Genetic risk of Alzheimer’s disease is associated with loss of brain network segregation in midlife

Alzheimer's disease (AD) neuropathology starts decades before clinical manifestations, but the early indicators of AD in midlife remain unclear. Functional segregation of brain networks is a key marker of brain health. It remains unknown, however, whether inherited risk of AD impacts network segregation from midlife in individuals who are cognitively healthy but carry inherited risk for late-life AD. To address this question, we investigate which brain networks show the strongest age-related segregation loss in the Cam-CAN lifespan cohort (18-88 years, N=652), and whether APOE ε4 genotype impacts segregation of age-vulnerable networks in the midlife PREVENT cohort (40-59 years, N=210), cross-sectionally and longitudinally. Higher-order networks showing the most significant age-related decline are the default mode (DMN), frontal-parietal control (FPN) and salience (SN) networks. Cognitively healthy midlife APOE ε4 carriers have higher segregation across the brain cross-sectionally, accompanied by greater longitudinal decline in the DMN over two years, relative to non-carriers. Higher DMN segregation is associated with better episodic and relational memory across the PREVENT cohort. These findings suggest that functional segregation may serve as a potential biomarker, providing insights into the mechanisms through which APOE influences brain function and cognition from healthy midlife, on average 23 years before dementia onset.