Genotypic effects of<i>APOE</i>-ε4 on resting-state connectivity in cognitively intact individuals support functional brain compensation
Raffaele Cacciaglia, Grégory Operto, Carles Falcón, José Maria González de Echavarri-Gómez, Gonzalo Sánchez‐Benavides, Anna Brugulat‐Serrat, Marta Milà‐Alomà, Kaj Blennow, Henrik Zetterberg, José Luís Molinuevo, Marc Suárez‐Calvet, Juan Domingo Gispert, for the ALFA study, Müge Akinci, Annabella Beteta, Alba Cañas, Irene Cumplido, Carme Deulofeu, Ruth Dominguez, Maria Emilio, Karine Fauria, Sherezade Fuentes, Oriol Grau‐Rivera, Laura L. Hernandez, Gema Huesa, Jordi Huguet, Eider M. Arenaza‐Urquijo, Eva Palacios, Paula Marne, Tania Menchón, Carolina Minguillón, Eleni Palpatzis, Cleofé Peña-Gómez, Albina Polo, Sandra Pradas, Blanca Rodríguez‐Fernández, Aleix Sala‐Vila, Gemma Salvadó, Mahnaz Shekari, Anna Soteras, Laura Stankeviciute, Marc Vilanova, Natàlia Vilor‐Tejedor
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.