Genotypic effects of APOE-ϵ4 on resting-state connectivity in cognitively intact individuals support functional brain compensation

Abstract

The investigation of resting-state functional connectivity (rsFC) in asymptomatic individuals at genetic risk for Alzheimer's disease (AD) enables discovering the earliest brain alterations in preclinical stages of the disease. The APOE-ϵ4 variant is the major genetic risk factor for AD, and previous studies have reported rsFC abnormalities in carriers of the ϵ4 allele. Yet, no study has assessed APOE-ϵ4 gene-dose effects on rsFC measures, and only a few studies included measures of cognitive performance to aid a clinical interpretation. We assessed the impact of APOE-ϵ4 on rsFC in a sample of 429 cognitively unimpaired individuals hosting a high number of ϵ4 homozygotes (n = 58), which enabled testing different models of genetic penetrance. We used independent component analysis and found a reduced rsFC as a function of the APOE-ϵ4 allelic load in the temporal default-mode and the medial temporal networks, while recessive effects were found in the extrastriate and limbic networks. Some of these results were replicated in a subsample with negative amyloid markers. Interaction with cognitive data suggests that such a network reorganization may support cognitive performance in the ϵ4-homozygotes. Our data indicate that APOE-ϵ4 shapes the functional architecture of the resting brain and favor the idea of a network-based functional compensation.