intervenes cholesterol- and isoprenoid-mediated amyloidogenic processing of AbetaPP in familial Alzheimer’s disease J. Alzheimers Dis. 2017 60 S3 S23 10.3233/JAD-161034 28059793 67. Xiong H Cholesterol retention in Alzheimer’s brain is responsible for high beta- and gamma-secretase activities and Abeta production Neurobiol. Dis. 2008 29 422 437 10.1016/j.nbd.2007.10.005 18086530 68. Kojro E Gimpl G Lammich S Marz W Fahrenholz F Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the alpha -secretase ADAM 10 Proc. Natl. Acad. Sci. USA 2001 98 5815 5820 10.1073/pnas.081612998 11309494 69. Kim Y Kim C Jang HY Mook-Jung I Inhibition of cholesterol biosynthesis reduces gamma-secretase activity and amyloid-beta generation J. Alzheimers Dis. 2016 51 1057 1068 10.3233/JAD-150982 26923021 70. Panchal M Enrichment of cholesterol in microdissected Alzheimer’s disease senile plaques as assessed by mass spectrometry J. Lipid Res 2010 51 598 605 10.1194/jlr.M001859 19779135 71. Terakawa MS Impact of membrane curvature on amyloid aggregation Biochim. Biophys. Acta Biomembr. 2018 1860 1741 1764 10.1016/j.bbamem.2018.04.012 29709613 72. Matsuzaki K Formation of toxic amyloid fibrils by amyloid beta-protein on ganglioside clusters Int J. Alzheimers Dis. 2011 2011 956104 21318142 73. Henry S Interaction of Abeta(1–42) peptide or their variant with model membrane of different composition probed by infrared nanospectroscopy Nanoscale 2018 10 936 940 10.1039/C7NR07489A 29292465 74. Yang DS Cyclodextrin has conflicting actions on autophagy flux in vivo in brains of normal and Alzheimer model mice Hum. Mol. Genet 2017 26 843 859 28062666 75. DeKosky ST Scheff SW Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity Ann. Neurol. 1990 27 457 464 10.1002/ana.410270502 2360787 76. Shankar GM Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory Nat. Med 2008 14 837 842 10.1038/nm1782 18568035 77. Townsend M Shankar GM Mehta T Walsh DM Selkoe DJ Effects of secreted oligomers of amyloid beta-protein on hippocampal synaptic plasticity: a potent role for trimers J. Physiol. 2006 572 477 492 10.1113/jphysiol.2005.103754 16469784 78. Luscher C Malenka RC NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD) Cold Spring Harb. Perspect. Biol. 2012 4 a005710 10.1101/cshperspect.a005710 22510460 79. Magdesian MH Amyloid-beta binds to the extracellular cysteine-rich domain of Frizzled and inhibits Wnt/beta-catenin signaling J. Biol. Chem. 2008 283 9359 9368 10.1074/jbc.M707108200 18234671 80. Li S Soluble Abeta oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors J. Neurosci. 2011 31 6627 6638 10.1523/JNEUROSCI.0203-11.2011 21543591 81. Lu W Subunit composition of synaptic AMPA receptors revealed by a single-cell genetic approach Neuron 2009 62 254 268 10.1016/j.neuron.2009.02.027 19409270 82. Terashima A Suh YH Isaac JTR The AMPA receptor subunit GluA1 is required for CA1 hippocampal long-term potentiation but is not essential for synaptic transmission Neurochem Res 2019 44 549 561 10.1007/s11064-017-2425-3 29098531 83. Diering GH Huganir RL The AMPA receptor code of synaptic plasticity Neuron 2018 100 314 329 10.1016/j.neuron.2018.10.018 30359599 84. Wenthold RJ Petralia RS Blahos J II Niedzielski AS Evidence for multiple AMPA receptor complexes in hippocampal CA1/CA2 neurons J. Neurosci. 1996 16 1982 1989 10.1523/JNEUROSCI.16-06-01982.1996 8604042 85. Hsieh H AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss Neuron 2006 52 831 843 10.1016/j.neuron.2006.10.035 17145504 86. Zhang Y Guo O Huo Y Wang G Man HY Amyloid-beta Induces AMPA Receptor Ubiquitination and Degradation in Primary Neurons and Human Brains of Alzheimer’s Disease J. Alzheimers Dis. 2018 62 1789 1801 10.3233/JAD-170879 29614651 87. Moreno H Synaptic transmission block by presynaptic injection of oligomeric amyloid beta Proc. Natl. Acad. Sci. USA 2009 106 5901 5906 10.1073/pnas.0900944106 19304802 88. Pigino G Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta Proc. Natl. Acad. Sci. USA 2009 106 5907 5912 10.1073/pnas.0901229106 19321417 89. Matsuzaki M Honkura N Ellis-Davies GC Kasai H Structural basis of long-term potentiation in single dendritic spines Nature 2004 429 761 766 10.1038/nature02617 15190253 90. Zhou Q Homma KJ Poo MM Shrinkage of dendritic spines associated with long-term depression of hippocampal synapses Neuron 2004 44 749 757 10.1016/j.neuron.2004.11.011 15572107 91. Chabrier MA Cheng D Castello NA Green KN LaFerla FM Synergistic effects of amyloid-beta and wild-type human tau on dendritic spine loss in a floxed double transgenic model of Alzheimer’s disease Neurobiol. Dis. 2014 64 107 117 10.1016/j.nbd.2014.01.007 24440055 92. Ittner LM Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer’s disease mouse models Cell 2010 142 387 397 10.1016/j.cell.2010.06.036 20655099 93. Marcatti M Abeta/tau oligomer interplay at human synapses supports shifting therapeutic targets for Alzheimer’s disease Cell Mol. Life Sci. 2022 79 222 10.1007/s00018-022-04255-9 35377002 94. Tai HC Frequent and symmetric deposition of misfolded tau oligomers within presynaptic and postsynaptic terminals in Alzheimer’s disease Acta Neuropathol. Commun. 2014 2 146 25330988 95. Kaniyappan S Chandupatla RR Mandelkow EM Mandelkow E Extracellular low-n oligomers of tau cause selective synaptotoxicity without affecting cell viability Alzheimers Dement 2017 13 1270 1291 10.1016/j.jalz.2017.04.002 28528849 96. Koch G Reversal of LTP-like cortical plasticity in Alzheimer’s disease patients with tau-related faster clinical progression J. Alzheimers Dis. 2016 50 605 616 10.3233/JAD-150813 26757193 97. Zhou L Tau association with synaptic vesicles causes presynaptic dysfunction Nat. Commun. 2017 8 15295 10.1038/ncomms15295 28492240 98. Liu C Song X Nisbet R Gotz J Co-immunoprecipitation with Tau Isoform-specific Antibodies Reveals Distinct Protein Interactions and Highlights a Putative Role for 2N Tau in Disease J. Biol. Chem. 2016 291 8173 8188 10.1074/jbc.M115.641902 26861879 99. Moreno H Tau pathology-mediated presynaptic dysfunction Neuroscience 2016 325 30 38 10.1016/j.neuroscience.2016.03.044 27012611 100. Mondragon-Rodriguez S Interaction of endogenous tau protein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation J. Biol. Chem. 2012 287 32040 32053 10.1074/jbc.M112.401240 22833681 101. Zhao X Caspase-2 cleavage of tau reversibly impairs memory Nat. Med 2016 22 1268 1276 10.1038/nm.4199 27723722 102. Shipton OA Tau protein is required for amyloid beta-induced impairment of hippocampal long-term potentiation J. Neurosci. 2011 31 1688 1692 10.1523/JNEUROSCI.2610-10.2011 21289177 103. Pallo SP DiMaio J Cook A Nilsson B Johnson GVW Mechanisms of tau and Abeta-induced excitotoxicity Brain Res. 2016 1634 119 131 10.1016/j.brainres.2015.12.048 26731336 104. Grundke-Iqbal I Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology Proc. Natl. Acad. Sci. USA 1986 83 4913 4917 10.1073/pnas.83.13.4913 3088567 105. Ihara Y Nukina N Miura R Ogawara M Phosphorylated tau protein is integrated into paired helical filaments in Alzheimer’s disease J. Biochem 1986 99 1807 1810 10.1093/oxfordjournals.jbchem.a135662 2427509 106. Goedert M Spillantini MG Cairns NJ Crowther RA Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms Neuron 1992 8 159 168 10.1016/0896-6273(92)90117-V 1530909 107. Greenberg SG Davies P Schein JD Binder LI Hydrofluoric acid-treated tau PHF proteins display the same biochemical properties as normal tau J. Biol. Chem. 1992 267 564 569 10.1016/S0021-9258(18)48531-6 1370450 108. Oddo S Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction Neuron 2003 39 409 421 10.1016/S0896-6273(03)00434-3 12895417 109. Busche MA Hyman BT Synergy between amyloid-beta and tau in Alzheimer’s disease Nat. Neurosci. 2020 23 1183 1193 10.1038/s41593-020-0687-6 32778792 110. Jack CR The bivariate distribution of amyloid-beta and tau: relationship with established neurocognitive clinical syndromes Brain 2019 142 3230 3242 10.1093/brain/awz268 31501889 111. Hanseeuw BJ Association of amyloid and tau with cognition in preclinical Alzheimer disease: A longitudinal study JAMA Neurol. 2019 76 915 924 10.1001/jamaneurol.2019.1424 31157827 112. Ising C NLRP3 inflammasome activation drives tau pathology Nature 2019 575 669 673 10.1038/s41586-019-1769-z 31748742 113. Zhang Y Dong Z Song W NLRP3 inflammasome as a novel therapeutic target for Alzheimer’s disease Signal Transduct. Target Ther. 2020 5 37 10.1038/s41392-020-0145-7 32296063 114. He Z Amyloid-beta plaques enhance Alzheimer’s brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation Nat. Med. 2018 24 29 38 10.1038/nm.4443 29200205 115. Pickett EK Amyloid beta and tau cooperate to cause reversible behavioral and transcriptional deficits in a model of Alzheimer’s disease Cell Rep. 2019 29 3592 3604 10.1016/j.celrep.2019.11.044 31825838 116. Plattner F Angelo M Giese KP The roles of cyclin-dependent kinase 5 and glycogen synthase kinase 3 in tau hyperphosphorylation J. Biol. Chem. 2006 281 25457 25465 10.1074/jbc.M603469200 16803897 117. Hernandez P Lee G Sjoberg M Maccioni RB Tau phosphorylation by cdk5 and Fyn in response to amyloid peptide Abeta (25–35): involvement of lipid rafts J. Alzheimers Dis. 2009 16 149 156 10.3233/JAD-2009-0933 19158430 118. Terwel D Amyloid activates GSK-3beta to aggravate neuronal tauopathy in bigenic mice Am. J. Pathol. 2008 172 786 798 10.2353/ajpath.2008.070904 18258852 119. Ly PT Inhibition of GSK3beta-mediated BACE1 expression reduces Alzheimer-associated phenotypes J. Clin. Invest 2013 123 224 235 10.1172/JCI64516 23202730 120. Iijima K Gatt A Iijima-Ando K Tau Ser262 phosphorylation is critical for Abeta42-induced tau toxicity in a transgenic Drosophila model of Alzheimer’s disease Hum. Mol. Genet 2010 19 2947 2957 10.1093/hmg/ddq200 20466736 121. Liu F Iqbal K Grundke-Iqbal I Gong CX Involvement of aberrant glycosylation in phosphorylation of tau by cdk5 and GSK-3beta FEBS Lett. 2002 530 209 214 10.1016/S0014-5793(02)03487-7 12387894 122. Mazanetz MP Fischer PM Untangling tau hyperphosphorylation in drug design for neurodegenerative diseases Nat. Rev. Drug Disco. 2007 6 464 479 10.1038/nrd2111 123. Medina M Avila J Glycogen synthase kinase-3 (GSK-3) inhibitors for the treatment of Alzheimer’s disease Curr. Pharm. Des. 2010 16 2790 2798 10.2174/138161210793176581 20698823 124. Zheng WH Bastianetto S Mennicken F Ma W Kar S Amyloid beta peptide induces tau phosphorylation and loss of cholinergic neurons in rat primary septal cultures Neuroscience 2002 115 201 211 10.1016/S0306-4522(02)00404-9 12401334 125. Swatton JE Increased MAP kinase activity in Alzheimer’s and Down syndrome but not in schizophrenia human brain Eur. J. Neurosci. 2004 19 2711 2719 10.1111/j.0953-816X.2004.03365.x 15147305 126. Salazar SV Strittmatter SM Cellular prion protein as a receptor for amyloid-beta oligomers in Alzheimer’s disease Biochem Biophys. Res Commun. 2017 483 1143 1147 10.1016/j.bbrc.2016.09.062 27639648 127. Kostylev MA Prion-protein-interacting amyloid-beta oligomers of high molecular weight are tightly correlated with memory impairment in multiple alzheimer mouse models J. Biol. Chem. 2015 290 17415 17438 10.1074/jbc.M115.643577 26018073 128. Rezaie P Pontikis CC Hudson L Cairns NJ Lantos PL Expression of cellular prion protein in the frontal and occipital lobe in Alzheimer’s disease, diffuse Lewy body disease, and in normal brain: an immunohistochemical study J. Histochem. Cytochem. 2005 53 929 940 10.1369/jhc.4A6551.2005 16055747 129. Takahashi RH Accumulation of cellular prion protein within dystrophic neurites of amyloid plaques in the Alzheimer’s disease brain Neuropathology 2011 31 208 214 10.1111/j.1440-1789.2010.01158.x 21062360 130. Velayos JL The cellular prion protein and its role in Alzheimer disease Prion 2009 3 110 117 10.4161/pri.3.2.9135 19556894 131. Um JW Alzheimer amyloid-beta oligomer bound to postsynaptic prion protein activates Fyn to impair neurons Nat. Neurosci. 2012 15 1227 1235 10.1038/nn.3178 22820466 132. Lau DH Critical residues involved in tau binding to fyn: implications for tau phosphorylation in Alzheimer’s disease Acta Neuropathol. Commun. 2016 4 49 10.1186/s40478-016-0317-4 27193083 133. Larson M The complex PrP(c)-Fyn couples human oligomeric Abeta with pathological tau changes in Alzheimer’s disease J. Neurosci. 2012 32 16857 16871a 10.1523/JNEUROSCI.1858-12.2012 23175838 134. Gamblin TC Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer’s disease Proc. Natl. Acad. Sci. USA 2003 100 10032 10037 10.1073/pnas.1630428100 12888622 135. Shafiei SS Guerrero-Munoz MJ Castillo-Carranza DL Tau oligomers: Cytotoxicity, propagation, and mitochondrial damage Front Aging Neurosci. 2017 9 83 10.3389/fnagi.2017.00083 28420982 136. Nilson AN Tau oligomers associate with inflammation in the brain and retina of tauopathy mice and in neurodegenerative diseases J. Alzheimers Dis. 2017 55 1083 1099 10.3233/JAD-160912 27716675 137. Bloom GS Amyloid-beta and tau: the trigger and bullet in Alzheimer disease pathogenesis JAMA Neurol. 2014 71 505 508 10.1001/jamaneurol.2013.5847 24493463 138. Leroy K Lack of tau proteins rescues neuronal cell death and decreases amyloidogenic processing of APP in APP/PS1 mice Am. J. Pathol. 2012 181 1928 1940 10.1016/j.ajpath.2012.08.012 23026200 139. Miyamoto T Phosphorylation of tau at Y18, but not tau-fyn binding, is required for tau to modulate NMDA receptor-dependent excitotoxicity in primary neuronal culture Mol. Neurodegener. 2017 12 41 10.1186/s13024-017-0176-x 28526038 140. Avila J Our working point of view of tau protein J. Alzheimers Dis. 2018 62 1277 1285 10.3233/JAD-170600 29036830 141. Campion D Pottier C Nicolas G Le Guennec K Rovelet-Lecrux A Alzheimer disease: modeling an Abeta-centered biological network Mol. Psychiatry 2016 21 861 871 10.1038/mp.2016.38 27021818 142. Petersen RC Neuropathologic features of amnestic mild cognitive impairment Arch. Neurol. 2006 63 665 672 10.1001/archneur.63.5.665 16682536 143. Roberson ED Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer’s disease mouse model Science 2007 316 750 754 10.1126/science.1141736 17478722 144. Kaufman AC Fyn inhibition rescues established memory and synapse loss in Alzheimer mice Ann. Neurol. 2015 77 953 971 10.1002/ana.24394 25707991 145. Nygaard HB Targeting Fyn Kinase in Alzheimer’s Disease Biol. Psychiatry 2018 83 369 376 10.1016/j.biopsych.2017.06.004 28709498 146. Hanseeuw BJ Fluorodeoxyglucose metabolism associated with tau-amyloid interaction predicts memory decline Ann. Neurol. 2017 81 583 596 10.1002/ana.24910 28253546 147. Schultz AP Phases of hyperconnectivity and hypoconnectivity in the default mode and salience networks track with amyloid and tau in clinically normal individuals J. Neurosci. 2017 37 4323 4331 10.1523/JNEUROSCI.3263-16.2017 28314821 148. Albert M Predicting progression from normal cognition to mild cognitive impairment for individuals at 5 years Brain 2018 141 877 887 10.1093/brain/awx365 29365053 149. Kazim SF Neuronal network excitability in alzheimer’s disease: the puzzle of similar versus divergent roles of amyloid beta and tau eNeuro 2021 8 ENEURO.0418-20.2020 10.1523/ENEURO.0418-20.2020 33741601 150. Busche MA Tau impairs neural circuits, dominating amyloid-beta effects, in Alzheimer models in vivo Nat. Neurosci. 2019 22 57 64 10.1038/s41593-018-0289-8 30559471 151. Ransohoff RM How neuroinflammation contributes to neurodegeneration Science 2016 353 777 783 10.1126/science.aag2590 27540165 152. Grammas P Neurovascular dysfunction, inflammation and endothelial activation: implications for the pathogenesis of Alzheimer’s disease J. Neuroinflammation 2011 8 26 10.1186/1742-2094-8-26 21439035 153. Combs CK Johnson DE Karlo JC Cannady SB Landreth GE Inflammatory mechanisms in Alzheimer’s disease: inhibition of beta-amyloid-stimulated proinflammatory responses and neurotoxicity by PPARgamma agonists J. Neurosci. 2000 20 558 567 10.1523/JNEUROSCI.20-02-00558.2000 10632585 154. Griffin WS Sheng JG Roberts GW Mrak RE Interleukin-1 expression in different plaque types in Alzheimer’s disease: significance in plaque evolution J. Neuropathol. Exp. Neurol. 1995 54 276 281 10.1097/00005072-199503000-00014 7876895 155. Rich JB Nonsteroidal anti-inflammatory drugs in Alzheimer’s disease Neurology 1995 45 51 55 10.1212/WNL.45.1.51 7824134 156. Rogers J Luber-Narod J Styren SD Civin WH Expression of immune system-associated antigens by cells of the human central nervous system: relationship to the pathology of Alzheimer’s disease Neurobiol. Aging 1988 9 339 349 10.1016/S0197-4580(88)80079-4 3263583 157. Zhang Y An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex J. Neurosci. 2014 34 11929 11947 10.1523/JNEUROSCI.1860-14.2014 25186741 158. Baik SH A breakdown in metabolic reprogramming causes microglia dysfunction in Alzheimer’s disease Cell Metab. 2019 30 493 507 10.1016/j.cmet.2019.06.005 31257151 159. Pastore A Raimondi F Rajendran L Temussi PA Why does the Abeta peptide of Alzheimer share structural similarity with antimicrobial peptides? Commun. Biol. 2020 3 135 10.1038/s42003-020-0865-9 32193491 160. Arispe N Rojas E Pollard HB Alzheimer disease amyloid beta protein forms calcium channels in bilayer membranes: blockade by tromethamine and aluminum Proc. Natl. Acad. Sci. USA 1993 90 567 571 10.1073/pnas.90.2.567 8380642 161. Greter M Merad M Regulation of microglia development and homeostasis Glia 2013 61 121 127 10.1002/glia.22408 22927325 162. Glenn JA Ward SA Stone CR Booth PL Thomas WE Characterisation of ramified microglial cells: detailed morphology, morphological plasticity and proliferative capability J. Anat. 1992 180 109 118 1452465 163. Eyo UB Dailey ME Microglia: key elements in neural development, plasticity, and pathology J. Neuroimmune Pharm. 2013 8 494 509 10.1007/s11481-013-9434-z 164. Madry C Attwell D Receptors, ion channels, and signaling mechanisms underlying microglial dynamics J. Biol. Chem. 2015 290 12443 12450 10.1074/jbc.R115.637157 25855789 165. Bolmont T Dynamics of the microglial/amyloid interaction indicate a role in plaque maintenance J. Neurosci. 2008 28 4283 4292 10.1523/JNEUROSCI.4814-07.2008 18417708 166. Baik SH Kang S Son SM Mook-Jung I Microglia contributes to plaque growth by cell death due to uptake of amyloid beta in the brain of Alzheimer’s disease mouse model Glia 2016 64 2274 2290 10.1002/glia.23074 27658617 167. Grubman A Transcriptional signature in microglia associated with Abeta plaque phagocytosis Nat. Commun. 2021 12 3015 10.1038/s41467-021-23111-1 34021136 168. Johansson JU Prostaglandin signaling suppresses beneficial microglial function in Alzheimer’s disease models J. Clin. Invest 2015 125 350 364 10.1172/JCI77487 25485684 169. Griciuc A Alzheimer’s disease risk gene CD33 inhibits microglial uptake of amyloid beta Neuron 2013 78 631 643 10.1016/j.neuron.2013.04.014 23623698 170. Michelucci A Heurtaux T Grandbarbe L Morga E Heuschling P Characterization of the microglial phenotype under specific pro-inflammatory and anti-inflammatory conditions: Effects of oligomeric and fibrillar amyloid-beta J. Neuroimmunol. 2009 210 3 12 10.1016/j.jneuroim.2009.02.003 19269040 171. Hickman SE Allison EK El Khoury J Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer’s disease mice J. Neurosci. 2008 28 8354 8360 10.1523/JNEUROSCI.0616-08.2008 18701698 172. Lai AY McLaurin J Clearance of amyloid-beta peptides by microglia and macrophages: the issue of what, when and where Future Neurol. 2012 7 165 176 10.2217/fnl.12.6 22737039 173. Hawkes CA McLaurin J Selective targeting of perivascular macrophages for clearance of beta-amyloid in cerebral amyloid angiopathy Proc. Natl Acad. Sci. USA 2009 106 1261 1266 10.1073/pnas.0805453106 19164591 174. Jay TR TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models J. Exp. Med 2015 212 287 295 10.1084/jem.20142322 25732305 175. Ulrich JD Altered microglial response to Abeta plaques in APPPS1-21 mice heterozygous for TREM2 Mol. Neurodegener. 2014 9 20 10.1186/1750-1326-9-20 24893973 176. Tan YJ Higher Peripheral TREM2 mRNA Levels Relate to Cognitive Deficits and Hippocampal Atrophy in Alzheimer’s Disease and Amnestic Mild Cognitive Impairment J. Alzheimers Dis. 2017 58 413 423 10.3233/JAD-161277 28453482 177. Hu N Increased expression of TREM2 in peripheral blood of Alzheimer’s disease patients J. Alzheimers Dis. 2014 38 497 501 10.3233/JAD-130854 24002183 178. Jay TR Disease progression-dependent effects of TREM2 deficiency in a mouse model of Alzheimer’s disease J. Neurosci. 2017 37 637 647 10.1523/JNEUROSCI.2110-16.2016 28100745 179. Farhy-Tselnicker I Allen NJ Astrocytes, neurons, synapses: a tripartite view on cortical circuit development Neural Dev. 2018 13 7 10.1186/s13064-018-0104-y 29712572 180. Wilhelmsson U Redefining the concept of reactive astrocytes as cells that remain within their unique domains upon reaction to injury Proc. Natl. Acad. Sci. USA 2006 103 17513 17518 10.1073/pnas.0602841103 17090684 181. Brambilla R Inhibition of astroglial nuclear factor kappaB reduces inflammation and improves functional recovery after spinal cord injury J. Exp. Med 2005 202 145 156 10.1084/jem.20041918 15998793 182. Brambilla R Transgenic inhibition of astroglial NF-kappa B improves functional outcome in experimental autoimmune encephalomyelitis by suppressing chronic central nervous system inflammation J. Immunol. 2009 182 2628 2640 10.4049/jimmunol.0802954 19234157 183. van Tijn P Mutant ubiquitin decreases amyloid beta plaque formation in a transgenic mouse model of Alzheimer’s disease Neurochem Int 2012 61 739 748 10.1016/j.neuint.2012.07.007 22797007 184. Vehmas AK Kawas CH Stewart WF Troncoso JC Immune reactive cells in senile plaques and cognitive decline in Alzheimer’s disease Neurobiol. Aging 2003 24 321 331 10.1016/S0197-4580(02)00090-8 12498966 185. Hughes C Beta amyloid aggregates induce sensitised TLR4 signalling causing long-term potentiation deficit and rat neuronal cell death Commun. Biol. 2020 3 79 10.1038/s42003-020-0792-9 32071389 186. Yang J Wise L Fukuchi KI TLR4 Cross-Talk With NLRP3 Inflammasome and Complement Signaling Pathways in Alzheimer’s Disease Front Immunol. 2020 11 724 10.3389/fimmu.2020.00724 32391019 187. Zhao J O’Connor T Vassar R The contribution of activated astrocytes to Abeta production: implications for Alzheimer’s disease pathogenesis J. Neuroinflammation 2011 8 150 10.1186/1742-2094-8-150 22047170 188. Allen NJ Lyons DA Glia as architects of central nervous system formation and function Science 2018 362 181 185 10.1126/science.aat0473 30309945 189. Wegiel J The role of microglial cells and astrocytes in fibrillar plaque evolution in transgenic APP(SW) mice Neurobiol. Aging 2001 22 49 61 10.1016/S0197-4580(00)00181-0 11164276 190. Liddelow SA Neurotoxic reactive astrocytes are induced by activated microglia Nature 2017 541 481 487 10.1038/nature21029 28099414 191. Lian H Astrocyte-microglia cross talk through complement activation modulates amyloid pathology in mouse models of Alzheimer’s disease J. Neurosci. 2016 36 577 589 10.1523/JNEUROSCI.2117-15.2016 26758846 192. Devine MJ Kittler JT Mitochondria at the neuronal presynapse in health and disease Nat. Rev. Neurosci. 2018 19 63 80 10.1038/nrn.2017.170 29348666 193. Ashrafi G de Juan-Sanz J Farrell RJ Ryan TA Molecular tuning of the axonal mitochondrial Ca(2+) uniporter ensures metabolic flexibility of neurotransmission Neuron 2020 105 678 687 10.1016/j.neuron.2019.11.020 31862210 194. Guo L Tian J Du H Mitochondrial dysfunction and synaptic transmission failure in Alzheimer’s disease J. Alzheimers Dis. 2017 57 1071 1086 10.3233/JAD-160702 27662318 195. Ryu JC Zimmer ER Rosa-Neto P Yoon SO Consequences of metabolic disruption in Alzheimer’s disease pathology Neurotherapeutics 2019 16 600 610 10.1007/s13311-019-00755-y 31270743 196. Ashleigh T Swerdlow RH Beal MF The role of mitochondrial dysfunction in Alzheimer’s disease pathogenesis Alzheimers Dement 2023 19 333 342 10.1002/alz.12683 35522844 197. Wang X Impaired balance of mitochondrial fission and fusion in Alzheimer’s disease J. Neurosci. 2009 29 9090 9103 10.1523/JNEUROSCI.1357-09.2009 19605646 198. Park J Loss of mitofusin 2 links beta-amyloid-mediated mitochondrial fragmentation and Cdk5-induced oxidative stress in neuron cells J. Neurochem 2015 132 687 702 10.1111/jnc.12984 25359615 199. Cho DH S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial fission and neuronal injury Science 2009 324 102 105 10.1126/science.1171091 19342591 200. Wang X Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins Proc. Natl Acad. Sci. USA 2008 105 19318 19323 10.1073/pnas.0804871105 19050078 201. Shields LY Mitochondrial fission is a critical modulator of mutant APP-induced neural toxicity J. Biol. Chem. 2021 296 100469 10.1016/j.jbc.2021.100469 33639169 202. Fox TD Mitochondrial protein synthesis, import, and assembly Genetics 2012 192 1203 1234 10.1534/genetics.112.141267 23212899 203. Sorrentino V Enhancing mitochondrial proteostasis reduces amyloid-beta proteotoxicity Nature 2017 552 187 193 10.1038/nature25143 29211722 204. Devi L Prabhu BM Galati DF Avadhani NG Anandatheerthavarada HK Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer’s disease brain is associated with mitochondrial dysfunction J. Neurosci. 2006 26 9057 9068 10.1523/JNEUROSCI.1469-06.2006 16943564 205. Cenini G Rub C Bruderek M Voos W Amyloid beta-peptides interfere with mitochondrial preprotein import competence by a coaggregation process Mol. Biol. Cell 2016 27 3257 3272 10.1091/mbc.E16-05-0313 27630262 206. Csordas G Weaver D Hajnoczky G Endoplasmic reticulum-mitochondrial contactology: Structure and signaling functions Trends Cell Biol. 2018 28 523 540 10.1016/j.tcb.2018.02.009 29588129 207. Marchi S Patergnani S Pinton P The endoplasmic reticulum-mitochondria connection: one touch, multiple functions Biochim Biophys. Acta 2014 1837 461 469 10.1016/j.bbabio.2013.10.015 24211533 208. Hedskog L Modulation of the endoplasmic reticulum-mitochondria interface in Alzheimer’s disease and related models Proc. Natl Acad. Sci. USA 2013 110 7916 7921 10.1073/pnas.1300677110 23620518 209. Area-Gomez E A key role for MAM in mediating mitochondrial dysfunction in Alzheimer disease Cell Death Dis. 2018 9 335 10.1038/s41419-017-0215-0 29491396 210. Schreiner B Hedskog L Wiehager B Ankarcrona M Amyloid-beta peptides are generated in mitochondria-associated endoplasmic reticulum membranes J. Alzheimers Dis. 2015 43 369 374 10.3233/JAD-132543 25096627 211. Calvo-Rodriguez M Hernando-Perez E Nunez L Villalobos C Amyloid beta oligomers increase ER-mitochondria Ca(2+) cross talk in young hippocampal neurons and exacerbate aging-induced intracellular Ca(2+) remodeling Front Cell Neurosci. 2019 13 22 10.3389/fncel.2019.00022 30800057 212. Pera M Increased localization of APP-C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease EMBO J. 2017 36 3356 3371 10.15252/embj.201796797 29018038 213. Turrens JF Boveris A Generation of superoxide anion by the NADH dehydrogenase of bovine heart mitochondria Biochem. J. 1980 191 421 427 10.1042/bj1910421 6263247 214. Sugioka K Mechanism of O2- generation in reduction and oxidation cycle of ubiquinones in a model of mitochondrial electron transport systems Biochim. Biophys. Acta 1988 936 377 385 10.1016/0005-2728(88)90014-X 2848580 215. Balaban RS Nemoto S Finkel T Mitochondria, oxidants, and aging Cell 2005 120 483 495 10.1016/j.cell.2005.02.001 15734681 216. Chakrabarti S Mitochondrial dysfunction during brain aging: role of oxidative stress and modulation by antioxidant supplementation Aging Dis. 2011 2 242 256 22396876 217. Smith MA Harris PL Sayre LM Perry G Iron accumulation in Alzheimer disease is a source of redox-generated free radicals Proc. Natl Acad. Sci. USA 1997 94 9866 9868 10.1073/pnas.94.18.9866 9275217 218. Mao P Reddy PH Aging and amyloid beta-induced oxidative DNA damage and mitochondrial dysfunction in Alzheimer’s disease: implications for early intervention and therapeutics Biochim Biophys. Acta 2011 1812 1359 1370 10.1016/j.bbadis.2011.08.005 21871956 219. Nakamura M Three histidine residues of amyloid-beta peptide control the redox activity of copper and iron Biochemistry 2007 46 12737 12743 10.1021/bi701079z 17929832 220. Bousejra-ElGarah F Bijani C Coppel Y Faller P Hureau C Iron(II) binding to amyloid-beta, the Alzheimer’s peptide Inorg. Chem. 2011 50 9024 9030 10.1021/ic201233b 21800824 221. Leuner K Mitochondrion-derived reactive oxygen species lead to enhanced amyloid beta formation Antioxid. Redox Signal 2012 16 1421 1433 10.1089/ars.2011.4173 22229260 222. Snyder EM Regulation of NMDA receptor trafficking by amyloid-beta Nat. Neurosci. 2005 8 1051 1058 10.1038/nn1503 16025111 223. Busche MA Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer’s disease Science 2008 321 1686 1689 10.1126/science.1162844 18802001 224. Malinow R New developments on the role of NMDA receptors in Alzheimer’s disease Curr. Opin. Neurobiol. 2012 22 559 563 10.1016/j.conb.2011.09.001 21962484 225. Brito-Moreira J Abeta oligomers induce glutamate release from hippocampal neurons Curr. Alzheimer Res 2011 8 552 562 10.2174/156720511796391917 21244351 226. Kullmann DM Lamsa KP Long-term synaptic plasticity in hippocampal interneurons Nat. Rev. Neurosci. 2007 8 687 699 10.1038/nrn2207 17704811 227. Li S Soluble oligomers of amyloid Beta protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake Neuron 2009 62 788 801 10.1016/j.neuron.2009.05.012 19555648 228. Talantova M Abeta induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss Proc. Natl Acad. Sci. USA 2013 110 E2518 E2527 10.1073/pnas.1306832110 23776240 229. Shankar GM Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway J. Neurosci. 2007 27 2866 2875 10.1523/JNEUROSCI.4970-06.2007 17360908 230. Wei W Amyloid beta from axons and dendrites reduces local spine number and plasticity Nat. Neurosci. 2010 13 190 196 10.1038/nn.2476 20037574 231. Reinders NR Amyloid-beta effects on synapses and memory require AMPA receptor subunit GluA3 Proc. Natl. Acad. Sci. USA 2016 113 E6526 E6534 10.1073/pnas.1614249113 27708157 232. Chang EH AMPA receptor downscaling at the onset of Alzheimer’s disease pathology in double knockin mice Proc. Natl. Acad. Sci. USA 2006 103 3410 3415 10.1073/pnas.0507313103 16492745 233. Geula C Mesulam MM Systematic regional variations in the loss of cortical cholinergic fibers in Alzheimer’s disease Cereb. Cortex 1996 6 165 177 10.1093/cercor/6.2.165 8670647 234. Kerbler GM Basal forebrain atrophy correlates with amyloid beta burden in Alzheimer’s disease Neuroimage Clin. 2015 7 105 113 10.1016/j.nicl.2014.11.015 25610772 235. Grothe MJ Heinsen H Amaro E Jr. Grinberg LT Teipel SJ Cognitive Correlates of Basal Forebrain Atrophy and Associated Cortical Hypometabolism in Mild Cognitive Impairment Cereb. Cortex 2016 26 2411 2426 10.1093/cercor/bhv062 25840425 236. Chiesa PA Relationship between basal forebrain resting-state functional connectivity and brain amyloid-beta deposition in cognitively intact older adults with subjective memory complaints Radiology 2019 290 167 176 10.1148/radiol.2018180268 30351255 237. Beach TG Honer WG Hughes LH Cholinergic fibre loss associated with diffuse plaques in the non-demented elderly: the preclinical stage of Alzheimer’s disease? Acta Neuropathol. 1997 93 146 153 10.1007/s004010050595 9039461 238. Lai MK Selective effects of the APOE epsilon4 allele on presynaptic cholinergic markers in the neocortex of Alzheimer’s disease Neurobiol. Dis. 2006 22 555 561 10.1016/j.nbd.2005.12.016 16473016 239. Chhatwal JP Preferential degradation of cognitive networks differentiates Alzheimer’s disease from ageing Brain 2018 141 1486 1500 10.1093/brain/awy053 29522171 240. Buckley RF Functional network integrity presages cognitive decline in preclinical Alzheimer disease Neurology 2017 89 29 37 10.1212/WNL.0000000000004059 28592457 241. Hampton OL Resting-state functional connectivity and amyloid burden influence longitudinal cortical thinning in the default mode network in preclinical Alzheimer’s disease Neuroimage Clin. 2020 28 102407 10.1016/j.nicl.2020.102407 32942175 242. Morrissey ZD Hippocampal functional connectivity across age in an App knock-in mouse model of Alzheimer’s disease Front Aging Neurosci. 2022 14 1085989 10.3389/fnagi.2022.1085989 36711209 243. He X Abnormal salience network in normal aging and in amnestic mild cognitive impairment and Alzheimer’s disease Hum. Brain Mapp. 2014 35 3446 3464 10.1002/hbm.22414 24222384 244. Myers N Within-patient correspondence of amyloid-beta and intrinsic network connectivity in Alzheimer’s disease Brain 2014 137 2052 2064 10.1093/brain/awu103 24771519 245. Grothe MJ Teipel SJ Alzheimer’s Disease Neuroimaging, I. Spatial patterns of atrophy, hypometabolism, and amyloid deposition in Alzheimer’s disease correspond to dissociable functional brain networks Hum. Brain Mapp. 2016 37 35 53 10.1002/hbm.23018 26441321 246. Brier MR Loss of intranetwork and internetwork resting state functional connections with Alzheimer’s disease progression J. Neurosci. 2012 32 8890 8899 10.1523/JNEUROSCI.5698-11.2012 22745490 247. Lin C The effect of amyloid deposition on longitudinal resting-state functional connectivity in cognitively normal older adults Alzheimers Res Ther. 2020 12 7 10.1186/s13195-019-0573-1 31907079 248. Pannee J Reference measurement procedure for CSF amyloid beta (Abeta)(1-42) and the CSF Abeta(1–42) /Abeta(1–40) ratio - a cross-validation study against amyloid PET J. Neurochem 2016 139 651 658 10.1111/jnc.13838 27579672 249. Krishnadas N Villemagne VL Dore V Rowe CC Advances in brain amyloid imaging Semin Nucl. Med 2021 51 241 252 10.1053/j.semnuclmed.2020.12.005 33482999 250. Hansson O Lehmann S Otto M Zetterberg H Lewczuk P Advantages and disadvantages of the use of the CSF Amyloid beta (Abeta) 42/40 ratio in the diagnosis of Alzheimer’s Disease Alzheimers Res Ther. 2019 11 34 10.1186/s13195-019-0485-0 31010420 251. Klunk WE Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B Ann. Neurol. 2004 55 306 319 10.1002/ana.20009 14991808 252. Wong DF In vivo imaging of amyloid deposition in Alzheimer disease using the radioligand 18F-AV-45 (florbetapir [corrected] F 18) J. Nucl. Med 2010 51 913 920 10.2967/jnumed.109.069088 20501908 253. Rowe CC Imaging of amyloid beta in Alzheimer’s disease with 18F-BAY94-9172, a novel PET tracer: proof of mechanism Lancet Neurol. 2008 7 129 135 10.1016/S1474-4422(08)70001-2 18191617 254. Serdons K Synthesis of 18F-labelled 2-(4’-fluorophenyl)-1,3-benzothiazole and evaluation as amyloid imaging agent in comparison with [11C]PIB Bioorg. Med Chem. Lett. 2009 19 602 605 10.1016/j.bmcl.2008.12.069 19147351 255. Olsson B CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis Lancet Neurol. 2016 15 673 684 10.1016/S1474-4422(16)00070-3 27068280 256. Seppala TT CSF biomarkers for Alzheimer disease correlate with cortical brain biopsy findings Neurology 2012 78 1568 1575 10.1212/WNL.0b013e3182563bd0 22517093 257. Wolk DA Association between in vivo fluorine 18-labeled flutemetamol amyloid positron emission tomography imaging and in vivo cerebral cortical histopathology Arch. Neurol. 2011 68 1398 1403 10.1001/archneurol.2011.153 21747004 258. Palmqvist S Mattsson N Hansson O Alzheimer’s Disease Neuroimaging I Cerebrospinal fluid analysis detects cerebral amyloid-beta accumulation earlier than positron emission tomography Brain 2016 139 1226 1236 10.1093/brain/aww015 26936941 259. Jack CR Jr. Advances in Alzheimer’s disease research over the past two decades Lancet Neurol. 2022 21 866 869 10.1016/S1474-4422(22)00298-8 36115352 260. Pike KE Beta-amyloid imaging and memory in non-demented individuals: evidence for preclinical Alzheimer’s disease Brain 2007 130 2837 2844 10.1093/brain/awm238 17928318 261. Rowe CC Predicting Alzheimer disease with beta-amyloid imaging: results from the Australian imaging, biomarkers, and lifestyle study of ageing Ann. Neurol. 2013 74 905 913 10.1002/ana.24040 24448836 262. Blennow K Mattsson N Scholl M Hansson O Zetterberg H Amyloid biomarkers in Alzheimer’s disease Trends Pharm. Sci. 2015 36 297 309 10.1016/j.tips.2015.03.002 25840462 263. Shaw LM Qualification of the analytical and clinical performance of CSF biomarker analyses in ADNI Acta Neuropathol. 2011 121 597 609 10.1007/s00401-011-0808-0 21311900 264. Villemagne VL Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study Lancet Neurol. 2013 12 357 367 10.1016/S1474-4422(13)70044-9 23477989 265. Toledo JB Shaw LM Trojanowski JQ Plasma amyloid beta measurements - a desired but elusive Alzheimer’s disease biomarker Alzheimers Res Ther. 2013 5 8 10.1186/alzrt162 23470128 266. Jack CR Jr. Holtzman DM Biomarker modeling of Alzheimer’s disease Neuron 2013 80 1347 1358 10.1016/j.neuron.2013.12.003 24360540 267. Halle M Methods to monitor monocytes-mediated amyloid-beta uptake and phagocytosis in the context of adjuvanted immunotherapies J. Immunol. Methods 2015 424 64 79 10.1016/j.jim.2015.05.002 26002154 268. Frenkel D Scara1 deficiency impairs clearance of soluble amyloid-beta by mononuclear phagocytes and accelerates Alzheimer’s-like disease progression Nat. Commun. 2013 4 2030 10.1038/ncomms3030 23799536 269. Cheng Y Tian DY Wang YJ Peripheral clearance of brain-derived Abeta in Alzheimer’s disease: pathophysiology and therapeutic perspectives Transl. Neurodegener. 2020 9 16 10.1186/s40035-020-00195-1 32381118 270. Perneczky R Soluble amyloid precursor protein beta as blood-based biomarker of Alzheimer’s disease Transl. Psychiatry 2013 3 e227 10.1038/tp.2013.11 23423136 271. Palmqvist S Cerebrospinal fluid and plasma biomarker trajectories with increasing amyloid deposition in Alzheimer’s disease EMBO Mol. Med 2019 11 e11170 10.15252/emmm.201911170 31709776 272. Palmqvist S Performance of Fully Automated Plasma Assays as Screening Tests for Alzheimer Disease-Related beta-Amyloid Status JAMA Neurol. 2019 76 1060 1069 10.1001/jamaneurol.2019.1632 31233127 273. Damotte V Plasma amyloid beta levels are driven by genetic variants near APOE, BACE1, APP, PSEN2: A genome-wide association study in over 12,000 non-demented participants Alzheimers Dement 2021 17 1663 1674 10.1002/alz.12333 34002480 274. Nakamura A High performance plasma amyloid-beta biomarkers for Alzheimer’s disease Nature 2018 554 249 254 10.1038/nature25456 29420472 275. Yuyama K Immuno-digital invasive cleavage assay for analyzing Alzheimer’s amyloid ss-bound extracellular vesicles Alzheimers Res Ther. 2022 14 140 10.1186/s13195-022-01073-w 36184615 276. Bu XL Blood-derived amyloid-beta protein induces Alzheimer’s disease pathologies Mol. Psychiatry 2018 23 1948 1956 10.1038/mp.2017.204 29086767 277. Wang J Gu BJ Masters CL Wang YJ A systemic view of Alzheimer disease - insights from amyloid-beta metabolism beyond the brain Nat. Rev. Neurol. 2017 13 612 623 10.1038/nrneurol.2017.111 28960209 278. Endres K Increased CSF APPs-alpha levels in patients with Alzheimer disease treated with acitretin Neurology 2014 83 1930 1935 10.1212/WNL.0000000000001017 25344383 279. Rosenberg JB AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer’s Disease Hum. Gene Ther. Clin. Dev. 2018 29 24 47 10.1089/humc.2017.231 29409358 280. Decourt B MCLENA-1: A phase II clinical trial for the assessment of safety, tolerability, and efficacy of lenalidomide in patients with mild cognitive impairment due to Alzheimer’s disease Open Access J. Clin. Trials 2020 12 1 13 10.2147/OAJCT.S221914 32123490 281. Bakker A Albert MS Krauss G Speck CL Gallagher M Response of the medial temporal lobe network in amnestic mild cognitive impairment to therapeutic intervention assessed by fMRI and memory task performance Neuroimage Clin. 2015 7 688 698 10.1016/j.nicl.2015.02.009 25844322 282. Maccecchini ML Posiphen as a candidate drug to lower CSF amyloid precursor protein, amyloid-beta peptide and tau levels: target engagement, tolerability and pharmacokinetics in humans J. Neurol. Neurosurg. Psychiatry 2012 83 894 902 10.1136/jnnp-2012-302589 22791904 283. Cummings JL Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer’s disease Alzheimers Res Ther. 2016 8 4 10.1186/s13195-016-0173-2 26822146 284. Ismail R The effect of 40-Hz light therapy on amyloid load in patients with prodromal and clinical Alzheimer’s disease Int J. Alzheimers Dis. 2018 2018 6852303 30155285 285. Baruch K Breaking immune tolerance by targeting Foxp3(+) regulatory T cells mitigates Alzheimer’s disease pathology Nat. Commun. 2015 6 7967 10.1038/ncomms8967 26284939 286. Haas LT Silent allosteric modulation of mGluR5 maintains glutamate signaling while rescuing Alzheimer’s mouse phenotypes Cell Rep. 2017 20 76 88 10.1016/j.celrep.2017.06.023 28683325 287. Spurrier J Reversal of synapse loss in Alzheimer mouse models by targeting mGluR5 to prevent synaptic tagging by C1Q Sci. Transl. Med 2022 14 eabi8593 10.1126/scitranslmed.abi8593 35648810 288. Krafft GA Jerecic J Siemers E Cline EN ACU193: An immunotherapeutic poised to test the amyloid beta oligomer hypothesis of Alzheimer’s disease Front Neurosci. 2022 16 848215 10.3389/fnins.2022.848215 35557606 289. Izzo NJ Preclinical and clinical biomarker studies of CT1812: A novel approach to Alzheimer’s disease modification Alzheimers Dement 2021 17 1365 1382 10.1002/alz.12302 33559354 290. Craft S Safety, efficacy, and feasibility of intranasal insulin for the treatment of mild cognitive impairment and Alzheimer disease dementia: A randomized clinical trial JAMA Neurol. 2020 77 1099 1109 10.1001/jamaneurol.2020.1840 32568367 291. Kellar D Intranasal insulin reduces white matter hyperintensity progression in association with improvements in cognition and CSF biomarker profiles in mild cognitive impairment and Alzheimer’s disease J. Prev. Alzheimers Dis. 2021 8 240 248 34101779 292. Kellar D Intranasal insulin modulates cerebrospinal fluid markers of neuroinflammation in mild cognitive impairment and Alzheimer’s disease: a randomized trial Sci. Rep. 2022 12 1346 10.1038/s41598-022-05165-3 35079029 293. Wang HY PTI-125 binds and reverses an altered conformation of filamin A to reduce Alzheimer’s disease pathogenesis Neurobiol. Aging 2017 55 99 114 10.1016/j.neurobiolaging.2017.03.016 28438486 294. Wang HY PTI-125 reduces biomarkers of Alzheimer’s disease in patients J. Prev. Alzheimers Dis. 2020 7 256 264 32920628 295. Hey JA Clinical pharmacokinetics and safety of ALZ-801, a novel prodrug of tramiprosate in development for the treatment of Alzheimer’s disease Clin. Pharmacokinet. 2018 57 315 333 10.1007/s40262-017-0608-3 29063518 296. Kutzsche J Safety and pharmacokinetics of the orally available antiprionic compound PRI-002: A single and multiple ascending dose phase I study Alzheimers Dement (N. Y.) 2020 6 e12001 32211506 297. de la Torre R Dierssen M Therapeutic approaches in the improvement of cognitive performance in Down syndrome: past, present, and future Prog. Brain Res 2012 197 1 14 10.1016/B978-0-444-54299-1.00001-7 22541285 298. Lannfelt L Safety, efficacy, and biomarker findings of PBT2 in targeting Abeta as a modifying therapy for Alzheimer’s disease: a phase IIa, double-blind, randomised, placebo-controlled trial Lancet Neurol. 2008 7 779 786 10.1016/S1474-4422(08)70167-4 18672400 299. Scheltens P Safety, tolerability and efficacy of the glutaminyl cyclase inhibitor PQ912 in Alzheimer’s disease: results of a randomized, double-blind, placebo-controlled phase 2a study Alzheimers Res. Ther. 2018 10 107 10.1186/s13195-018-0431-6 30309389 300. Vassar R Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE Science 1999 286 735 741 10.1126/science.286.5440.735 10531052 301. Hussain I Identification of a novel aspartic protease (Asp 2) as beta-secretase Mol. Cell Neurosci. 1999 14 419 427 10.1006/mcne.1999.0811 10656250 302. Yan R Membrane-anchored aspartyl protease with Alzheimer’s disease beta-secretase activity Nature 1999 402 533 537 10.1038/990107 10591213 303. Sinha S Purification and cloning of amyloid precursor protein beta-secretase from human brain Nature 1999 402 537 540 10.1038/990114 10591214 304. May PC The potent BACE1 inhibitor LY2886721 elicits robust central Abeta pharmacodynamic responses in mice, dogs, and humans J. Neurosci. 2015 35 1199 1210 10.1523/JNEUROSCI.4129-14.2015 25609634 305. Sperling R Findings of efficacy, safety, and biomarker outcomes of atabecestat in preclinical Alzheimer disease: A truncated randomized phase 2b/3 clinical trial JAMA Neurol. 2021 78 293 301 10.1001/jamaneurol.2020.4857 33464300 306. Madrasi K Systematic in silico analysis of clinically tested drugs for reducing amyloid-beta plaque accumulation in Alzheimer’s disease Alzheimers Dement 2021 17 1487 1498 10.1002/alz.12312 33938131 307. Sakamoto K BACE1 inhibitor lanabecestat (AZD3293) in a phase 1 study of healthy Japanese subjects: Pharmacokinetics and effects on plasma and cerebrospinal fluid abeta peptides J. Clin. Pharm. 2017 57 1460 1471 10.1002/jcph.950 308. Zimmer JA Lanabecestat: Neuroimaging results in early symptomatic Alzheimer’s disease Alzheimers Dement (N. Y) 2021 7 e12123 33614894 309. Neumann U The BACE-1 inhibitor CNP520 for prevention trials in Alzheimer’s disease EMBO Mol. Med. 2018 10 e9316 10.15252/emmm.201809316 30224383 310. Al-Tel TH Design, synthesis, and qualitative structure-activity evaluations of novel beta-secretase inhibitors as potential Alzheimer’s drug leads J. Med Chem. 2011 54 8373 8385 10.1021/jm201181f 22044119 311. Benjannet S Post-translational processing of beta-secretase (beta-amyloid-converting enzyme) and its ectodomain shedding. The pro- and transmembrane/cytosolic domains affect its cellular activity and amyloid-beta production J. Biol. Chem. 2001 276 10879 10887 10.1074/jbc.M009899200 11152688 312. Yuan J Structure-based design of beta-site APP cleaving enzyme 1 (BACE1) inhibitors for the treatment of Alzheimer’s disease J. Med Chem. 2013 56 4156 4180 10.1021/jm301659n 23509904 313. Artavanis-Tsakonas S Rand MD Lake RJ Notch signaling: cell fate control and signal integration in development Science 1999 284 770 776 10.1126/science.284.5415.770 10221902 314. Albright CF Pharmacodynamics of selective inhibition of gamma-secretase by avagacestat J. Pharm. Exp. Ther. 2013 344 686 695 10.1124/jpet.112.199356 315. Coric V Targeting prodromal Alzheimer disease with avagacestat: A randomized clinical trial JAMA Neurol. 2015 72 1324 1333 10.1001/jamaneurol.2015.0607 26414022 316. Raven F Soluble gamma-secretase modulators attenuate Alzheimer’s beta-amyloid pathology and induce conformational changes in presenilin 1 EBioMedicine 2017 24 93 101 10.1016/j.ebiom.2017.08.028 28919280 317. Rogers K Modulation of gamma-secretase by EVP-0015962 reduces amyloid deposition and behavioral deficits in Tg2576 mice Mol. Neurodegener. 2012 7 61 10.1186/1750-1326-7-61 23249765 318. Fox NC Effects of Abeta immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease Neurology 2005 64 1563 1572 10.1212/01.WNL.0000159743.08996.99 15883317 319. Orgogozo JM Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization Neurology 2003 61 46 54 10.1212/01.WNL.0000073623.84147.A8 12847155 320. Bayer AJ Evaluation of the safety and immunogenicity of synthetic Abeta42 (AN1792) in patients with AD Neurology 2005 64 94 101 10.1212/01.WNL.0000148604.77591.67 15642910 321. Gilman S Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial Neurology 2005 64 1553 1562 10.1212/01.WNL.0000159740.16984.3C 15883316 322. Ryan JM Grundman M Anti-amyloid-beta immunotherapy in Alzheimer’s disease: ACC-001 clinical trials are ongoing J. Alzheimers Dis. 2009 17 243 10.3233/JAD-2009-1118 19502708 323. Arai H Suzuki H Yoshiyama T Vanutide cridificar and the QS-21 adjuvant in Japanese subjects with mild to moderate Alzheimer’s disease: results from two phase 2 studies Curr. Alzheimer Res 2015 12 242 254 10.2174/1567205012666150302154121 25731629 324. Davtyan H Immunogenicity, efficacy, safety, and mechanism of action of epitope vaccine (Lu AF20513) for Alzheimer’s disease: prelude to a clinical trial J. Neurosci. 2013 33 4923 4934 10.1523/JNEUROSCI.4672-12.2013 23486963 325. Sandberg A Stabilization of neurotoxic Alzheimer amyloid-beta oligomers by protein engineering Proc. Natl. Acad. Sci. USA 2010 107 15595 15600 10.1073/pnas.1001740107 20713699 326. Lacosta AM Safety, tolerability and immunogenicity of an active anti-Abeta40 vaccine (ABvac40) in patients with Alzheimer’s disease: a randomised, double-blind, placebo-controlled, phase I trial Alzheimers Res. Ther. 2018 10 12 10.1186/s13195-018-0340-8 29378651 327. Wang CY Site-specific UBITh amyloid-beta vaccine for immunotherapy of Alzheimer’s disease Vaccine 2007 25 3041 3052 10.1016/j.vaccine.2007.01.031 17287052 328. Petrushina I Characterization and preclinical evaluation of the cGMP grade DNA based vaccine, AV-1959D to enter the first-in-human clinical trials Neurobiol. Dis. 2020 139 104823 10.1016/j.nbd.2020.104823 32119976 329. Davtyan H Testing a MultiTEP-based combination vaccine to reduce Abeta and tau pathology in Tau22/5xFAD bigenic mice Alzheimers Res Ther. 2019 11 107 10.1186/s13195-019-0556-2 31847886 330. Waldmann H Human monoclonal antibodies: The benefits of humanization Methods Mol. Biol. 2019 1904 1 10 10.1007/978-1-4939-8958-4_1 30539464 331. van Lengerich B A TREM2-activating antibody with a blood-brain barrier transport vehicle enhances microglial metabolism in Alzheimer’s disease models Nat. Neurosci. 2023 26 416 429 36635496 332. Bard F Epitope and isotype specificities of antibodies to beta -amyloid peptide for protection against Alzheimer’s disease-like neuropathology Proc. Natl. Acad. Sci. USA 2003 100 2023 2028 10.1073/pnas.0436286100 12566568 333. DeMattos RB Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer’s disease Proc. Natl. Acad. Sci. USA 2001 98 8850 8855 10.1073/pnas.151261398 11438712 334. Bard F Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease Nat. Med. 2000 6 916 919 10.1038/78682 10932230 335. Salloway S Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease N. Engl. J. Med 2014 370 322 333 10.1056/NEJMoa1304839 24450891 336. Klein G Gantenerumab reduces amyloid-beta plaques in patients with prodromal to moderate Alzheimer’s disease: a PET substudy interim analysis Alzheimers Res Ther. 2019 11 101 10.1186/s13195-019-0559-z 31831056 337. Moulder KL Dominantly Inherited Alzheimer Network: facilitating research and clinical trials Alzheimers Res. Ther. 2013 5 48 10.1186/alzrt213 24131566 338. Salloway S A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease Nat. Med. 2021 27 1187 1196 10.1038/s41591-021-01369-8 34155411 339. Adolfsson O An effector-reduced anti-beta-amyloid (Abeta) antibody with unique abeta binding properties promotes neuroprotection and glial engulfment of Abeta J. Neurosci. 2012 32 9677 9689 10.1523/JNEUROSCI.4742-11.2012 22787053 340. Meilandt WJ Characterization of the selective in vitro and in vivo binding properties of crenezumab to oligomeric Abeta Alzheimers Res Ther. 2019 11 97 10.1186/s13195-019-0553-5 31787113 341. Rios-Romenets S Baseline demographic, clinical, and cognitive characteristics of the Alzheimer’s Prevention Initiative (API) Autosomal-Dominant Alzheimer’s Disease Colombia Trial Alzheimers Dement 2020 16 1023 1030 10.1002/alz.12109 32418361 342. Ostrowitzki S Evaluating the safety and efficacy of crenezumab vs placebo in adults with early Alzheimer disease: Two phase 3 randomized placebo-controlled trials JAMA Neurol. 2022 79 1113 1121 10.1001/jamaneurol.2022.2909 36121669 343. Tariot PN The Alzheimer’s Prevention Initiative Autosomal-Dominant Alzheimer’s Disease Trial: A study of crenezumab versus placebo in preclinical PSEN1 E280A mutation carriers to evaluate efficacy and safety in the treatment of autosomal-dominant Alzheimer’s disease, including a placebo-treated noncarrier cohort Alzheimers Dement (N. Y.) 2018 4 150 160 10.1016/j.trci.2018.02.002 29955659 344. Demattos RB A plaque-specific antibody clears existing beta-amyloid plaques in Alzheimer’s disease mice Neuron 2012 76 908 920 10.1016/j.neuron.2012.10.029 23217740 345. Honig LS Trial of solanezumab for mild dementia due to Alzheimer’s disease N. Engl. J. Med. 2018 378 321 330 10.1056/NEJMoa1705971 29365294 346. Schwarz AJ Magnetic resonance imaging measures of brain atrophy from the EXPEDITION3 trial in mild Alzheimer’s disease Alzheimers Dement (N. Y.) 2019 5 328 337 10.1016/j.trci.2019.05.007 31388559 347. Sevigny J Addendum: The antibody aducanumab reduces Abeta plaques in Alzheimer’s disease Nature 2017 546 564 10.1038/nature22809 28640269 348. Knopman DS Jones DT Greicius MD Failure to demonstrate efficacy of aducanumab: An analysis of the EMERGE and ENGAGE trials as reported by Biogen, December 2019 Alzheimers Dement 2021 17 696 701 10.1002/alz.12213 33135381 349. Mullard A FDA approval for Biogen’s aducanumab sparks Alzheimer disease firestorm Nat. Rev. Drug Disco. 2021 20 496 350. Logovinsky V Safety and tolerability of BAN2401-a clinical study in Alzheimer’s disease with a protofibril selective Abeta antibody Alzheimers Res Ther. 2016 8 14 10.1186/s13195-016-0181-2 27048170 351. Swanson CJ A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Abeta protofibril antibody Alzheimers Res Ther. 2021 13 80 10.1186/s13195-021-00813-8 33865446 352. Couzin-Frankel J Piller C Alzheimer’s drug stirs excitement-and concerns Science 2022 378 1030 1031 10.1126/science.adg1899 36480604 353. Rafii, M. S. et al. The AHEAD 3–45 Study: Design of a prevention trial for Alzheimer’s disease. Alzheimers Dement, (2022). 354. Ullah R Park TJ Huang X Kim MO Abnormal amyloid beta metabolism in systemic abnormalities and Alzheimer’s pathology: Insights and therapeutic approaches from periphery Ageing Res Rev. 2021 71 101451 10.1016/j.arr.2021.101451 34450351 355. Cirrito JR Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo Neuron 2005 48 913 922 10.1016/j.neuron.2005.10.028 16364896 356. Abramov E Amyloid-beta as a positive endogenous regulator of release probability at hippocampal synapses Nat. Neurosci. 2009 12 1567 1576 10.1038/nn.2433 19935655 357. Morley JE A physiological role for amyloid-beta protein:enhancement of learning and memory J. Alzheimers Dis. 2010 19 441 449 10.3233/JAD-2010-1230 19749407 358. Dineley KT Bell KA Bui D Sweatt JD beta -Amyloid peptide activates alpha 7 nicotinic acetylcholine receptors expressed in Xenopus oocytes J. Biol. Chem. 2002 277 25056 25061 10.1074/jbc.M200066200 11983690 359. Chen Y Dong C Abeta40 promotes neuronal cell fate in neural progenitor cells Cell Death Differ. 2009 16 386 394 10.1038/cdd.2008.94 18566600 360. Scott G Amyloid pathology and axonal injury after brain trauma Neurology 2016 86 821 828 10.1212/WNL.0000000000002413 26843562 361. Bird SM Cerebral amyloid-beta accumulation and deposition following traumatic brain injury-A narrative review and meta-analysis of animal studies Neurosci. Biobehav Rev. 2016 64 215 228 10.1016/j.neubiorev.2016.01.004 26899257 362. Mannix RC Zhang J Berglass J Qui J Whalen MJ Beneficial effect of amyloid beta after controlled cortical impact Brain Inj. 2013 27 743 748 10.3109/02699052.2013.771797 23672448 363. Clarke J Overexpression of APP provides neuroprotection in the absence of functional benefit following middle cerebral artery occlusion in rats Eur. J. Neurosci. 2007 26 1845 1852 10.1111/j.1460-9568.2007.05807.x 17897395 364. Kontush A Amyloid-beta is an antioxidant for lipoproteins in cerebrospinal fluid and plasma Free Radic. Biol. Med 2001 30 119 128 10.1016/S0891-5849(00)00458-5 11134902 365. Kumar DK Amyloid-beta peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease Sci. Transl. Med 2016 8 340ra372 10.1126/scitranslmed.aaf1059 366. Frain L Association of cancer and Alzheimer’s disease risk in a national cohort of veterans Alzheimers Dement 2017 13 1364 1370 10.1016/j.jalz.2017.04.012 28711346 367. Shafi O Inverse relationship between Alzheimer’s disease and cancer, and other factors contributing to Alzheimer’s disease: a systematic review BMC Neurol. 2016 16 236 10.1186/s12883-016-0765-2 27875990 368. Lanni C Beta-amyloid short- and long-term synaptic entanglement Pharm. Res. 2019 139 243 260 10.1016/j.phrs.2018.11.018 369. Cai, W., Li, L., Sang, S., Pan, X. & Zhong, C. Physiological Roles of beta-amyloid in Regulating Synaptic Function: Implications for AD Pathophysiology. Neurosci. Bull.10.1007/s12264-022-00985-9 (2022). 370. Giuffrida ML Monomeric ss-amyloid interacts with type-1 insulin-like growth factor receptors to provide energy supply to neurons Front Cell Neurosci. 2015 9 297 10.3389/fncel.2015.00297 26300732 371. Zimbone S Amyloid Beta monomers regulate cyclic adenosine monophosphate response element binding protein functions by activating type-1 insulin-like growth factor receptors in neuronal cells Aging Cell 2018 17 e12684 10.1111/acel.12684 29094448 372. Nagahara AH Tuszynski MH Potential therapeutic uses of BDNF in neurological and psychiatric disorders Nat. Rev. Drug Disco. 2011 10 209 219 10.1038/nrd3366 373. Seabrook GR Mechanisms contributing to the deficits in hippocampal synaptic plasticity in mice lacking amyloid precursor protein Neuropharmacology 1999 38 349 359 10.1016/S0028-3908(98)00204-4 10219973 374. Garcia-Osta A Alberini CM Amyloid beta mediates memory formation Learn Mem. 2009 16 267 272 10.1101/lm.1310209 19318468 375. Puzzo D Endogenous amyloid-beta is necessary for hippocampal synaptic plasticity and memory Ann. Neurol. 2011 69 819 830 10.1002/ana.22313 21472769 376. Galanis C Amyloid-beta mediates homeostatic synaptic plasticity J. Neurosci. 2021 41 5157 5172 10.1523/JNEUROSCI.1820-20.2021 33926999 377. Kamenetz F APP processing and synaptic function Neuron 2003 37 925 937 10.1016/S0896-6273(03)00124-7 12670422 378. Ikegaya Y Beta-amyloid enhances glial glutamate uptake activity and attenuates synaptic efficacy J. Biol. Chem. 2002 277 32180 32186 10.1074/jbc.M203764200 12070161 379. Sudweeks SN Yakel JL Functional and molecular characterization of neuronal nicotinic ACh receptors in rat CA1 hippocampal neurons J. Physiol. 2000 527 515 528 10.1111/j.1469-7793.2000.00515.x 10990538 380. Papouin T Dunphy JM Tolman M Dineley KT Haydon PG Septal cholinergic neuromodulation tunes the astrocyte-dependent gating of hippocampal NMDA receptors to wakefulness Neuron 2017 94 840 854.e847 10.1016/j.neuron.2017.04.021 28479102 381. Castro NG Albuquerque EX alpha-Bungarotoxin-sensitive hippocampal nicotinic receptor channel has a high calcium permeability Biophys. J. 1995 68 516 524 10.1016/S0006-3495(95)80213-4 7696505 382. Unwin N Nicotinic acetylcholine receptor and the structural basis of neuromuscular transmission: insights from Torpedo postsynaptic membranes Q Rev. Biophys. 2013 46 283 322 10.1017/S0033583513000061 24050525 383. Dougherty JJ Wu J Nichols RA Beta-amyloid regulation of presynaptic nicotinic receptors in rat hippocampus and neocortex J. Neurosci. 2003 23 6740 6747 10.1523/JNEUROSCI.23-17-06740.2003 12890766 384. Letsinger AC Gu Z Yakel JL alpha7 nicotinic acetylcholine receptors in the hippocampal circuit: taming complexity Trends Neurosci. 2022 45 145 157 10.1016/j.tins.2021.11.006 34916082 385. Townsend M alpha7-nAChR agonist enhances neural plasticity in the hippocampus via a GABAergic circuit J. Neurophysiol. 2016 116 2663 2675 10.1152/jn.00243.2016 27655963 386. Nagele RG D’Andrea MR Anderson WJ Wang HY Intracellular accumulation of beta-amyloid(1-42) in neurons is facilitated by the alpha 7 nicotinic acetylcholine receptor in Alzheimer’s disease Neuroscience 2002 110 199 211 10.1016/S0306-4522(01)00460-2 11958863 387. Belloy ME Napolioni V Greicius MD A quarter century of APOE and Alzheimer’s disease: Progress to date and the path forward Neuron 2019 101 820 838 10.1016/j.neuron.2019.01.056 30844401 388. Cecon E Quantitative assessment of oligomeric amyloid beta peptide binding to alpha7 nicotinic receptor Br. J. Pharm. 2019 176 3475 3488 10.1111/bph.14688 389. Gulisano W Neuromodulatory action of picomolar extracellular Abeta42 oligomers on presynaptic and postsynaptic mechanisms underlying synaptic function and memory J. Neurosci. 2019 39 5986 6000 10.1523/JNEUROSCI.0163-19.2019 31127002 390. Tropea MR Genetic deletion of alpha7 nicotinic acetylcholine receptors induces an age-dependent Alzheimer’s disease-like pathology Prog. Neurobiol. 2021 206 102154 10.1016/j.pneurobio.2021.102154 34453977 391. Martinsson I APP depletion alters selective pre- and post-synaptic proteins Mol. Cell Neurosci. 2019 95 86 95 10.1016/j.mcn.2019.02.003 30763689 392. Young-Pearse TL A critical function for beta-amyloid precursor protein in neuronal migration revealed by in utero RNA interference J. Neurosci. 2007 27 14459 14469 10.1523/JNEUROSCI.4701-07.2007 18160654 393. Saura CA Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration Neuron 2004 42 23 36 10.1016/S0896-6273(04)00182-5 15066262 394. Puzzo D Picomolar amyloid-beta positively modulates synaptic plasticity and memory in hippocampus J. Neurosci. 2008 28 14537 14545 10.1523/JNEUROSCI.2692-08.2008 19118188 395. Chen XH Johnson VE Uryu K Trojanowski JQ Smith DH A lack of amyloid beta plaques despite persistent accumulation of amyloid beta in axons of long-term survivors of traumatic brain injury Brain Pathol. 2009 19 214 223 10.1111/j.1750-3639.2008.00176.x 18492093 396. Pajoohesh-Ganji A Inhibition of amyloid precursor protein secretases reduces recovery after spinal cord injury Brain Res. 2014 1560 73 82 10.1016/j.brainres.2014.02.049 24630972 397. Grant JL Reversal of paralysis and reduced inflammation from peripheral administration of beta-amyloid in TH1 and TH17 versions of experimental autoimmune encephalomyelitis Sci. Transl. Med 2012 4 145ra105 10.1126/scitranslmed.3004145 22855462 398. Soscia SJ The Alzheimer’s disease-associated amyloid beta-protein is an antimicrobial peptide PLoS One 2010 5 e9505 10.1371/journal.pone.0009505 20209079 399. Bourgade K Protective effect of amyloid-beta peptides against herpes simplex virus-1 infection in a neuronal cell culture model J. Alzheimers Dis. 2016 50 1227 1241 10.3233/JAD-150652 26836158 400. Wozniak MA Mee AP Itzhaki RF Herpes simplex virus type 1 DNA is located within Alzheimer’s disease amyloid plaques J. Pathol. 2009 217 131 138 10.1002/path.2449 18973185 401. Miklossy J Bacterial amyloid and DNA are important constituents of senile plaques: Further evidence of the spirochetal and biofilm nature of senile plaques J. Alzheimers Dis. 2016 53 1459 1473 10.3233/JAD-160451 27314530 402. Spitzer P Amyloidogenic amyloid-beta-peptide variants induce microbial agglutination and exert antimicrobial activity Sci. Rep. 2016 6 32228 10.1038/srep32228 27624303 403. Eimer WA Alzheimer’s disease-associated beta-amyloid is rapidly seeded by herpesviridae to protect against brain infection Neuron 2018 99 56 63.e53 10.1016/j.neuron.2018.06.030 30001512 404. Bourgade K beta-Amyloid peptides display protective activity against the human Alzheimer’s disease-associated herpes simplex virus-1 Biogerontology 2015 16 85 98 10.1007/s10522-014-9538-8 25376108 405. White MR Alzheimer’s associated beta-amyloid protein inhibits influenza A virus and modulates viral interactions with phagocytes PLoS One 2014 9 e101364 10.1371/journal.pone.0101364 24988208 406. Di Domizio J Nucleic acid-containing amyloid fibrils potently induce type I interferon and stimulate systemic autoimmunity Proc. Natl Acad. Sci. USA 2012 109 14550 14555 10.1073/pnas.1206923109 22904191 407. Mastrangelo MA Sudol KL Narrow WC Bowers WJ Interferon-gamma differentially affects Alzheimer’s disease pathologies and induces neurogenesis in triple transgenic-AD mice Am. J. Pathol. 2009 175 2076 2088 10.2353/ajpath.2009.090059 19808651 408. Wu Y Microglia and amyloid precursor protein coordinate control of transient Candida cerebritis with memory deficits Nat. Commun. 2019 10 58 10.1038/s41467-018-07991-4 30610193 409. Zhao H Bioluminescence imaging reveals inhibition of tumor cell proliferation by Alzheimer’s amyloid beta protein Cancer Cell Int 2009 9 15 10.1186/1475-2867-9-15 19480719 410. Paris D Inhibition of angiogenesis by Abeta peptides Angiogenesis 2004 7 75 85 10.1023/B:AGEN.0000037335.17717.bf 15302999 411. Paris D Impaired orthotopic glioma growth and vascularization in transgenic mouse models of Alzheimer’s disease J. Neurosci. 2010 30 11251 11258 10.1523/JNEUROSCI.2586-10.2010 20739545 412. Ohyagi Y Intracellular Abeta42 activates p53 promoter: a pathway to neurodegeneration in Alzheimer’s disease FASEB J. 2005 19 255 257 10.1096/fj.04-2637fje 15548589 413. Alves da Costa C Presenilin-dependent gamma-secretase-mediated control of p53-associated cell death in Alzheimer’s disease J. Neurosci. 2006 26 6377 6385 10.1523/JNEUROSCI.0651-06.2006 16763046 414. Yamamori H Tanaka T Kudo T Takeda M Amyloid-beta down-regulates XIAP expression in human SH-SY5Y neuroblastoma cells Neuroreport 2004 15 851 854 10.1097/00001756-200404090-00023 15073529 415. Chaudhary AK A potential role of X-linked inhibitor of apoptosis protein in mitochondrial membrane permeabilization and its implication in cancer therapy Drug Disco. Today 2016 21 38 47 10.1016/j.drudis.2015.07.014 416. Clementi ME Alzheimer’s amyloid beta-peptide (1–42) induces cell death in human neuroblastoma via bax/bcl-2 ratio increase: an intriguing role for methionine 35 Biochem Biophys. Res. Commun. 2006 342 206 213 10.1016/j.bbrc.2006.01.137 16472763 417. Liu Z Direct activation of Bax protein for cancer therapy Med Res Rev. 2016 36 313 341 10.1002/med.21379 26395559 418. Baruch-Suchodolsky R Fischer B Abeta40, either soluble or aggregated, is a remarkably potent antioxidant in cell-free oxidative systems Biochemistry 2009 48 4354 4370 10.1021/bi802361k 19320465 419. Faller P Copper and zinc binding to amyloid-beta: coordination, dynamics, aggregation, reactivity and metal-ion transfer Chembiochem 2009 10 2837 2845 10.1002/cbic.200900321 19877000 420. Smith DG Cappai R Barnham KJ The redox chemistry of the Alzheimer’s disease amyloid beta peptide Biochim. Biophys. Acta 2007 1768 1976 1990 10.1016/j.bbamem.2007.02.002 17433250 421. Zou K Gong JS Yanagisawa K Michikawa M A novel function of monomeric amyloid beta-protein serving as an antioxidant molecule against metal-induced oxidative damage J. Neurosci. 2002 22 4833 4841 10.1523/JNEUROSCI.22-12-04833.2002 12077180 422. Gibson GE Zhang H Sheu KR Park LC Differential alterations in antioxidant capacity in cells from Alzheimer patients Biochim Biophys. Acta 2000 1502 319 329 10.1016/S0925-4439(00)00057-0 11068175 423. Guo Q Increased vulnerability of hippocampal neurons from presenilin-1 mutant knock-in mice to amyloid beta-peptide toxicity: central roles of superoxide production and caspase activation J. Neurochem 1999 72 1019 1029 10.1046/j.1471-4159.1999.0721019.x 10037473 424. Wang L Current understanding of metal ions in the pathogenesis of Alzheimer’s disease Transl. Neurodegener. 2020 9 10 10.1186/s40035-020-00189-z 32266063 425. Eriksson PS Neurogenesis in the adult human hippocampus Nat. Med. 1998 4 1313 1317 10.1038/3305 9809557 426. Alvarez-Buylla A Garcia-Verdugo JM Neurogenesis in adult subventricular zone J. Neurosci. 2002 22 629 634 10.1523/JNEUROSCI.22-03-00629.2002 11826091 427. Babu H Ramirez-Rodriguez G Fabel K Bischofberger J Kempermann G Synaptic Network Activity Induces Neuronal Differentiation of Adult Hippocampal Precursor Cells through BDNF Signaling Front Neurosci. 2009 3 49 20582276 428. Jin K Increased hippocampal neurogenesis in Alzheimer’s disease Proc. Natl. Acad. Sci. USA 2004 101 343 347 10.1073/pnas.2634794100 14660786 429. Li B Failure of neuronal maturation in Alzheimer disease dentate gyrus J. Neuropathol. Exp. Neurol. 2008 67 78 84 10.1097/nen.0b013e318160c5db 18091557 430. Crews L Increased BMP6 levels in the brains of Alzheimer’s disease patients and APP transgenic mice are accompanied by impaired neurogenesis J. Neurosci. 2010 30 12252 12262 10.1523/JNEUROSCI.1305-10.2010 20844121 431. Tobin MK Human hippocampal neurogenesis persists in aged adults and Alzheimer’s disease patients Cell Stem Cell 2019 24 974 982 10.1016/j.stem.2019.05.003 31130513 432. Lopez-Toledano MA Shelanski ML Neurogenic effect of beta-amyloid peptide in the development of neural stem cells J. Neurosci. 2004 24 5439 5444 10.1523/JNEUROSCI.0974-04.2004 15190117 433. Sotthibundhu A Li QX Thangnipon W Coulson EJ Abeta(1–42) stimulates adult SVZ neurogenesis through the p75 neurotrophin receptor Neurobiol. Aging 2009 30 1975 1985 10.1016/j.neurobiolaging.2008.02.004 18374455 434. Atwood CS Bishop GM Perry G Smith MA Amyloid-beta: a vascular sealant that protects against hemorrhage? J. Neurosci. Res. 2002 70 356 10.1002/jnr.10388 12391596 435. Atwood CS Dramatic aggregation of Alzheimer abeta by Cu(II) is induced by conditions representing physiological acidosis J. Biol. Chem. 1998 273 12817 12826 10.1074/jbc.273.21.12817 9582309 436. Roberts GW Beta amyloid protein deposition in the brain after severe head injury: implications for the pathogenesis of Alzheimer’s disease J. Neurol. Neurosurg. Psychiatry 1994 57 419 425 10.1136/jnnp.57.4.419 8163989 437. Castro MA Verteporfin is a substrate-selective gamma-secretase inhibitor that binds the amyloid precursor protein transmembrane domain J. Biol. Chem. 2022 298 101792 10.1016/j.jbc.2022.101792 35247387 438. Liu F Cleavage of potassium channel Kv2.1 by BACE2 reduces neuronal apoptosis Mol. Psychiatry 2018 23 1542 1554 10.1038/s41380-018-0060-2 29703946 439. Turner RT 3rd Hong L Koelsch G Ghosh AK Tang J Structural locations and functional roles of new subsites S5, S6, and S7 in memapsin 2 (beta-secretase) Biochemistry 2005 44 105 112 10.1021/bi048106k 15628850 440. Sun XY Fc effector of anti-Abeta antibody induces synapse loss and cognitive deficits in Alzheimer’s disease-like mouse model Signal Transduct. Target Ther. 2023 8 30 10.1038/s41392-022-01273-8 36693826 441. Bekris LM Yu CE Bird TD Tsuang DW Genetics of Alzheimer disease J. Geriatr. Psychiatry Neurol. 2010 23 213 227 10.1177/0891988710383571 21045163 442. Daviglus ML National Institutes of Health State-of-the-Science Conference statement: preventing alzheimer disease and cognitive decline Ann. Intern Med 2010 153 176 181 10.7326/0003-4819-153-3-201008030-00260 20547888 443. Chen ZY Zhang Y Animal models of Alzheimer’s disease: Applications, evaluation, and perspectives Zool. Res 2022 43 1026 1040 10.24272/j.issn.2095-8137.2022.289 36317468 444. Drummond E Wisniewski T Alzheimer’s disease: experimental models and reality Acta Neuropathol. 2017 133 155 175 10.1007/s00401-016-1662-x 28025715 445. Hsiao K Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice Science 1996 274 99 102 10.1126/science.274.5284.99 8810256 446. Davis J Early-onset and robust cerebral microvascular accumulation of amyloid beta-protein in transgenic mice expressing low levels of a vasculotropic Dutch/Iowa mutant form of amyloid beta-protein precursor J. Biol. Chem. 2004 279 20296 20306 10.1074/jbc.M312946200 14985348 447. Sturchler-Pierrat C Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology Proc. Natl. Acad. Sci. USA 1997 94 13287 13292 10.1073/pnas.94.24.13287 9371838 448. Mucke L High-level neuronal expression of abeta 1–42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation J. Neurosci. 2000 20 4050 4058 10.1523/JNEUROSCI.20-11-04050.2000 10818140 449. Chishti MA Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695 J. Biol. Chem. 2001 276 21562 21570 10.1074/jbc.M100710200 11279122 450. Schneider I Mutant presenilins disturb neuronal calcium homeostasis in the brain of transgenic mice, decreasing the threshold for excitotoxicity and facilitating long-term potentiation J. Biol. Chem. 2001 276 11539 11544 10.1074/jbc.M010977200 11278803 451. Duff K Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1 Nature 1996 383 710 713 10.1038/383710a0 8878479 452. Levy-Lahad E Candidate gene for the chromosome 1 familial Alzheimer’s disease locus Science 1995 269 973 977 10.1126/science.7638622 7638622 453. Rogaev EI Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene Nature 1995 376 775 778 10.1038/376775a0 7651536 454. Saito T Potent amyloidogenicity and pathogenicity of Abeta43 Nat. Neurosci. 2011 14 1023 1032 10.1038/nn.2858 21725313 455. Radde R Abeta42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology EMBO Rep. 2006 7 940 946 10.1038/sj.embor.7400784 16906128 456. Jankowsky JL Co-expression of multiple transgenes in mouse CNS: a comparison of strategies Biomol. Eng. 2001 17 157 165 10.1016/S1389-0344(01)00067-3 11337275 457. Jankowsky JL Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase Hum. Mol. Genet 2004 13 159 170 10.1093/hmg/ddh019 14645205 458. Qing H Valproic acid inhibits Abeta production, neuritic plaque formation, and behavioral deficits in Alzheimer’s disease mouse models J. Exp. Med 2008 205 2781 2789 10.1084/jem.20081588 18955571 459. Zhang S Upregulation of MIF as a defense mechanism and a biomarker of Alzheimer’s disease Alzheimers Res. Ther. 2019 11 54 10.1186/s13195-019-0508-x 31174614 460. Oakley H Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation J. Neurosci. 2006 26 10129 10140 10.1523/JNEUROSCI.1202-06.2006 17021169 461. Willuweit A Early-onset and robust amyloid pathology in a new homozygous mouse model of Alzheimer’s disease PLoS One 2009 4 e7931 10.1371/journal.pone.0007931 19936202 462. D’Souza I Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements Proc. Natl. Acad. Sci. USA 1999 96 5598 5603 10.1073/pnas.96.10.5598 10318930 463. Jackson RJ Human tau increases amyloid beta plaque size but not amyloid beta-mediated synapse loss in a novel mouse model of Alzheimer’s disease Eur. J. Neurosci. 2016 44 3056 3066 10.1111/ejn.13442 27748574 464. Stover KR Campbell MA Van Winssen CM Brown RE Early detection of cognitive deficits in the 3xTg-AD mouse model of Alzheimer’s disease Behav. Brain Res 2015 289 29 38 10.1016/j.bbr.2015.04.012 25896362 465. Platt B Abnormal cognition, sleep, EEG and brain metabolism in a novel knock-in Alzheimer mouse, PLB1 PLoS One 2011 6 e27068 10.1371/journal.pone.0027068 22096518 466. Serneels L Modeling the beta-secretase cleavage site and humanizing amyloid-beta precursor protein in rat and mouse to study Alzheimer’s disease Mol. Neurodegener. 2020 15 60 10.1186/s13024-020-00399-z 33076948 467. Zheng H beta-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity Cell 1995 81 525 531 10.1016/0092-8674(95)90073-X 7758106 468. Saito T Single App knock-in mouse models of Alzheimer’s disease Nat. Neurosci. 2014 17 661 663 10.1038/nn.3697 24728269 469. Saito T Humanization of the entire murine Mapt gene provides a murine model of pathological human tau propagation J. Biol. Chem. 2019 294 12754 12765 10.1074/jbc.RA119.009487 31273083 470. Hashimoto S Tau binding protein CAPON induces tau aggregation and neurodegeneration Nat. Commun. 2019 10 2394 10.1038/s41467-019-10278-x 31160584 471. Sims-Robinson C Kim B Rosko A Feldman EL How does diabetes accelerate Alzheimer disease pathology? Nat. Rev. Neurol. 2010 6 551 559 10.1038/nrneurol.2010.130 20842183 472. Justice NJ Posttraumatic stress disorder-like induction elevates beta-amyloid levels, which directly activates corticotropin-releasing factor neurons to exacerbate stress responses J. Neurosci. 2015 35 2612 2623 10.1523/JNEUROSCI.3333-14.2015 25673853 473. Migliore L Coppede F Gene-environment interactions in Alzheimer disease: the emerging role of epigenetics Nat. Rev. Neurol 2022 18 643 660 10.1038/s41582-022-00714-w 36180553 474. Jevtic S Sengar AS Salter MW McLaurin J The role of the immune system in Alzheimer disease: Etiology and treatment Ageing Res Rev. 2017 40 84 94 10.1016/j.arr.2017.08.005 28941639 475. Mestas J Hughes CC Of mice and not men: differences between mouse and human immunology J. Immunol. 2004 172 2731 2738 10.4049/jimmunol.172.5.2731 14978070 476. Franco R Cedazo-Minguez A Successful therapies for Alzheimer’s disease: why so many in animal models and none in humans? Front Pharm. 2014 5 146 10.3389/fphar.2014.00146 477. Benzinger TL Regional variability of imaging biomarkers in autosomal dominant Alzheimer’s disease Proc. Natl. Acad. Sci. USA 2013 110 E4502 E4509 10.1073/pnas.1317918110 24194552 478. McDade E Longitudinal cognitive and biomarker changes in dominantly inherited Alzheimer disease Neurology 2018 91 e1295 e1306 10.1212/WNL.0000000000006277 30217935 479. Dale J Alcorn N Capell H Madhok R Combination therapy for rheumatoid arthritis: methotrexate and sulfasalazine together or with other DMARDs Nat. Clin. Pr. Rheumatol. 2007 3 450 458 10.1038/ncprheum0562 480. Bartlett JA An updated systematic overview of triple combination therapy in antiretroviral-naive HIV-infected adults AIDS 2006 20 2051 2064 10.1097/01.aids.0000247578.08449.ff 17053351 481. Spuch C Ortolano S Navarro C New insights in the amyloid-Beta interaction with mitochondria J. Aging Res 2012 2012 324968 10.1155/2012/324968 22523685 482. Wilkins HM Interactions between amyloid, amyloid precursor protein, and mitochondria Biochem Soc. Trans. 2023 51 173 182 10.1042/BST20220518 36688439 483. Fava A The effect of lipoic acid therapy on cognitive functioning in patients with Alzheimer’s disease J. Neurodegener. Dis. 2013 2013 454253 26316990 484. Sano M A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. The Alzheimer’s Disease Cooperative Study N. Engl. J. Med. 1997 336 1216 1222 10.1056/NEJM199704243361704 9110909 485. Dias-Santagata D Fulga TA Duttaroy A Feany MB Oxidative stress mediates tau-induced neurodegeneration in Drosophila J. Clin. Invest 2007 117 236 245 10.1172/JCI28769 17173140 486. Murakami K Vitamin C restores behavioral deficits and amyloid-beta oligomerization without affecting plaque formation in a mouse model of Alzheimer’s disease J. Alzheimers Dis. 2011 26 7 18 10.3233/JAD-2011-101971 21558647 487. Hira S beta-Carotene: A natural compound improves cognitive impairment and oxidative stress in a mouse model of streptozotocin-induced Alzheimer’s disease Biomolecules 2019 9 441 10.3390/biom9090441 31480727 488. Klyubin I Amyloid beta protein immunotherapy neutralizes Abeta oligomers that disrupt synaptic plasticity in vivo Nat. Med 2005 11 556 561 10.1038/nm1234 15834427 489. Peng L Bestard-Lorigados I Song W The synapse as a treatment avenue for Alzheimer’s Disease Mol. Psychiatry 2022 27 2940 2949 10.1038/s41380-022-01565-z 35444256 490. Sagare AP Bell RD Zlokovic BV Neurovascular dysfunction and faulty amyloid beta-peptide clearance in Alzheimer disease Cold Spring Harb. Perspect. Med 2012 2 a011452 10.1101/cshperspect.a011452 23028132 491. Drachman DA The amyloid hypothesis, time to move on: Amyloid is the downstream result, not cause, of Alzheimer’s disease Alzheimers Dement 2014 10 372 380 10.1016/j.jalz.2013.11.003 24589433 492. Herrup K The case for rejecting the amyloid cascade hypothesis Nat. Neurosci. 2015 18 794 799 10.1038/nn.4017 26007212 493. Cavieres VA Tetrahydrohyperforin inhibits the proteolytic processing of amyloid precursor protein and enhances its degradation by Atg5-dependent autophagy PLoS One 2015 10 e0136313 10.1371/journal.pone.0136313 26308941 494. Di Meco A Curtis ME Lauretti E Pratico D Autophagy dysfunction in Alzheimer’s disease: Mechanistic insights and new therapeutic opportunities Biol. Psychiatry 2020 87 797 807 10.1016/j.biopsych.2019.05.008 31262433 495. Nilsson P Abeta secretion and plaque formation depend on autophagy Cell Rep. 2013 5 61 69 10.1016/j.celrep.2013.08.042 24095740 496. Nilsson P Autophagy-related protein 7 deficiency in amyloid beta (Abeta) precursor protein transgenic mice decreases Abeta in the multivesicular bodies and induces Abeta accumulation in the Golgi Am. J. Pathol. 2015 185 305 313 10.1016/j.ajpath.2014.10.011 25433221 497. Mueller-Steiner S Antiamyloidogenic and neuroprotective functions of cathepsin B: implications for Alzheimer’s disease Neuron 2006 51 703 714 10.1016/j.neuron.2006.07.027 16982417 498. Nixon RA Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study J. Neuropathol. Exp. Neurol. 2005 64 113 122 10.1093/jnen/64.2.113 15751225 499. Luo R Activation of PPARA-mediated autophagy reduces Alzheimer disease-like pathology and cognitive decline in a murine model Autophagy 2020 16 52 69 10.1080/15548627.2019.1596488 30898012 500. Deng Z Dong Y Zhou X Lu JH Yue Z Pharmacological modulation of autophagy for Alzheimer’s disease therapy: Opportunities and obstacles Acta Pharm. Sin. B 2022 12 1688 1706 10.1016/j.apsb.2021.12.009 35847516 501. Hay N Sonenberg N Upstream and downstream of mTOR Genes Dev. 2004 18 1926 1945 10.1101/gad.1212704 15314020 502. Juenemann K Reits EA Alternative macroautophagic pathways Int J. Cell Biol. 2012 2012 189794 10.1155/2012/189794 22536246 503. Caccamo A Majumder S Richardson A Strong R Oddo S Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-beta, and Tau: effects on cognitive impairments J. Biol. Chem. 2010 285 13107 13120 10.1074/jbc.M110.100420 20178983 504. Majumder S Richardson A Strong R Oddo S Inducing autophagy by rapamycin before, but not after, the formation of plaques and tangles ameliorates cognitive deficits PLoS One 2011 6 e25416 10.1371/journal.pone.0025416 21980451 505. Liu J Wang S Zhang Y Fan HT Lin HS Traditional Chinese medicine and cancer: History, present situation, and development Thorac. Cancer 2015 6 561 569 10.1111/1759-7714.12270 26445604 506. Chen HY Lin YH Huang JW Chen YC Chinese herbal medicine network and core treatments for allergic skin diseases: Implications from a nationwide database J. Ethnopharmacol. 2015 168 260 267 10.1016/j.jep.2015.04.002 25865681 507. Xie W Zhao Y Zhang Y Traditional chinese medicines in treatment of patients with type 2 diabetes mellitus Evid. Based Complement Altern. Med 2011 2011 726723 10.1155/2011/726723 508. Huang K Traditional Chinese Medicine (TCM) in the treatment of COVID-19 and other viral infections: Efficacies and mechanisms Pharm. Ther. 2021 225 107843 10.1016/j.pharmthera.2021.107843 509. Durairajan SS Berberine ameliorates beta-amyloid pathology, gliosis, and cognitive impairment in an Alzheimer’s disease transgenic mouse model Neurobiol. Aging 2012 33 2903 2919 10.1016/j.neurobiolaging.2012.02.016 22459600 510. Wu Y Berberine reduces Abeta42 deposition and tau hyperphosphorylation via ameliorating endoplasmic reticulum stress Front Pharm. 2021 12 640758 10.3389/fphar.2021.640758 511. Zang C Gardenia jasminoides J.Ellis extract GJ-4 alleviated cognitive deficits of APP/PS1 transgenic mice Phytomedicine 2021 93 153780 10.1016/j.phymed.2021.153780 34607163 512. Zhang Z GJ-4 alleviates Abeta25-35-induced memory dysfunction in mice through protecting the neurovascular unit Biomed. Pharmacother. 2020 127 110131 10.1016/j.biopha.2020.110131 32325348 513. Li F Zhang Y Lu X Shi J Gong Q Icariin improves the cognitive function of APP/PS1 mice via suppressing endoplasmic reticulum stress Life Sci. 2019 234 116739 10.1016/j.lfs.2019.116739 31400352 514. Zhu T Long-term icariin treatment ameliorates cognitive deficits via CD4(+) T cell-mediated immuno-inflammatory responses in APP/PS1 mice Clin. Inter. Aging 2019 14 817 826 10.2147/CIA.S208068 515. Liu Q Characterization of a pectin from Lonicera japonica Thunb. and its inhibition effect on Abeta42 aggregation and promotion of neuritogenesis Int J. Biol. Macromol. 2018 107 112 120 10.1016/j.ijbiomac.2017.08.154 28863894 516. Wang P A glucan isolated from flowers of Lonicera japonica Thunb. inhibits aggregation and neurotoxicity of Abeta42 Carbohydr. Polym. 2014 110 142 147 10.1016/j.carbpol.2014.03.060 24906740 517. Chen K Morroniside prevents H2O2 or Abeta1-42-induced apoptosis via attenuating JNK and p38 MAPK phosphorylation Eur. J. Pharm. 2018 834 295 304 10.1016/j.ejphar.2018.07.047 518. Ji YJ Crude saponin from platycodon grandiflorum attenuates abeta-induced neurotoxicity via antioxidant, anti-inflammatory and anti-apoptotic signaling pathways Antioxid. (Basel) 2021 10 1968 10.3390/antiox10121968 519. Nam Y Platycodon grandiflorum root protects against abeta-induced cognitive dysfunction and pathology in female models of Alzheimer’s disease Antioxid. (Basel) 2021 10 1968 520. Marambaud P Zhao H Davies P Resveratrol promotes clearance of Alzheimer’s disease amyloid-beta peptides J. Biol. Chem. 2005 280 37377 37382 10.1074/jbc.M508246200 16162502 521. El-Sayed NS Bayan Y Possible role of resveratrol targeting estradiol and neprilysin pathways in lipopolysaccharide model of Alzheimer disease Adv. Exp. Med Biol. 2015 822 107 118 10.1007/978-3-319-08927-0_12 25416980 522. Bermejo-Bescos P Jimenez-Aliaga KL Benedi J Martin-Aragon S A diet containing rutin ameliorates brain intracellular redox homeostasis in a mouse model of Alzheimer’s disease Int J. Mol. Sci. 2023 24 4863 10.3390/ijms24054863 36902309 523. Pan RY Sodium rutin ameliorates Alzheimer’s disease-like pathology by enhancing microglial amyloid-beta clearance Sci. Adv. 2019 5 eaau6328 10.1126/sciadv.aau6328 30820451 524. Sun XY Rutin prevents tau pathology and neuroinflammation in a mouse model of Alzheimer’s disease J. Neuroinflammation 2021 18 131 10.1186/s12974-021-02182-3 34116706 525. Ding B Tanshinone IIA attenuates neuroinflammation via inhibiting RAGE/NF-kappaB signaling pathway in vivo and in vitro J. Neuroinflammation 2020 17 302 10.1186/s12974-020-01981-4 33054814 526. He Y Tanshinone IIA ameliorates cognitive deficits by inhibiting endoplasmic reticulum stress-induced apoptosis in APP/PS1 transgenic mice Neurochem Int 2020 133 104610 10.1016/j.neuint.2019.104610 31778727 527. Xu P Neuroprotection of triptolide against amyloid-Beta1-42-induced toxicity via the Akt/mTOR/p70S6K-mediated autophagy pathway Acad. Bras. Cienc. 2022 94 e20210938 10.1590/0001-3765202220210938 528. Lancaster MA Cerebral organoids model human brain development and microcephaly Nature 2013 501 373 379 10.1038/nature12517 23995685 529. Chan WK Griffiths R Price DJ Mason JO Cerebral organoids as tools to identify the developmental roots of autism Mol. Autism 2020 11 58 10.1186/s13229-020-00360-3 32660622 530. Smits LM Modeling Parkinson’s disease in midbrain-like organoids NPJ Parkinsons Dis. 2019 5 5 10.1038/s41531-019-0078-4 30963107 531. Pavoni S Small-molecule induction of Abeta-42 peptide production in human cerebral organoids to model Alzheimer’s disease associated phenotypes PLoS One 2018 13 e0209150 10.1371/journal.pone.0209150 30557391 532. Gonzalez C Modeling amyloid beta and tau pathology in human cerebral organoids Mol. Psychiatry 2018 23 2363 2374 10.1038/s41380-018-0229-8 30171212 533. Raja WK Self-organizing 3D human neural tissue derived from induced pluripotent stem cells recapitulate Alzheimer’s disease phenotypes PLoS One 2016 11 e0161969 10.1371/journal.pone.0161969 27622770 534. Lin YT APOE4 causes widespread molecular and cellular alterations associated with Alzheimer’s disease phenotypes in human iPSC-derived brain cell types Neuron 2018 98 1141 1154.e1147 10.1016/j.neuron.2018.05.008 29861287 535. Cazzaniga A Fedele G Castiglioni S Maier JA The presence of blood-brain barrier modulates the response to magnesium salts in human brain organoids Int J. Mol. Sci. 2022 23 5133 10.3390/ijms23095133 35563524 536. Dong X Human cerebral organoids establish subcortical projections in the mouse brain after transplantation Mol. Psychiatry 2021 26 2964 2976 10.1038/s41380-020-00910-4 33051604 537. Pham MT Generation of human vascularized brain organoids Neuroreport 2018 29 588 593 10.1097/WNR.0000000000001014 29570159 538. Cakir B Engineering of human brain organoids with a functional vascular-like system Nat. Methods 2019 16 1169 1175 10.1038/s41592-019-0586-5 31591580 539. Cummings J The role of biomarkers in Alzheimer’s disease drug development Adv. Exp. Med Biol. 2019 1118 29 61 10.1007/978-3-030-05542-4_2 30747416 540. Park JC Han SH Mook-Jung I Peripheral inflammatory biomarkers in Alzheimer’s disease: a brief review BMB Rep. 2020 53 10 19 10.5483/BMBRep.2020.53.1.309 31865964 541. Colom-Cadena M The clinical promise of biomarkers of synapse damage or loss in Alzheimer’s disease Alzheimers Res Ther. 2020 12 21 10.1186/s13195-020-00588-4 32122400 542. Kubis-Kubiak A Dyba A Piwowar A The interplay between diabetes and alzheimer’s disease-in the hunt for biomarkers Int J. Mol. Sci. 2020 21 2744 10.3390/ijms21082744 32326589 543. Ahmed Z Accelerated lipofuscinosis and ubiquitination in granulin knockout mice suggest a role for progranulin in successful aging Am. J. Pathol. 2010 177 311 324 10.2353/ajpath.2010.090915 20522652 544. Suarez-Calvet M CSF progranulin increases in the course of Alzheimer’s disease and is associated with sTREM2, neurodegeneration and cognitive decline EMBO Mol. Med 2018 10 e9712 10.15252/emmm.201809712 30482868 545. Guadano-Ferraz A Vinuela A Oeding G Bernal J Rausell E RC3/neurogranin is expressed in pyramidal neurons of motor and somatosensory cortex in normal and denervated monkeys J. Comp. Neurol. 2005 493 554 570 10.1002/cne.20774 16304627 546. Zhong L Gerges NZ Neurogranin and synaptic plasticity balance Commun. Integr. Biol. 2010 3 340 342 10.4161/cib.3.4.11763 20798820 547. Portelius E Cerebrospinal fluid neurogranin: relation to cognition and neurodegeneration in Alzheimer’s disease Brain 2015 138 3373 3385 10.1093/brain/awv267 26373605 548. Kester MI Neurogranin as a cerebrospinal fluid biomarker for synaptic loss in symptomatic Alzheimer disease JAMA Neurol. 2015 72 1275 1280 10.1001/jamaneurol.2015.1867 26366630 549. Goetzl EJ Decreased synaptic proteins in neuronal exosomes of frontotemporal dementia and Alzheimer’s disease FASEB J. 2016 30 4141 4148 10.1096/fj.201600816R 27601437 550. Wellington H Increased CSF neurogranin concentration is specific to Alzheimer disease Neurology 2016 86 829 835 10.1212/WNL.0000000000002423 26826204 551. Dehghani R Rahmani F Rezaei N MicroRNA in Alzheimer’s disease revisited: implications for major neuropathological mechanisms Rev. Neurosci. 2018 29 161 182 10.1515/revneuro-2017-0042 28941357 552. Xia X Exosomal miRNAs in central nervous system diseases: biomarkers, pathological mediators, protective factors and therapeutic agents Prog. Neurobiol. 2019 183 101694 10.1016/j.pneurobio.2019.101694 31542363 553. Tsai Y Ocular changes in TgF344-AD rat model of Alzheimer’s disease Invest Ophthalmol. Vis. Sci. 2014 55 523 534 10.1167/iovs.13-12888 24398104 554. Chang LY Alzheimer’s disease in the human eye. Clinical tests that identify ocular and visual information processing deficit as biomarkers Alzheimers Dement 2014 10 251 261 10.1016/j.jalz.2013.06.004 24011928 555. Frost S Retinal vascular biomarkers for early detection and monitoring of Alzheimer’s disease Transl. Psychiatry 2013 3 e233 10.1038/tp.2012.150 23443359 556. Chan CK Depressive symptoms and CSF Alzheimer’s disease biomarkers in relation to clinical symptom onset of mild cognitive impairment Alzheimers Dement (Amst.) 2020 12 e12106 33005725