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The Role of Dopamine in Cognitive Resilience to Alzheimer's Disease Pathology in Healthy Older Adults

Award Number: F31AG079515
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 05/16/2023
PERIOD OF PERFORMANCE END DATE: 08/15/2024

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The Role of Dopamine in Cognitive Resilience to Alzheimer's Disease Pathology in Healthy Older Adults - PROJECT SUMMARY Alzheimer’s disease (AD) is characterized by β-amyloid and tau neuropathology, which are linked to disruptions in memory performance. Advances in human neuroimaging approaches that quantify pathology in vivo have revealed a promising target for AD therapeutics known as cognitive reserve, which is the capacity for some individuals to have better-than-expected cognition given their level of pathology. Our proposed research examines the role of brain dopamine in maintaining optimal cognitive function and youth-like patterns of brain activity despite pathology. Successful maintenance of dopamine function in aging may protect against pathology- related alterations in cognition as dopamine inputs directly into the hippocampus and supports optimal memory performance. The functional impact of hippocampal AD-related pathology can be assessed in humans using emerging fMRI analysis methods that measure local functional connectivity (i.e. regional homogeneity). This is a sensitive predictor of memory performance and pathology burden in rodent models and humans and is gaining traction as a functional neuroimaging biomarker. Local functional connectivity is also affected by neuromodulator systems like dopamine, which may support compensatory changes in aging and could have applications for AD. The extent to which AD-related pathology accumulation in aging interacts with dopamine neuromodulator functions to affect local functional connectivity and memory is not known. The proposed research will fill this gap by assessing, within an older adult sample, relationships among memory, positron emission tomography (PET) measured AD-related pathology (tau) and dopamine synthesis capacity, and local functional connectivity in AD-vulnerable regions. Connectivity will be measured with resting-state fMRI, and memory will be measured with standard neuropsychological assessment. The proposed research will examine interactions between dopamine synthesis capacity and tau pathology to test the hypothesis that elevated dopamine synthesis capacity counteracts effects of pathology on memory and local functional connectivity, thus representing a cognitive reserve mechanism. Aim 1 will establish age and tau pathology effects on local functional connectivity in AD-vulnerable regions. Aim 2 will investigate interactive effects of dopamine synthesis capacity and AD pathology on local functional connectivity and memory in older adults. This proposal uniquely integrates AD-relevant research and dopamine mechanisms in human subjects and may support AD treatment efforts. Completion of this research will achieve the applicant’s training goals including training in (1) multi-modal neuroimaging, (2) memory systems in aging, (3) statistics (4) scientific communication, and (5) mentorship. Brandeis University, Boston College, and Massachusetts General Hospital provide exceptional faculty and neuroimaging facilities. Dr. Anne Berry (sponsor) and Dr. Elizabeth Kensinger (co-sponsor) are experienced mentors and specialize in cognitive aging, fMRI, PET, and memory systems. The proposed project and training will successfully advance the applicant’s qualifications for successful pursuit of a career in aging and AD, dopamine, and memory systems.


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 = -$26,082 )
2025	2024	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Aging Research	001	2	6/25/2025	NON-COMPETING CONTINUATION	-$2,539
2025	2024	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Aging Research	000	2	3/13/2025	NON-COMPETING CONTINUATION	-$23,543
														Subtotal = -$26,082

Issue Date FY: 2024 ( Subtotal = $35,211 )
2024	2024	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Aging Research	000	2	6/11/2024	NON-COMPETING CONTINUATION	$35,211
														Subtotal = $35,211

Issue Date FY: 2023 ( Subtotal = $33,846 )
2023	2023	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Aging Research	001	1	5/3/2023	NEW	$0
2023	2023	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Aging Research	000	1	5/3/2023	NEW	$33,846
														Subtotal = $33,846

Grand Total All Awards = $42,975

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The Role of Dopamine in Cognitive Resilience to Alzheimer's Disease Pathology in Healthy Older Adults

Award Number: F31AG079515

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 05/16/2023

PERIOD OF PERFORMANCE END DATE: 08/15/2024

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