One of the most common Alzheimer’s Disease Related Dementias (ADRD) is Lewy body dementia. This umbrella term comprises two clinically distinct ADRDs: Parkinson’s disease dementia (PD-dementia) and dementia with Lewy bodies (DLB). There has been a growing interest in the genetic bases of DLB, however, PD-dementia has not yet been studied using large-scale genetic analyses. Nevertheless, it has been shown that dysfunction of the endolysosomal pathway plays a key role in Alzheimer’s disease and ADRDs. This involvement, however, is not fully understood and the exact failure points for each disease have yet to be identified. This application aims to identify genetic variability that modulates risk for PD-dementia and its neuropathological features, determining the overlap with other ADRDs and the immediate downstream effects on endolysosomal function. The hypothesis, based on preliminary data, is that PD-dementia has a measurable and unique genetic architecture and that its integration with current knowledge of the molecular bases of other ADRDs, will improve the understanding of the lysosome as a central pathological hub in neurodegenerative diseases.

This hypothesis will be tested by pursuing three specific aims: 1) identify candidate risk-modulating variants for PD-dementia; 2) determine neuropathological correlates of genetic risk; and 3) identify downstream effects of high-risk variability in neurons and glial cells across ADRDs. One cohort of clinically diagnosed PD- dementia cases and one cohort of neuropathological diagnosed cases will be tested under a GWAS framework to identify risk modulating variants in a two-stage study.

The proposed research focuses for the first time on PD-dementia cases, as a strict diagnosis, taking advantage of large-scale unbiased genetic analyses and integrating that with related disorders. The proposed research is significant because it will provide a composite genetic profile specific for this Lewy body dementia. The proposed study design has the potential to identify targets that are common to different forms of ADRDs, as well as novel, personalized, disease-specific targets; this proposal is a direct response to the National Alzheimer’s Project Act (NAPA) Public Law 111-375, NAPA 2012 2013, and NAPA 2016.

Jose Bras
Van Andel Research Institute

This study was funded by 1R56AG070857-01.

Acknowledgment statement for any data distributed by NIAGADS:

Data for this study were prepared, archived, and distributed by the National Institute on Aging Alzheimer's Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24-AG041689), funded by the National Institute on Aging.

For investigators using Dementia in Parkinson's Disease data:

The American cohort of samples for this project was collected by Dr. Cyrus Zabetian and Dora Yearout at VA Puget Sound. The Portuguese cohort was collected by Dr. Ana Morgadinho. Drs. Rita Guerreiro and Jose Bras as well as Kimberly Paquette, Kaitlyn Westra, and Andrew Pyman were involved in preparing the data. This work was supported by grant funding from NIH R56 AG070857. The author(s) thank the Van Andel Institute Genomics Core (RRID:SCR_022913) (Grand Rapids, MI) for providing whole-genome genotyping facilities and services.