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Neural Correlates of Apathy Across the Alzheimer's Disease Continuum

Award Number: R01AG067021
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2020
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Neural Correlates of Apathy Across the Alzheimer's Disease Continuum - Project Summary Apathy is one of the earliest and most clinically distressing neuropsychiatric symptoms (NPS) in Alzheimer’s disease (AD), whose neurobiology across the AD clinical spectrum is poorly understood. Although apathy can be reliably measured by several validated scales and has been associated with clinical progression of AD, there are currently few effective interventions for apathy or biomarkers of treatment response. Recently, the ‘mild behavioral impairment (MBI)’ construct has been proposed to capture emergent, prominent NPS that may be among the earliest presentation of underlying AD pathology in non-demented older adults, preceding or coincident with cognitive impairment. MBI consists of 5 domains including a “decreased motivation, interest, and drive” domain, capturing the reward circuitry and positive valence disturbance of apathy. Despite the clinical relevance of apathy, a major research question is whether the disturbances in brain circuits underlying apathy are shared with or different than those underlying cognitive and functional impairment in AD, and whether these mechanisms vary through the behavioral and cognitive spectrum of AD. In the current project, we will visualize the in vivo regional distribution of tau and amyloid and structural and functional brain circuits (network connectivity and white matter abnormalities) to determine whether altered baseline brain circuits and concurrent AD pathology predict baseline severity and future worsening of apathy across individuals with the “full dimensionality of neurobehavioral functioning” (RFA-MH-19-510): 1) Cognitively normal (CN) older adults, 2) amnestic mild cognitive impairment (MCI), 3) MBI-decreased motivation domain, and 4) mild AD dementia. Attaining a better understanding of these neural mechanisms across early-stage AD is crucial for developing new treatment strategies and biomarkers for clinical trials. Our preliminary work investigating brain-behavior relations of apathy in AD has revealed evidence of early inferior temporal and parietal involvement and later frontal-subcortical circuit alterations. Our experience with flortaucipir positron emission tomography suggests that in preclinical AD, tau has an inferior temporal predilection where it is also associated with depressive symptoms, while in MCI and AD dementia, there is wider spread, including to frontal regions that are associated with apathy. We therefore hypothesize that as AD pathology spreads and fronto-parietal circuits are disrupted, apathy will emerge and worsen. We will assess the relationships among baseline measures of functional and structural brain circuits using Connectome sequences, concomitant in vivo regional tau and amyloid pathology, and baseline and longitudinal apathy over 3 years in 200 participants (50 CN, 50 MCI, 50 MBI-decreased motivation, and 50 mild AD dementia). We will leverage funded R01 AG053184 (PI: Marshall) to cover imaging costs for CN and MCI participants, while the current study will cover imaging costs for MBI-decreased motivation and AD dementia participants, and apathy clinical assessment costs for all participants.


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: 2026 ( Subtotal = $0 )
2026	2025	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Aging Research	000	5	12/10/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $556,665 )
2025	2025	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Aging Research	001	5	8/12/2025	NON-COMPETING CONTINUATION	$45,444
2025	2025	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Aging Research	000	5	1/28/2025	NON-COMPETING CONTINUATION	$511,221
														Subtotal = $556,665

Issue Date FY: 2024 ( Subtotal = $574,096 )
2024	2024	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Aging Research	000	4	12/1/2023	NON-COMPETING CONTINUATION	$516,686
2024	2024	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Aging Research	001	4	6/4/2024	NON-COMPETING CONTINUATION	$57,410
														Subtotal = $574,096

Issue Date FY: 2023 ( Subtotal = $834,296 )
2023	2023	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Aging Research	000	3	1/5/2023	NON-COMPETING CONTINUATION	$834,296
														Subtotal = $834,296

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Aging Research	001	2	3/11/2022	NON-COMPETING CONTINUATION	$0
2022	2021	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Aging Research	000	2	1/21/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $836,968 )
2021	2021	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Aging Research	000	2	1/29/2021	NON-COMPETING CONTINUATION	$836,968
														Subtotal = $836,968

Issue Date FY: 2020 ( Subtotal = $827,561 )
2020	2020	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Aging Research	000	1	1/22/2020	NEW	$827,561
														Subtotal = $827,561

Grand Total All Awards = $3,629,586

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Neural Correlates of Apathy Across the Alzheimer's Disease Continuum

Award Number: R01AG067021

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2020

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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