Advanced age and Apolipoprotein E4 (APOE4) allele are major risk factors for Alzheimer’s disease (AD), with APOE4 linked to synaptic dysfunction and accelerated biological aging. To explore APOE4-related functional connectivity (FC) changes across different disease stages of AD, we conducted two studies.

In the first study, we analyzed 128 resting-state functional resonance magnetic imaging (fMRI) scans from Alzheimer’s disease Neuroimaging Initiative database (ADNI) of individuals from cognitive normals to dementia. Using graph-theory met- ric, eigenvector centrality and partial least squares correlation (PLSC) analysis, we identified distinct FC patterns influenced by age and APOE4 status.

In the second study, we investigated the FC changes in 188 healthy female at high risk of developing AD, associated with plasma biomarkers. We found an amyloid-driven FC changes specific to APOE4 carriers in key brain networks while non-carriers exhibited a tau-related connectivity changes.

These findings highlight distinct genotype-specific connectivity patterns and underscore the need for targeted therapeutic strategies addressing pathological pathways in APOE4 carriers and non-carriers. This targeted approach could significantly advance personalized AD diagnosis, treatments and more effective interventions.