Decades of accumulated scientific evidence has demonstrated that vital factors (e.g., amyloid-β (Aβ) and the gene apolipoprotein E (APOE) ε4) contribute to the neuropathological changes and memory deficits observed in Alzheimer's disease (AD) and related dementias. Identifying these factors prior to disease onset could facilitate earlier access to disease-modifying treatments or promote healthy lifestyle modifications that might reduce neuropathology or cognitive deficits. However, the relationship between plasma-derived Aβ, APOE ε4, and brain atrophy in older adults before the manifestation of clinically relevant memory loss remains unclear. Furthermore, brain stimulation has emerged as a powerful approach for developing novel neuromodulatory therapies for those with deficits in cognition. Thus, these techniques may be used as potential treatments for those at risk for AD and other severe memory impairments.

The studies from this dissertation investigated the neural correlates and causal outcomes of cognitive and memory-related systems in the aging human brain. The first study examined the relationship between plasma-derived Aβ, APOE ε4, and brain atrophy in a large sample of 160 healthy older adults (ages 50+). The second and third studies showed promising effects on memory using invasive and non-invasive brain stimulation in cognitively healthy adults without memory impairments. Together these findings suggest that genetic, biological, and neural determinants could be combined with neuroimaging-guided brain stimulation to better identify individuals at risk for AD and improve their hippocampal-related memory.

Future studies of brain aging in healthy and memory-impaired older adults should monitor the molecular and neurobiological markers indicative of cognitive function and study novel methods like brain stimulation therapies. Since cognition is detrimentally influenced by these factors ensuring memory-enhancing therapies are effective despite indicators of impairment is necessary for the development of clinically viable treatments of benign senescence or more advanced impairment. Using different MRI modalities, the structural and microstructural properties of the brain can be used to predict treatment response or optimize hippocampal network targeting to restore aberrant function and alleviate the deficits associated with progressive memory loss.