APOE-by-sex interactions on brain structure and metabolism in healthy elderly controls

Abstract

// Frederic Sampedro 1, 2, 3, * , Eduard Vilaplana 1, 2, * , Mony J de Leon 4 , Daniel Alcolea 1, 2 , Jordi Pegueroles 1, 2 , Victor Montal 1, 2 , María Carmona-Iragui 1, 2 , Isabel Sala 1, 2 , María-Belén Sánchez-Saudinos 1, 2 , Sofía Antón-Aguirre 1, 2 , Estrella Morenas-Rodríguez 1, 2 , Valle Camacho 3 , Carles Falcón 5, 7 , Javier Pavía 6, 7 , Domènec Ros 5, 7 , Jordi Clarimón 1, 2 , Rafael Blesa 1, 2 , Alberto Lleó 1, 2 , Juan Fortea 1, 2 for the Alzheimer’s Disease Neuroimaging Initiative ** 1 Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau- Biomedical Research Institute Sant Pau- Universitat Autònoma de Barcelona, Barcelona, Spain 2 Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas. CIBERNED, Madrid, Spain 3 Nuclear Medicine Department, Hospital de la Santa Creu i Sant Pau- Biomedical Research Institute Sant Pau- Universitat Autònoma de Barcelona, Barcelona, Spain 4 New York University School of Medicine, New York, NY, USA 5 Unitat de Biofísica i Bioenginyeria, Departament de Ciències Fisiològiques I, Facultat de Medicina, Universitat de Barcelona – IDIBAPS, Barcelona, Spain 6 Nuclear Medicine Department. Hospital Clínic de Barcelona, Barcelona, Spain 7 Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine - CIBER-BBN, Barcelona, Spain * These authors have contributed equally to this work ** Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf . Correspondence to: Juan Fortea, e-mail: jfortea@santpau.cat Keywords: Gerotarget, Alzheimer’s disease, aging, APOE, MRI, PET-FDG Received: June 29, 2015 Accepted: August 28, 2015 Published: September 10, 2015 ABSTRACT Background: The APOE effect on Alzheimer Disease (AD) risk is stronger in women than in men but its mechanisms have not been established. We assessed the APOE -by-sex interaction on core CSF biomarkers, brain metabolism and structure in healthy elderly control individuals (HC). Methods: Cross-sectional study. HC from the Alzheimer’s Disease Neuroimaging Initiative with available CSF ( n = 274) and/or 3T-MRI ( n = 168) and/or a FDG-PET analyses ( n = 328) were selected. CSF amyloid-β 1–42 (Aβ 1–42 ), total-tau (t-tau) and phospho-tau (p-tau 181p ) levels were measured by Luminex assays. We analyzed the APOE -by-sex interaction on the CSF biomarkers in an analysis of covariance (ANCOVA). FDG uptake was analyzed by SPM8 and cortical thickness (CTh) was measured by FreeSurfer. FDG and CTh difference maps were derived from interaction and group analyses. Results: APOE4 carriers had lower CSF Aβ 1–42 and higher CSF p-tau 181p values than non-carriers, but there was no APOE -by-sex interaction on CSF biomarkers. The APOE -by-sex interaction on brain metabolism and brain structure was significant. Sex stratification showed that female APOE4 carriers presented widespread brain hypometabolism and cortical thinning compared to female non-carriers whereas male APOE4 carriers showed only a small cluster of hypometabolism and regions of cortical thickening compared to male non-carriers. Conclusions: The impact of APOE4 on brain metabolism and structure is modified by sex. Female APOE4 carriers show greater hypometabolism and atrophy than male carriers. This APOE -by-sex interaction should be considered in clinical trials in preclinical AD where APOE4 status is a selection criterion.