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

Cacciaglia, Raffaele; Operto, Grégory; Falcón, Carles; González de Echávarri, José Maria; Sánchez Benavides, Gonzalo; Brugulat Serrat, Anna, 1986-; Milà Alomà, Marta; Blennow, Kaj; Zetterberg, Henrik; Molinuevo, José Luis; Suárez-Calvet, Marc; Gispert López, Juan Domingo; ALFA Study

doi:http://dx.doi.org/10.1093/cercor/bhac239

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

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Cacciaglia R, Operto G, Falcón C, de Echavarri-Gómez JMG, Sánchez-Benavides G, Brugulat-Serrat A, et al. Genotypic effects of APOE-ε4 on resting-state connectivity in cognitively intact individuals support functional brain compensation. Cereb Cortex. 2022 Jun 27: 1-13. DOI: 10.1093/cercor/bhac239.

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.