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

> **NIH NIH K01** · UNIVERSITY OF CALIFORNIA BERKELEY · 2024 · $131,274

## Abstract

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...

## Key facts

- **NIH application ID:** 10879127
- **Project number:** 5K01AG078443-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** Theresa M. Harrison
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $131,274
- **Award type:** 5
- **Project period:** 2022-08-15 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10879127

## Citation

> US National Institutes of Health, RePORTER application 10879127, Linking basal forebrain and entorhinal cortex vulnerability to preclinical Alzheimer's disease (5K01AG078443-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10879127. Licensed CC0.

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