Research Papers: Gerotarget (Focus on Aging):

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

Frederic Sampedro, Eduard Vilaplana, Mony J. de Leon, Daniel Alcolea, Jordi Pegueroles, Victor Montal, María Carmona-Iragui, Isabel Sala, María-Belén Sánchez-Saudinos, Sofía Antón-Aguirre, Estrella Morenas-Rodríguez, Valle Camacho, Carles Falcón, Javier Pavía, Domènec Ros, Jordi Clarimón, Rafael Blesa, Alberto Lleó _ and Juan Fortea

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Oncotarget. 2015; 6:26663-26674. https://doi.org/10.18632/oncotarget.5185

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Frederic Sampedro1,2,3,*, Eduard Vilaplana1,2,*, Mony J de Leon4, Daniel Alcolea1,2, Jordi Pegueroles1,2, Victor Montal1,2, María Carmona-Iragui1,2, Isabel Sala1,2, María-Belén Sánchez-Saudinos1,2, Sofía Antón-Aguirre1,2, Estrella Morenas-Rodríguez1,2, Valle Camacho3, Carles Falcón5,7, Javier Pavía6,7, Domènec Ros5,7, Jordi Clarimón1,2, Rafael Blesa1,2, Alberto Lleó1,2, Juan Fortea1,2 for the Alzheimer’s Disease Neuroimaging Initiative**

1Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau- Biomedical Research Institute Sant Pau- Universitat Autònoma de Barcelona, Barcelona, Spain

2Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas. CIBERNED, Madrid, Spain

3Nuclear Medicine Department, Hospital de la Santa Creu i Sant Pau- Biomedical Research Institute Sant Pau- Universitat Autònoma de Barcelona, Barcelona, Spain

4New York University School of Medicine, New York, NY, USA

5Unitat de Biofísica i Bioenginyeria, Departament de Ciències Fisiològiques I, Facultat de Medicina, Universitat de Barcelona – IDIBAPS, Barcelona, Spain

6Nuclear Medicine Department. Hospital Clínic de Barcelona, Barcelona, Spain

7Biomedical 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: [email protected]

Keywords: Gerotarget, Alzheimer’s disease, aging, APOE, MRI, PET-FDG

Received: June 29, 2015     Accepted: August 28, 2015     Published: September 10, 2015


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-β1–42 (Aβ1–42), total-tau (t-tau) and phospho-tau (p-tau181p) 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 Aβ1–42 and higher CSF p-tau181p 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.

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