Uncovering dynamic brain circuit mechanisms associated with apathy and disinhibition in Alzheimer's Dementia

This project addresses the pressing and widespread challenges posed by Alzheimer's disease and related dementias (ADRD), particularly the frequently co-occurring neuropsychiatric symptoms (NPS). ADRD are prevalent, debilitating conditions that severely impair daily functioning and place a significant burden on patients, families and society. NPS affect nearly 80% of individuals with dementia, with symptoms such as apathy and disinhibition closely linked to deficits in the motivation and cognitive control systems. Neuroimaging studies have identified structural, functional and metabolic abnormalities in these systems among old adults exhibiting apathy and/or disinhibition. However, a mechanistic understanding of how dysfunction in motivation and cognitive control systems contribute to these symptoms remains lacking. Recent cognitive neuroscience models highlight the critical roles of neural dynamics in supporting motivation and cognitive control functions. Our recent findings indicate that both healthy and pathological aging significantly impact on brain circuit dynamics, influencing cognitive functioning in older adults. However, little is known about how AD pathology affects brain circuit dynamics and how aberrant neural dynamics in the motivation and cognitive control systems contribute to apathy and disinhibition. This proposal seeks to fill these critical gaps by investigating the intricate relationships between AD pathology, brain circuit dynamics in the motivation and cognitive control systems, and NPS in individuals with ADRD. Grounded in the Research Domain Criteria (RDoC) framework, our study focuses on cognitive and positive valence systems, which are highly relevant to apathy and disinhibition. We will leverage a novel computational model developed in our lab to identify latent brain states and characterize their temporal and spatial properties, including state-specific posterior probability, mean lifetime, and functional connectivity within the motivation and cognitive control systems. By integrating fMRI and PET data from the same participants, we will examine how accumulation of Aβ and tau proteins disrupts brain circuit dynamics in these systems and its downstream effects on daily functioning. Furthermore, we will develop statistical models to predict apathy and disinhibition in ADRD. To ensure reproducibility and generalizability, we will conduct reproducibility analyses to validate our findings using two independent large- scale neuroimaging datasets of ADRD. The proposed research has far-reaching implications. It will shed light on the neurobiological mechanisms underlying NPS manifested in ADRD, particularly disinhibition and apathy. Ultimately, this study will pave the way for the development of more effective diagnosis and intervention strategies for the NPS, thus significantly advancing both the healthcare system and the field of research dedicated to ADRD. Essentially, the integrative cognitive, neuroscience and computational framework developed in this study can be broadly applied to investigate numerous other psychiatric and neurological disorders that share similar cognitive deficits. Project Number: 1R21AG093006-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Weidong Cai | Institution: STANFORD UNIVERSITY, STANFORD, CA | Award Amount: $423,500 | Activity Code: R21 | Study Section: Cognitive Disorders and Brain Aging Study Section[CDBA] View on NIH RePORTER: https://reporter.nih.gov/project-details/11303548