Date of Award

2026

Embargo Period

12-31-2027

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD) in Health & Rehabilitation Science

Department

Physiology and Neuroscience

College

College of Health Professions

First Advisor

DeAnna Baker Frost

Second Advisor

Adviye Ergul

Third Advisor

Sara Knox

Abstract

Alzheimer’s disease (AD) is a complex and progressive neurodegenerative disorder affecting approximately 7.2 million Americans aged 65 and older. While advancing age remains the primary risk factor, lifestyle factors also play a significant role in disease progression. AD is no longer viewed exclusively as a condition defined by amyloid plaque deposition and neurofibrillary tangles; it is now recognized as a multifaceted pathology involving significant disruption of the brain’s vascular system, leading to impaired cerebral blood flow and neuroinflammation.

Obesity, which affects nearly half of the adult population in the United States, has been strongly linked to cognitive impairment and an increased risk of age-related dementia. Based on an extensive review of the literature (Chapter 2), the central hypothesis of this dissertation proposes that high-fat diet (HFD)-induced mid-life obesity drives metabolic stress and early cerebrovascular dysfunction. These changes result in impaired cerebral blood flow, which in turn prime neuroinflammatory signaling pathways and accelerate AD-related pathology and cognitive decline (Chapter 1).

To test this hypothesis, multiple aspects of disease pathology were examined as described in the methodology section (Chapter 3). These included measurement of cortical cerebral blood flow, circulating serum biomarkers, amyloid pathology, differential gene expression, exploratory behavior, and cognitive function in APP/PS1 mice, a preclinical mouse model of AD following diet-induced obesity. Our findings show (Chapter 4) that the metabolic dysfunction induced by the HFD leads to region-specific impairments in cerebral blood flow, alterations in circulating biomarkers, changes in exploratory behavior, and shifts in gene expression associated with hypoperfusion, metabolic stress, and early immune priming. Notably, these changes occur prior to clear cognitive deficits or significant amyloid plaque accumulation. As discussed in Chapter 5, we conclude that diet-induced obesity exacerbates early signs of AD via cerebrovascular axis.

Rights

Copyright is held by the author. All rights reserved.

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Available for download on Friday, December 31, 2027

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