Raffaele Cacciaglia 1 , 2 , 3 , José Luis Molinuevo 1 , 2 , 3 , 4 , Carles Falcón 1 , 2 , 5 , Eider M Arenaza-Urquijo 1 , 2 , 3 , Gonzalo Sánchez-Benavides 1 , 2 , 3 , Anna Brugulat-Serrat 1 , 2 , 3 , 6 , Kaj Blennow 7 , 8 , Henrik Zetterberg 7 , 8 , 9 , 10 , Juan Domingo Gispert 1 , 2 , 4 , 5 , for the ALFA study
12 March 2020
Gray matter networks (GMn) provide essential information on the intrinsic organization of the brain and appear to be disrupted in Alzheimer’s disease (AD). Apolipoprotein E ( APOE)-ε4 represents the major genetic risk factor for AD, yet the association between APOE-ε4 and GMn has remained unexplored. Here, we determine the impact of APOE-ε4 on GMn in a large sample of cognitively unimpaired individuals, which was enriched for the genetic risk of AD. We used independent component analysis to retrieve sources of structural covariance and analyzed APOE group differences within and between networks. Analyses were repeated in a subsample of amyloid-negative subjects. Compared with noncarriers and heterozygotes, APOE-ε4 homozygotes showed increased covariance in one network including primarily right-lateralized, parietal, inferior frontal, as well as inferior and middle temporal regions, which mirrored the formerly described AD-signature. This result was confirmed in a subsample of amyloid-negative individuals. APOE-ε4 carriers showed reduced covariance between two networks encompassing frontal and temporal regions, which constitute preferential target of amyloid deposition. Our data indicate that, in asymptomatic individuals, APOE-ε4 shapes the cerebral organization in a way that recapitulates focal morphometric alterations observed in AD patients, even in absence of amyloid pathology. This suggests that structural vulnerability in neuronal networks associated with APOE-ε4 may be an early event in AD pathogenesis, possibly upstream of amyloid deposition.