INTRODUCTION: Harboring two copies of the apolipoprotein E (APOE) ε2 allele strongly protects against Alzheimer's disease (AD). However, the effect of this genotype on gray matter (GM) volume in cognitively unimpaired individuals has not yet been described. METHODS: Multicenter brain magnetic resonance images (MRIs) from cognitively unimpaired ε2 homozygotes were matched (1:1) against all other APOE genotypes for relevant confounders (n = 223). GM volumes of ε2 genotypic groups were compared to each other and to the reference group (APOE ε3/ε3). RESULTS: Carrying at least one ε2 allele was associated with larger GM volumes in brain areas typically affected by AD and also in areas associated with cognitive resilience. APOE ε2 homozygotes, but not APOE ε2 heterozygotes, showed larger GM volumes in areas related to successful aging. DISCUSSION: In addition to the known resistance against amyloid-β deposition, the larger GM volumes in key brain regions may confer APOE ε2 homozygotes additional protection against AD-related cognitive decline.

Alzheimer Center Amsterdam Department of Neurology Amsterdam Neuroscience Vrije Universiteit Amsterdam Amsterdam UMC Amsterdam the Netherlands

Barcelonaβeta Brain Research Center Pasqual Maragall Foundation Barcelona Spain

Centre for Genomic Regulation The Barcelona Institute for Science and Technology Barcelona Spain

Centro de Investigación Biomédica en Red de Bioingeniería Biomateriales y Nanomedicina Madrid Spain

CIBER Fragilidad y Envejecimiento Saludable Madrid Spain

Clinical Memory Research Unit Lund University Lund Sweden

Department of Clinical Genetics ERASMUS MC Rotterdam the Netherlands

Department of Clinical Sciences Clinical Memory Research Unit Lund University Lund Sweden

Department of Epidemiology and Biostatistics Amsterdam Neuroscience Vrije Universiteit Amsterdam Amsterdam UMC Amsterdam the Netherlands

Department of Neuroimaging Centre for Neuroimaging Sciences Institute of Psychiatry Psychology and Neuroscience King's College London London UK

Department of Radiology and Nuclear Medicine VU Medical Center Neuroscience Campus Amsterdam Amsterdam the Netherlands

Department of Radiology Mayo Clinic Rochester Minnesota USA

Diagnostic Radiology Institution for Clinical Sciences Lund University Lund Sweden

Division of Clinical Geriatrics Center for Alzheimer Research Department of Neurobiology Care Sciences and Society Karolinska Institutet Stockholm Sweden

Image and Function Skåne University Hospital Lund Sweden

IMIM Barcelona Spain

Institutes of Neurology and Healthcare Engineering University College London London UK

International Clinical Research Centre St Anne's University Hospital Brno Brno Czech Republic

Memory Clinic Department of Neurology Charles University 2nd Faculty of Medicine and Motol University Hospital Prague Czech Republic

Memory Clinic Skåne University Hospital Malmö Sweden

Neuropsychiatric Epidemiology Unit Department of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology Sahlgrenska Academy Centre for Ageing and Health at the University of Gothenburg Gothenburg Sweden

Universitat Pompeu Fabra Barcelona Spain

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