Date of Award

Fall 12-16-2022

Level of Access Assigned by Author

Open-Access Thesis

Degree Name

Master of Arts (MA)




Fayeza Ahmed

Second Committee Member

Thane Fremouw

Third Committee Member

Gareth Howell


Alzheimer’s disease (AD) is a neurodegenerative disorder with insidious onset and slow progression. AD research has traditionally been based on neuronal and glial dysfunction due to hallmark beta-amyloid and tau pathologies. Although literature supports an association between AD and cardiovascular disease and/or cardiovascular risk factors, vascular dysfunction as an etiology of AD has been overlooked. Cardiovascular risk factors have been associated with both cardiovascular and cerebrovascular disease in midlife individuals, an age at which modifiable risk factor management may be the most beneficial. Up to half of AD cases worldwide and in the USA are attributable to modifiable risk factors.

Until recently, despite years of research, treatments for AD have been purely symptomatic. Given the absence of disease-modifying treatments, as well as evidence supporting AD pathological changes occur decades prior to clinical onset of symptoms, non-pharmacological intervention approaches, such as exercise, have the potential improve or mitigate AD pathology and symptoms. One proposed mechanism of exercise benefits is the reduction of peripheral vascular risk factors. This risk factor reduction is due to exercise induced increases in circulating growth factors that either directly or indirectly mediate neurogenesis and angiogenesis and reduce systemic inflammation.

Health care providers often fail to diagnose AD in early stages therefore current and future AD researcher should be based on the 2018 NIA-AA Research Framework, a diagnostic framework in which AD onset can be detected based on biological changes in the brain and body prior to clinical onset of symptoms. This framework is based on widely used and validated biomarkers. Although highly accurate and reliably predictive, the current AD biomarkers are invasive, expensive, and not practical for early detection and/or longitudinal assessment. Disease altered protein expression in the peripheral blood can be measured via a simple venipuncture; identifying blood-based biomarkers of cognitive decline and determining whether they can be modified by exercise could provide mechanistic insight into a potential AD intervention.

This study provides a unique opportunity to determine whether exercise can modify blood based general health markers and peripheral growth factor concentrations in midlife humanized, APOE4 mice and midlife community participants. Animal studies allowed us the ability to produce equal numbers of APOE genotypes compared to that of community participants where the limitations of human studies prevented matched sample sizes however overall, using serum collected from each group and high throughput analytic assays, we see published growth factor increases and similar mouse to human trends with regards general health markers and growth factor increases as a result of exercise.