Dissertations, Theses, and Capstone Projects

Date of Degree

9-2023

Document Type

Dissertation

Degree Name

Ph.D.

Program

Psychology

Advisor

Nancy S. Foldi

Committee Members

Veronica Hinton

Carolyn Pytte

Laura Rabin

Desiree Byrd

Subject Categories

Clinical Psychology

Keywords

Genetics, Cognition, Neuropsychology, Alzheimer's Disease, APOE, Longitudinal

Abstract

Background: The apolipoprotein E (APOE) ε4 allele is the strongest susceptibility factor for sporadic, late-onset, Alzheimer’s disease (AD). However, not all persons who carry the ε4 allele show significant cognitive decline, and thus do not progress to dementia. The impact of the ε4 allele on memory decline has been documented primarily in populations already demonstrating cognitive impairment (i.e., those with mild cognitive impairment or dementia), with fewer investigations completed in baseline healthy older adults. Investigations of the ε4 allele and its influence on non-memory domains are also sparse in the literature. Furthermore, these cognitive investigations are typically cross-sectional and thus do not capture variation in longitudinal trajectory. Methods: This study used longitudinal data (maximum = eight years) from a cohort of baseline healthy older adults (N = 503) in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). First, we investigated whether the ε4 allele differentially impacts rate of decline across domains of memory, executive functioning, language, and visuospatial functioning. Second, we investigated whether preservation of non-memory domains (i.e., executive functioning, language) influences memory trajectory in the ε4 carrier versus non-ε4 carriers. Last, we investigated whether preservation of specific gray-matter regional volumes or decreased white matter hyperintensity (WMH) load differentially influenced cognitive trajectory in the ε4 carrier. Linear mixed-effects models were created to allow for random baseline intercepts and slopes over time. Findings: Firstly, ε4 carriers showed significantly faster decline in memory and visuospatial composite scores over time, relative to ε3 homozygotes. Secondly, average memory trajectory was only significantly positively influenced by preserved executive functioning or language skills in ε4 carriers relative to ε3 homozygotes. Exploratory analyses revealed that preserved executive functioning conferred a similar benefit to preservation of language over time in the ε4 carrier. Lastly, parahippocampal and cuneus regional volumes were significantly associated with preserved memory scores over time in ε4 carriers relative to ε3 homozygotes, even after correction for multiple comparisons. Lower total WMH load was surprisingly not associated with preserved memory scores over time in the ε4 carrier; rather, ε4 carriers showed accelerated memory decline at any positive value of WMH load. Conclusions: Our findings support the significant relationship between APOE-ε4 carrier status and accelerated memory decline, even in baseline cognitively normal individuals. They also add evidence to the need to monitor visuospatial skills as another area of decline in the ε4 carrier. Preserved executive functioning in the ε4 carrier significantly buffered memory and language decline only in ε4 carriers. Similar associations were found with preserved parahippocampus and cuneus volumes, suggesting targets beyond the hippocampus. Additionally, the ε4-specific effect of WMH load on accelerated memory decline adds to the evidence of white-matter changes as a driving force in AD-related decline. Future investigations will investigate the mediating role of cerebrospinal fluid markers, such as amyloid-beta and hyperphosphorylated tau in prognosticating cognitive decline in ε4 carriers.

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