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Genetic and molecular correlates of white matter pathology in Alzheimers disease

Award Number: R01AG069912
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Genetic and molecular correlates of white matter pathology in Alzheimers disease - PROJECT SUMMARY: Although Alzheimer's disease (AD) is typically defined by the accumulation of beta- amyloid and hyperphosphorylated tau proteins, synaptic loss and neuronal degeneration, the disease is not restricted to the gray matter. Neuroimaging and neuropathological studies have documented a significant loss of white matter in AD, which begins early in the disease course and is correlated with cognitive decline. In addition to contributions of hypoperfusion-related ischemic injury and neurodegeneration-associated axonal loss, emerging evidence indicates a decline and dysfunction of oligodendrocyte populations as additional factors in this multifactorial white matter disease process. Oligodendrocytes are the most abundant glial cell type in the brain, but are the least studied cell population in the context of neurodegeneration despite their vital role for myelin maintenance and neuronal support. With the increasing recognition of the role of myelin in AD, it becomes important to understand the genetic and molecular factors that link oligodendrocytes to the AD process. Our knowledge about genetic variants contributing to overall AD risk and influencing AD-associated endophenotypes is accelerating. Our proposal is designed to bring these two lines of investigation together and begin to explore genetic modifiers of oligodendrocyte and myelin abnormalities in AD and underlying molecular mechanisms using a quantitative trait approach of neuropathologically defined myelin endophenotypes. The central hypothesis of our proposal is that loss of myelin integrity and oligodendrocyte dysfunction in AD are associated with genetic variants and molecular changes. We will test this hypothesis by first performing genome-wide association studies (GWAS) of white and gray matter neuropathological endophenotypes in human postmortem brain tissue samples and will then conduct bulk and spatially defined gene expression studies to explore underlying molecular mechanisms. Our experiments are divided into two specific aims: Aim 1) To determine genetic modifiers of myelin and oligodendrocyte pathologies in AD. Aim 2) To determine associations between white matter gene expression changes and white matter pathologies in AD. The above aims benefit from the tight integration and leveraging of a diverse group of investigators with expertise in the neuropathology of AD and digitally quantified pathology endophenotypes (PI Kofler), AD- associated oligodendrocyte pathology (Co-I Herrup), GWAS data analysis (Co-Is Kamboh and Fan), biostatistical analysis of transcriptomics datasets (Co-I Ding) and digital image analysis and machine learning (Co-I Pearce). Upon completion of our proposed studies, we will have identified novel candidate genes as mediators of myelin pathology in AD, increased our understanding about the biology underlying their linkage to AD and revealed novel targets for therapeutic interventions. As our study design includes separate analyses of gray and white matter regions and stratification by sex, we will have further delineated regional and sex- specific differences in myelin and oligodendrocyte pathobiology in the context of AD.


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: 2025 ( Subtotal = $424,922 )
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Aging Research	001	5	1/14/2025	NON-COMPETING CONTINUATION	$0
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Aging Research	000	5	12/5/2024	NON-COMPETING CONTINUATION	$424,922
														Subtotal = $424,922

Issue Date FY: 2024 ( Subtotal = $607,284 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Aging Research	000	4	12/29/2023	NON-COMPETING CONTINUATION	$546,557
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Aging Research	001	4	5/31/2024	NON-COMPETING CONTINUATION	$60,727
														Subtotal = $607,284

Issue Date FY: 2023 ( Subtotal = $607,284 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Aging Research	000	3	1/5/2023	NON-COMPETING CONTINUATION	$607,284
														Subtotal = $607,284

Issue Date FY: 2022 ( Subtotal = $617,529 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Aging Research	001	2	4/26/2022	NON-COMPETING CONTINUATION	$61,753
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Aging Research	000	2	12/10/2021	NON-COMPETING CONTINUATION	$555,776
														Subtotal = $617,529

Issue Date FY: 2021 ( Subtotal = $521,155 )
2021	2021	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Aging Research	000	1	12/23/2020	NEW	$521,155
														Subtotal = $521,155

Grand Total All Awards = $2,778,174

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Genetic and molecular correlates of white matter pathology in Alzheimers disease

Award Number: R01AG069912

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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