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medRxiv
MEDRXIV
medRxiv
Cold Spring Harbor Laboratory

10.1101/2024.08.30.24312864
preprint
1
Article
Clinicopathological Heterogeneity of Lewy Body Diseases: The Profound Influence of Comorbid Alzheimer’s Disease
Beach Thomas G.
Serrano Geidy E. http://orcid.org/0000-0002-9527-2011

Zhang Nan
Driver-Dunckley Erika D.
Sue Lucia I.
Shill Holly A.
Mehta Shyamal H.
Belden Christine
Tremblay Cecilia
Choudhury Parichita
Atri Alireza
Adler Charles H.
04 9 2024
2024.08.30.24312864https://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/10.1101/2024.08.30.24312864
nihpp-2024.08.30.24312864.pdf
ABSTRACT

In recent years, proposals have been advanced to redefine or reclassify Lewy body disorders by merging the long-established entities of Parkinson’s disease (PD), Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB). These proposals reject the International DLB Consortium classification system that has evolved over three decades of consensus collaborations between neurologists, neuropsychologists and neuropathologists. While the Consortium’s “one year rule” for separating PD and DLB has been criticized as arbitrary, it has been a pragmatic and effective tool for splitting the continuum between the two entities. In addition to the decades of literature supporting the non-homogeneity of PD and DLB, it has become increasingly apparent that Lewy body disorders may fundamentally differ in their etiology. Most PD subjects, as well as most clinically-presenting DLB subjects, might best be classified as having a “primary synucleinopathy” while most clinically-unidentified DLB subjects, who also have concurrent neuropathology-criteria AD (AD/DLB), as well as those with neuropathological AD and amygdala-predominant LBD insufficient for a DLB diagnosis, may best be classified as having a “secondary synucleinopathy. Importantly, the DLB Consortium recognized the importance of comorbid AD pathology by defining “Low”, “Intermediate” and “High” subdivisions of DLB based on the relative brain stages of both Lewy body and AD pathology. If the one-year rule for separating PD from DLB, and for then dividing DLB into subtypes based on the presence and severity of comorbid AD pathology, is effective, then the divided groups should statistically differ in important ways. In this study we used the comprehensive clinicopathological database of the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) to empirically test this hypothesis. Furthermore, we used multivariable statistical models to test the hypothesis that comorbid AD neuropathology is a major predictor of the presence and severity of postmortem Lewy synucleinopathy. The results confirm the clinicopathological heterogeneity of Lewy body disorders as well as the profound influence of comorbid AD pathology.
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