Genetic Predisposition to Alzheimer's Disease Is Associated with Enlargement of Perivascular Spaces in Centrum Semiovale Region

Iacopo Ciampa, Grégory Operto, Carles Falcon, Carolina Minguillon, Manuel Castro de Moura, David Piñeyro, Manel Esteller, Jose Luis Molinuevo, Roderic Guigó, Arcadi Navarro, Juan Domingo Gispert, Natalia Vilor-Tejedor, For The Alfa Study, Iacopo Ciampa, Grégory Operto, Carles Falcon, Carolina Minguillon, Manuel Castro de Moura, David Piñeyro, Manel Esteller, Jose Luis Molinuevo, Roderic Guigó, Arcadi Navarro, Juan Domingo Gispert, Natalia Vilor-Tejedor, For The Alfa Study

Abstract

This study investigated whether genetic factors involved in Alzheimer's disease (AD) are associated with enlargement of Perivascular Spaces (ePVS) in the brain. A total of 680 participants with T2-weighted MRI scans and genetic information were acquired from the ALFA study. ePVS in the basal ganglia (BG) and the centrum semiovale (CS) were assessed based on a validated visual rating scale. We used univariate and multivariate logistic regression models to investigate associations between ePVS in BG and CS with BIN1-rs744373, as well as APOE genotypes. We found a significant association of the BIN1-rs744373 polymorphism in the CS subscale (p value = 0.019; OR = 2.564), suggesting that G allele carriers have an increased risk of ePVS in comparison with A allele carriers. In stratified analysis by APOE-ε4 status (carriers vs. non-carriers), these results remained significant only for ε4 carriers (p value = 0.011; OR = 1.429). To our knowledge, the present study is the first suggesting that genetic predisposition for AD is associated with ePVS in CS. These findings provide evidence that underlying biological processes affecting AD may influence CS-ePVS.

Trial registration: ClinicalTrials.gov NCT01835717.

Keywords: APOE-ε4; BIN1-rs744373; enlargement of perivascular spaces; neurogenetics; virchow robin spaces.

Conflict of interest statement

J.L.M. is currently a full time employee of Lundbeck and priorly has served as a consultant or at advisory boards for the following for-profit companies, or has given lectures in symposia sponsored by the following for-profit companies: Roche Diagnostics, Genentech, Novartis, Lundbeck, Oryzon, Biogen, Lilly, Janssen, Green Valley, MSD, Eisai, Alector, BioCross, GE Healthcare, ProMIS Neurosciences. The remaining authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1
Schema of the study. Hypothesized etiologies for enlargement of perivascular spaces. Created with BioRender.com, accessed on 10–22 May 2021.
Figure 2
Figure 2
Associations (Odds Ratios) between enlargement of Perivascular Spaces in basal ganglia and centrum semiovale regions and BIN1-rs744373 polymorphism, stratified by APOE genotypes. Models were adjusted by age, sex, and years of education. p-values were corrected using the false discovery rate (FDR) method. *** p-value < 5 × 10−5; ** p-value < 5 × 10−3; * p-value < 5 × 10−2.

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