
==== Front
medRxiv
MEDRXIV
medRxiv
Cold Spring Harbor Laboratory

10.1101/2024.09.11.24313493
preprint
1
Article
Proteogenomic signature of risk of Alzheimer’s disease and related dementia risk in individuals with a history of major depression disorder
Diniz Breno Satler
Chen Zhiduo
Steffens David C.
Pilling Luke http://orcid.org/0000-0002-3332-8454

Fortinsky Richard H.
Kuchel George A.
Kuo Chia-Ling
12 9 2024
2024.09.11.24313493https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://medrxiv.org/lookup/doi/10.1101/2024.09.11.24313493
nihpp-2024.09.11.24313493.pdf
Abstract

The mechanisms linking a history of major depressive disorder (MDD) to an increased risk of Alzheimer’s disease and related dementia (ADRD) are not fully understood. Using the UK Biobank available proteomic and genomic data, we evaluated the biological mechanisms linking both conditions. In participants with a history of MDD at baseline (n=3,615), we found that plasma levels of NfL, GFAP, PSG1 were associated with higher risk (HR=1.38; 1.37; 1.34, respectively; all adjusted p-values<0.05), while VGF, GET3, and HPGDS were associated with lower risk of incident ADRD (n=150) (HR=0.73; 0.71; 0.66, respectively; all adjusted p-values<0.05) during a mean follow-up of 13.7 years (SD=2.2). Two-sample Mendelian randomization analysis using cis-pQTLs genetic instruments revealed that a lower protein expression of apolipoprotein E and higher IL-10 receptor subunit B were causally linked to incident ADRD. Finally, we developed a Proteomic Risk Score (PrRS MDD-ADRD ), which showed strong discriminative power (C-statistic = 0.84) to identify participants with MDD that developed ADRD upon follow-up. In addition to demonstrating an association between plasma proteins associated with inflammation and future ADRD risk in individuals with MDD, our findings include an element of causality using Mendelian Randomization (MR) and PrRS MDD-ADRD can be useful to identify individuals with the highest risk to develop ADRD in a highly vulnerable population.
==== Body
pmc
