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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Bu G. Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy. Nat Rev Neurosci. 2009;10:333‐344. 10.1038/nrn2620 PubMed DOI PMC

Liu CC, Kanekiyo T, Xu H, Bu G. Apolipoprotein e and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 2013;9:106‐118. 10.1038/nrneurol.2012.263 PubMed DOI PMC

Reiman EM, Arboleda‐Velasquez JF, Quiroz YT, et al. Exceptionally low likelihood of Alzheimer's dementia in APOE2 homozygotes from a 5,000‐person neuropathological study. Nat Commun. 2020;11:667. 10.1038/s41467-019-14279-8 PubMed DOI PMC

Reiman EM, Chen K, Liu X, et al. Fibrillar amyloid‐beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease. Proc Natl Acad Sci U S A. 2009;106:6820‐6825. PubMed PMC

Cacciaglia R, Molinuevo JL, Falcón C, et al. Effects of APOE ‐ε4 allele load on brain morphology in a cohort of middle‐aged healthy individuals with enriched genetic risk for Alzheimer's disease. Alzheimer's Dement. 2018:1‐11. 10.1016/j.jalz.2018.01.016 PubMed DOI

Reiman EM, Chen K, Alexander GE, et al. Correlations between apolipoprotein E ε4 gene dose and brain‐imaging measurements of regional hypometabolism. Proc Natl Acad Sci U S A. 2005;102:8299‐8302. 10.1073/pnas.0500579102 PubMed DOI PMC

Stern Y, Arenaza‐Urquijo EM, Bartrés‐Faz D, et al. Whitepaper: defining and investigating cognitive reserve, brain reserve, and brain maintenance. Alzheimer's Dement. 2018:1305‐1311. 10.1016/j.jalz.2018.07.219 PubMed DOI PMC

Farrer LA, Cupples LA, Haines JL, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta‐analysis. J Am Med Assoc. 1997;278:1349‐1356. 10.1001/jama.278.16.1349 PubMed DOI

Grothe MJ, Villeneuve S, Dyrba M, Bartrés‐Faz D, Wirth M. Multimodal characterization of older APOE2 carriers reveals selective reduction of amyloid load. Neurology. 2017;88:569‐576. 10.1212/WNL.0000000000003585 PubMed DOI PMC

Salvadó G, Grothe MJ, Groot C, et al. Differential effects of APOE‐ε2 and APOE‐ε4 alleles on PET‐measured amyloid‐β and tau deposition in older individuals without dementia. Eur J Nucl Med Mol Imaging. 2021;48(7):2212‐2224. 10.1007/s00259-021-05192-8 PubMed DOI PMC

Li Z, Shue F, Zhao N, Shinohara M, Bu G. APOE2: protective mechanism and therapeutic implications for Alzheimer's disease. Mol Neurodegener. 2020;15:1‐19. 10.1186/s13024-020-00413-4 PubMed DOI PMC

Khan W, Giampietro V, Ginestet C, et al. No differences in hippocampal volume between carriers and non‐carriers of the ApoE ε4 and ε2 alleles in young healthy adolescents. J Alzheimers Dis. 2014;40:37‐43. 10.3233/JAD-131841 PubMed DOI

Fan M, Liu B, Zhou Y, Zhen X, Xu C, Jiang T. Cortical thickness is associated with different apolipoprotein E genotypes in healthy elderly adults. Neurosci Lett. 2010;479:332‐336. 10.1016/j.neulet.2010.05.092 PubMed DOI PMC

Alexopoulos P, Richter‐Schmidinger T, Horn M, et al. Hippocampal volume differences between healthy young apolipoprotein e ε2 and ε4 carriers. J Alzheimer's Dis. 2011;26:207‐210. 10.3233/JAD-2011-110356 PubMed DOI

Fennema‐Notestine C, Panizzon MS, Thompson WR, et al. Presence of ApoE ε4 allele associated with thinner frontal cortex in middle age. J Alzheimer's Dis. 2011;2:77‐88. 10.3233/978-1-60750-793-2-77 PubMed DOI PMC

Groot C, Sudre CH, Barkhof F, et al. Clinical phenotype, atrophy, and small vessel disease in APOEε2 carriers with Alzheimer disease. Neurology. 2018;91:e1851‐9. 10.1212/WNL.0000000000006503 PubMed DOI

Berlau DJ, Corrada MM, Head E, Kawas CH. ApoE ε2 is associated with intact cognition but increased Alzheimer pathology in the oldest old. Neurology. 2009;72:829‐834. 10.1212/01.wnl.0000343853.00346.a4 PubMed DOI PMC

Berlau DJ, Kahle‐Wrobleski K, Head E, Goodus M, Kim R, Kawas C. Dissociation of neuropathologic findings and cognition: case report of an apolipoprotein E epsilon2/epsilon2 genotype. Arch Neurol. 2007;64:1193‐1196. 10.1001/archneur.64.8.1193 PubMed DOI PMC

Jack CR, Wiste HJ, Weigand SD, et al. Different definitions of neurodegeneration produce similar amyloid/neurodegeneration biomarker group findings. Brain. 2015;138:3747‐3759. 10.1093/brain/awv283 PubMed DOI PMC

Dickerson BC, Bakkour A, Salat DH, et al. The cortical signature of Alzheimer's disease: regionally specific cortical thinning relates to symptom severity in very mild to mild AD dementia and is detectable in asymptomatic amyloid‐positive individuals. Cereb Cortex. 2009;19:497‐510. 10.1093/cercor/bhn113 PubMed DOI PMC

Arenaza‐Urquijo EM, Przybelski SA, Lesnick TL, et al. The metabolic brain signature of cognitive resilience in the 80+: beyond Alzheimer pathologies. Brain. 2019;142:1134‐1147. 10.1093/brain/awz037 PubMed DOI PMC

Ferreira D, Hansson O, Barroso J, et al. The interactive effect of demographic and clinical factors on hippocampal volume: a multicohort study on 1958 cognitively normal individuals. Hippocampus. 2017;27:653‐667. 10.1002/hipo.22721 PubMed DOI

Molinuevo JL, Gramunt N, Gispert JD, et al. The ALFA project: a research platform to identify early pathophysiological features of Alzheimer's disease. Alzheimer's. Dement Transl Res Clin Interv. 2016;2:82‐92. 10.1016/j.trci.2016.02.003 PubMed DOI PMC

van Der Flier WM, Scheltens P. Amsterdam dementia cohort: performing research to optimize care. J Alzheimer's Dis. 2018;62:1091‐1111. 10.3233/JAD-170850 PubMed DOI PMC

Slot RER, Verfaillie SCJ, Overbeek JM, et al. Subjective Cognitive Impairment Cohort (SCIENCe): study design and first results. Alzheimer's Res Ther. 2018;10:1‐13. 10.1186/s13195-018-0390-y PubMed DOI PMC

Rydberg Sterner T, Ahlner F, Blennow K, et al. The Gothenburg H70 Birth cohort study 2014‐16: design, methods and study population. Eur J Epidemiol. 2019;34:191‐209. 10.1007/s10654-018-0459-8 PubMed DOI PMC

Marcus DS, Wang TH, Parker J, Csernansky JC, Morris JC, Buckner RL. Open Access Series of Imaging Studies (OASIS): longitudinal MRI data in nondemented and demented older adults. J Cogn Neurosci. 2007;19:1498‐1507. 10.1162/jocn.2007.19.9.1498 PubMed DOI

Simmons A, Westman E, Muehlboeck S, et al. The AddNeuroMed framework for multi‐centre MRI assessment of Alzheimer's disease: experience from the first 24 months. Int J Geriatr Psychiatry. 2011;26:75‐82. 10.1002/gps.2491 PubMed DOI

Sheardova K, Vyhnalek M, Nedelska Z, et al. Czech Brain Aging Study (CBAS): prospective multicentre cohort study on risk and protective factors for dementia in the Czech Republic. BMJ Open. 2019;9:1‐8. 10.1136/bmjopen-2019-030379 PubMed DOI PMC

Desikan RS, Ségonne F, Fischl B, et al. An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. Neuroimage. 2006;31:968‐980. 10.1016/j.neuroimage.2006.01.021 PubMed DOI

Insel PS, Hansson O, Mattsson‐Carlgren N. Association between apolipoprotein E ε2 vs ε4, age, and β‐Amyloid in adults without cognitive impairment. JAMA Neurol. 2020;02:4‐10. 10.1001/jamaneurol.2020.3780 PubMed DOI PMC

Clarke GM, Anderson CA, Pettersson FH, Cardon LR, Morris AP, Zondervan KT. Basic statistical analysis in genetic case‐control studies. Nat Protoc. 2011;6:121‐133. 10.1038/nprot.2010.182 PubMed DOI PMC

Ossenkoppele R, Schonhaut DR, Schöll M, et al. Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer's disease. Brain. 2016;139:1551‐1567. 10.1093/brain/aww027 PubMed DOI PMC

Liu Y, Paajanen T, Westman E. APOE ε2 allele is associated with larger regional cortical thicknesses and Volumes. Dement Geriatr Cogn Disord. 2010;30:229‐237. 10.1159/000320136 PubMed DOI

Shaw P, Lerch JP, Pruessner JC, et al. Cortical morphology in children and adolescents with different apolipoprotein E gene polymorphisms: an observational study. Lancet Neurol. 2007;6:494‐500. 10.1016/S1474-4422 PubMed DOI

Sun FW, Stepanovic MR, Andreano J, Barrett LF, Touroutoglou A, Dickerson BC. Youthful brains in older adults: preserved neuroanatomy in the default mode and salience networks contributes to youthful memory in superaging. J Neurosci. 2016;36:9659‐9668. 10.1523/JNEUROSCI.1492-16.2016 PubMed DOI PMC

Shi Y, Yamada K, Liddelow SA, et al. ApoE4 markedly exacerbates tau‐mediated neurodegeneration in a mouse model of tauopathy. Nature. 2017;549:523‐527. 10.1038/nature24016 PubMed DOI PMC

Honea Ra, Vidoni E, Harsha A, Burns JM. Impact of APOE on the healthy aging brain: a Voxel‐based MRI and DTI study. J Alzheimer's Dis. 2009;18:553‐564. 10.3233/JAD-2009-1163.Impact PubMed DOI PMC

Alexander GE, Bergfield KL, Chen K, et al. Gray matter network associated with risk for Alzheimer's disease in young to middle‐aged adults. Neurobiol Aging. 2012;33:2723‐2732. 10.1016/j.neurobiolaging.2012.01.014 PubMed DOI PMC

Suri S, Heise V, Trachtenberg AJ, Mackay CE. The forgotten APOE allele: a review of the evidence and suggested mechanisms for the protective effect of APOE e2. Neurosci Biobehav Rev. 2013;37:2878‐2886. 10.1016/j.neubiorev.2013.10.010 PubMed DOI

Yamazaki Y, Zhao N, Caulfield TR, Liu CC, Bu G. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat Rev Neurol. 2019;15:501‐518. 10.1038/s41582-019-0228-7 PubMed DOI PMC

Hashimoto T, Serrano‐Pozo A, Hori Y, et al. Apolipoprotein E, especially apolipoprotein E4, increases the oligomerization of amyloid β peptide. J Neurosci. 2012;32:15181‐15192. 10.1523/JNEUROSCI.1542-12.2012 PubMed DOI PMC

Jansen WJ, Ossenkoppele R, Knol DL, et al. Prevalence of cerebral amyloid pathology in persons without dementia: a meta‐analysis. JAMA ‐ J Am Med Assoc. 2015;313:1924‐1938. 10.1001/jama.2015.4668 PubMed DOI PMC