Date of Award

Fall 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Interdepartmental Neuroscience Program

First Advisor

Fredericks, Carolyn

Abstract

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-? and tau, yet clinical progression varies widely across individuals. The central aim of this dissertation was to evaluate whether functional brain connectivity derived from resting-state fMRI can serve as a clinically meaningful predictive tool in the asymptomatic phase of the disease, preclinical AD. In Chapter 2, I develop connectome-based predictive models linking whole-brain functional connectivity to regional tau positron emission tomography (PET) signal in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) Study. These models predicted tau burden, particularly in regions vulnerable to tau deposition in Braak stages IV/V. In Chapter 3, I cluster patients using their tau-predictive connectivity features and identify subgroups of A4 participants with distinct clinical trajectories. One subgroup showed more rapid cognitive and functional decline in the natural course of the disease and demonstrated a measurable treatment response to solanezumab despite the overall null results of the trial. These results suggest that fMRI-based subtyping can reveal treatment effects masked by heterogeneity. By predicting tau pathology and revealing treatment-responsive subgroups, fMRI-based approaches offer a framework for early risk stratification and precision therapeutic targeting in preclinical AD.

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