Differential default mode network trajectories in asymptomatic individuals at risk for Alzheimer's disease

The longitudinal trajectories of functional brain dynamics and the impact of genetic risk factors in individuals at risk for Alzheimer's disease are poorly understood. In a large-scale monocentric cohort of 224 amyloid stratified individuals at risk for Alzheimer's disease, default mode network (DMN) resting state functional connectivity (FC) was investigated between two serial time points across 2 years. Widespread DMN FC changes were shown in frontal and posterior areas, as well as in the right hippocampus. There were no cross-sectional differences, however, apolipoprotein E ε4 (APOE ε4) carriers demonstrated slower increase in FC in frontal lobes. There was no impact of individual brain amyloid load status. For the first time, we demonstrated that the pleiotropic biological effect of the APOE ε4 allele impacts the dynamic trajectory of the DMN during aging. Dynamic functional biomarkers may become useful surrogate outcomes for the development of preclinical targeted therapeutic interventions. •Widespread default mode network (DMN) functional connectivity changes were shown.•APOE ε4 allele genotype leads to distinct DMN functional alterations.•APOE ε4 allele leads to DMN changes regardless of the amyloid β brain deposition.