LAUSR

We investigated the influence of the apolipoprotein E‐ɛ4 allele (APOE‐ɛ4) on longitudinal age‐related changes in brain functional connectivity (FC) and cognition, in view of mixed cross‐sectional findings. One hundred and twenty‐two healthy older adults (aged 58–79; 25 APOE‐ɛ4 carriers) underwent task‐free fMRI scans at baseline. Seventy‐eight (16 carriers) had at least one follow‐up (every 2 years). Changes in intra‐ and internetwork FCs among the default mode (DMN), executive control (ECN), and salience (SN) networks, as well as cognition, were quantified using linear mixed models. Cross‐sectionally, APOE‐ɛ4 carriers had lower functional connectivity between the ECN and SN than noncarriers. Carriers also showed a stronger age‐dependent decrease in visuospatial memory performance. Longitudinally, carriers had steeper increase in inter‐ECN‐DMN FC, indicating loss of functional segregation. The longitudinal change in processing speed performance was not moderated by APOE‐ɛ4 genotype, but the brain–cognition association was. In younger elderly, faster loss of segregation was correlated with greater decline in processing speed regardless of genotype. In older elderly, such relation remained for noncarriers but reversed for carriers. APOE‐ɛ4 may alter aging by accelerating the change in segregation between high‐level cognitive systems. Its modulation on the longitudinal brain–cognition relationship was age‐dependent.