Date of Award
Summer 2022
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Biological Sciences
Program
Neuroscience
First Advisor
Nielson, Kristy A.
Second Advisor
Gordon, Nakia
Third Advisor
Scheidt, Robert
Abstract
The Apolipoprotein-E (APOE) ε4 allele is the greatest genetic risk factor for late-onset Alzheimer’s disease (AD), but alone it is not sufficiently predictive. Because neuropathological changes associated with AD begin decades before cognitive symptoms, neuroimaging of healthy, cognitively intact ε4 carriers (ε4+) may enable early characterization of neural patterns associated with risk for future cognitive decline. Research has typically focused on the cerebral cortex, where elders and ε4+ tend to exhibit ‘recruitment’ (i.e., hyperactivation) to maintain cognitive functioning. Yet, recent evidence suggests that AD-related changes may occur even earlier in the cerebellum. Moreover, advances in electroencephalography (EEG) source localization now allow effective modelling of cerebellar activity while also providing the exceptional temporal resolution of EEG, which is ideal for disentangling the impact of age and ε4 on cognitive processes. Importantly, healthy aging and AD are associated with declines in both cerebellar functions and executive functions (EF). Indeed, frontal lobe-cerebellar connectivity is essential to effective EF. However, it is not known whether cortical-cerebellar functions can detect pre-symptomatic risk for AD. Thus, the current study analyzed EEG cerebellar source localization and cortical-cerebellar connectivity during an EF-dependent stop-signal task (i.e., inhibitory control) in healthy, intact older adults (Mage = 80 years; 20 ε4+ and 24 ε4-). Task performance was comparable between groups. Multiple moderation models showed that greater age predicted greater activation in the posterolateral cerebellum during the P300 window (i.e., performance evaluation) and greater frontal-cerebellar connectivity during the N200 window (i.e., conflict processing). However, these findings were attributable to ε4-. ε4+ had low cerebellar activity across age in this older sample. These patterns demonstrated age-related cerebellar compensatory recruitment resources that are used to maintain EF (i.e., cognitive control) in healthy ε4-, but these resources were already depleted in healthy ε4+. Thus, the posterolateral cerebellum and its connectivity with frontal cortex is sensitive to AD-related neural deficits in healthy elders at risk for AD. Characterization of these patterns may be essential for the earliest possible detection of AD, which would enable critical early intervention prior to symptom onset, when such efforts are most likely to be effective.