Linking basal forebrain and entorhinal cortex vulnerability to preclinical Alzheimer's disease

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Project Summary Alzheimer’s disease (AD) pathology begins to emerge in the brain and drives cognitive decline before the onset of clinical symptoms. It has been known for decades that the basal forebrain (BF) is vulnerable to early tau accumulation, and yet neuroimaging research of early, preclinical AD has largely focused on tau accumulation in the temporal lobe, beginning in entorhinal cortex (ERC), and subsequent memory decline. An overarching goal of the current proposal is to reinvigorate interest in BF research, especially in cognitively healthy older adults where the earliest, preclinical AD pathological changes can be observed. The broader implication of a better understanding of how preclinical AD unfolds across the brain is the opportunity to detect the disease before the emergence of symptoms when interventions can be most effective. Research Project: In this proposal, BF and ERC will be examined side-by-side to test the hypothesis that a common, preclinical AD process is unfolding in both regions. Atrophy and tau accumulation in BF and ERC will be explored, including how tightly correlated these changes are and whether there is evidence of temporal ordering of these changes (e.g., BF first or ERC first). Cognitive consequences of BF tau burden and atrophy will be assessed and compared to memory changes associated with ERC tau and atrophy. Specific gaps in the field will be addressed by exploring relationships of BF and ERC volume/atrophy with PET biomarkers and longitudinal, domain-specific cognition (Aim 1), determining how patterns of seed-based functional connectivity of BF and ERC relate to tau pathology burden and spread (Aim 2), and establishing correlated gene expression relationships across BF, ERC and connected regions to identify common pathways that may underlie their vulnerability to AD (Aim 3). These experiments will help uncover common drivers of AD vulnerability in BF and ERC and elucidate the role of BF in preclinical AD, including associations with generalized cognitive decline. Candidate Development and Environment: This proposal will promote the candidate’s ultimate career goal to build an independent research program that takes multimodal, innovative approaches to characterizing cognitive aging and preclinical AD. During the K award, the candidate will extend her expertise in neuroimaging of preclinical AD by integrating novel PET tracers and datasets while also acquiring new expertise in several key areas: the anatomy of the BF and cholinergic system, analysis of genetic expression data in concert with neuroimaging data and advanced statistical approaches grounded in causal inference. The candidate’s training plan outlines her approach to engage the rich resources available in her lab and the broader UC Berkeley community, including access to unique datasets, community-building seminars and retreats and world-renowned faculty across many disciplines. The diverse team of collaborators and advisors the candidate has assembled for this project will ensure she is successful in leveraging her unparalleled environment toward gaining independence.