Relationships between dementia risk and protective lifestyle factors with cognition and brain function in midlife

Abstract

It is now acknowledged that Alzheimer's disease (AD) neuropathology is present decades before the onset of clinical symptoms. Midlife is a critical period for the beginning of AD pathology and potentially a unique disease-altering window, prior to the manifestation of substantial brain damage. However, the indicators of AD in midlife and the impact of modifiable lifestyle factors on the incipient disease process remain poorly understood. This thesis aims to investigate (i) the impact of established risk factors for late-onset AD on brain function and cognition, and on brain-behaviour relationships in midlife, and (ii) the impact of modifiable lifestyle factors on early risk-related changes. Participants were recruited from the Imperial College London site of the large-scale international research programme PREVENT-Dementia. Neuropsychological assessments and resting-state functional Magnetic Resonance Imaging (fMRI) were obtained at baseline (N = 210) and at two-year follow-up (N = 188). Chapter 2 found that, cross-sectionally, apolipoprotein e4 (APOE e4) allele was associated with better cognition. Higher Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) score was associated with worse cognition. Critically, the CAIDE score significantly moderated the relationship between cognition and functional connectivity of the Locus Coeruleus (LC) and the hippocampus, two key brain structures in AD neuropathology. Chapter 3 found that, cross-sectionally, APOE e4 allele was associated with higher functional segregation of brain networks, an emerging measure of brain health. The default mode network (DMN) was the only individual network to show such an effect of the APOE e4 genotype. Longitudinally, only APOE e4 carriers showed a significant loss of segregation in the DMN over two years. Chapter 4 found that more frequent engagement in physically, socially and intellectually stimulating activities was associated with better cognition, particularly in people with a family history of dementia. In addition, these activities significantly moderated the relationship between functional network segregation and cognition. Specifically, cognition was decoupled from brain functional health in individuals with more engagement in these stimulating activities, particularly for those with a higher CAIDE score (CAIDE > 6). These findings shed light on some of the earliest effects of AD risk and protective lifestyle activities on cognition and brain function, and thus have implications for early detection and intervention strategies that may prevent or slow down Alzheimer's disease. In addition, they highlight the importance of targeting modifiable lifestyle activities from early midlife, in individuals with genetic and cardiovascular risk for late-life Alzheimer's disease.