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Role of the endolysosomal pathway in Lewy body dementia - from population genomics to single cells

Award Number: R56AG070857
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2023

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Role of the endolysosomal pathway in Lewy body dementia - from population genomics to single cells - PROJECT SUMMARY/ABSTRACT 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. Thus, there is a gap in knowledge regarding the specific molecular mechanisms underlying each disease. 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 neuropathological cases will also undergo whole- genome sequencing to identify common and rare genetic variability, allowing for the first genomics study with gold-standard characterization of neuropathology in a large cohort of PD-dementia cases. Last, the immediate cell-specific effects of disease-specific risk profile will be determined by performing single-cell RNA-seq in brain tissue from individuals with the highest polygenic risk for each of these two ADRDs and for AD. 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = -$665,133 )
2024	2021	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Aging Research	000	1	2/8/2024	NEW	-$665,133
														Subtotal = -$665,133

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Aging Research	000	1	12/6/2022	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Aging Research	000	1	6/25/2022	NEW	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $949,468 )
2021	2021	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Aging Research	000	1	6/22/2021	NEW	$949,468
														Subtotal = $949,468

Grand Total All Awards = $284,335

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Role of the endolysosomal pathway in Lewy body dementia - from population genomics to single cells

Award Number: R56AG070857

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2023

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