# Neural Correlates of Apathy Across the Alzheimer's Disease Continuum > **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $574,096 ## Abstract 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 th... ## Key facts - **NIH application ID:** 10760331 - **Project number:** 5R01AG067021-04 - **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL - **Principal Investigator:** GAD ASHER MARSHALL - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $574,096 - **Award type:** 5 - **Project period:** 2020-02-01 → 2025-12-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10760331 ## Citation > US National Institutes of Health, RePORTER application 10760331, Neural Correlates of Apathy Across the Alzheimer's Disease Continuum (5R01AG067021-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10760331. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*