title: The Vulnerability and Resiliency of the Retrosplenial Cortex in Alzheimer's Disease
Creators: name: Terstege, Dylan Johannes
Publisher: name: Graduate Studies
Year: 2025
Subjects: subject: Neuroscience

description: Alzheimer’s Disease (AD) is the most common form of dementia and, with a rapidly aging global population, its rate of incidence is expected to continue to rise. This devastating neurodegenerative disorder is characterized by cognitive decline and impaired ability to perform day-to-day tasks. With no cure and limited treatment options, AD is a significant burden to health care systems globally and causes considerable concern to affected individuals and their families. Among the most common concerns voiced by family members of those affected by AD is the uncertainty in its progression. While neurodegeneration and cognitive decline are expected in AD, the rate at which these occur varies drastically from patient to patient. This variability makes it difficult to identify individuals most imminently at risk of cognitive decline, but it also presents an opportunity to identify factors which may contribute to cognitive resiliency. In this thesis, a region which shows very early dysfunction during AD pathogenesis, the retrosplenial cortex (RSC), is thoroughly examined. Chapter 1 critically evaluates and reviews the literature surrounding AD, the sex-specific nature of many of its risk factors, how the RSC has been implicated in this disease, and factors which have been associated with resiliency to cognitive decline. Chapter 2 then leverages a large, multi-site, neuroimaging database to assess the ability of altered metabolic function of the RSC during early stages of AD to predict subsequent cognitive decline. After confirming this relationship, Chapter 3 thoroughly examines the RSC during early stages of AD to assess changes which occur concurrently to this altered metabolism. This examination identified sex-specific impairments in the function, connectivity, and survival of parvalbumin-expressing neurons, with broad consequences on the functional connectivity of the RSC. Chapter 4 assess the extent to which the functional connectivity of the RSC can be altered in non-invasive ways, through repeated exposure to spatial learning experiences. Chapter 5 then expands upon this by examining factors associated with resiliency to cognitive decline in AD, such as cognitive, physical, and social enrichment. In doing so, this chapter demonstrates that enriched lifestyle conditions can mitigate the impaired function of parvalbumin-expressing neurons in the RSC on brain-wide functional connectivity and cognitive function. This thesis advances the understanding of cognitive resiliency and vulnerability in AD across several timescales. Immediately, altered metabolic activity of the RSC as an early predictor of subsequent cognitive decline can be incorporated into predictive models for identifying at-risk individuals. This can ease uncertainty among families and can help to ensure that treatment resources are being given to those who are most in need. In the long-term, this thesis identifies altered functional connectivity signatures of the RSC – providing a potential diagnostic fingerprint – which coincides with a clear sex- and cell-type-specific vulnerability. Finally, this thesis demonstrates that lifestyle factors associated with increased resiliency to cognitive decline in AD preserve these vulnerable cell populations and protect against impaired functional connectivity.