title: The APOE4 allele shows opposite sex bias in microbleeds and Alzheimer's disease of humans and mice.
abstract: The apolipoprotein APOE4 allele confers greater risk of Alzheimer's disease (AD) for women than men, in conjunction with greater clinical deficits per unit of AD neuropathology (plaques, tangles). Cerebral microbleeds, which contribute to cognitive dysfunctions during AD, also show APOE4 excess, but sex-APOE allele interactions are not described. We report that elderly men diagnosed for mild cognitive impairment and AD showed a higher risk of cerebral cortex microbleeds with APOE4 allele dose effect in 2 clinical cohorts (ADNI and KIDS). Sex-APOE interactions were further analyzed in EFAD mice carrying human APOE alleles and familial AD genes (5XFAD (+/-) /human APOE(+/+)). At 7 months, E4FAD mice had cerebral cortex microbleeds with female excess, in contrast to humans. Cerebral amyloid angiopathy, plaques, and soluble Aβ also showed female excess. Both the cerebral microbleeds and cerebral amyloid angiopathy increased in proportion to individual Aβ load. In humans, the opposite sex bias of APOE4 allele for microbleeds versus the plaques and tangles is the first example of organ-specific, sex-linked APOE allele effects, and further shows AD as a uniquely human condition.
authors.affiliation: Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.
authors.forename: Mafalda
authors.initials: M
authors.lastname: Cacciottolo
authors.affiliation: Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Christensen
authors.affiliation: Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Moser
authors.affiliation: Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.
authors.forename: Jiahui
authors.initials: J
authors.lastname: Liu
authors.affiliation: Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Pike
authors.affiliation: Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Conor
authors.initials: C
authors.lastname: Smith
authors.affiliation: Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: LaDu
authors.affiliation: Department of Medicine, Duke University, Durham VA Medical Center and GRECC, Durham, NC, USA.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Sullivan
authors.affiliation: Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.
authors.forename: Todd E
authors.initials: TE
authors.lastname: Morgan
authors.affiliation: Department of Molecular and Computational Biology, University of Southern California, Los Angeles, CA, USA.
authors.forename: Egor
authors.initials: E
authors.lastname: Dolzhenko
authors.affiliation: Hemorrhagic Stroke Research Program, Department of Neurology, Massachusetts General Hospital Stroke Research Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Charidimou
authors.affiliation: Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet, Stockholm, Sweden; Division of Clinical Geriatrics, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Lars-Olof
authors.initials: LO
authors.lastname: Wahlund
authors.affiliation: Division of Medical Imaging and Technology, Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden; Department of Radiology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Maria Kristofferson
authors.initials: MK
authors.lastname: Wiberg
authors.affiliation: Division of Medical Imaging and Technology, Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden; Department of Radiology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Sara
authors.initials: S
authors.lastname: Shams
authors.affiliation: Department of Radiology, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Gloria Chia-Yi
authors.initials: GC
authors.lastname: Chiang
authors.affiliation: Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA; Department of Molecular and Computational Biology, University of Southern California, Los Angeles, CA, USA; Department of Biological Sciences, Dornsife College, University of Southern California, Los Angeles, CA, USA. Electronic address: cefinch@usc.edu.
authors.forename: Caleb E
authors.initials: CE
authors.lastname: Finch
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology* / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D016657:Cerebral Amyloid Angiopathy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002540:Cerebral Cortex / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000235:genetics* / Q000473:pathology*; D003071:Cognition; D060825:Cognitive Dysfunction / Q000235:genetics / Q000473:pathology; D004843:Epistasis, Genetic / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D012306:Risk; D012727:Sex Characteristics
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E
keywords: Alzheimer's Disease Neuroimaging Initiative (ADNI); Alzheimer's disease (AD); Amyloid β-peptide (Aβ); Apolipoprotein E (APOE); Cerebral amyloid angiopathy (CAA); Cerebral microbleeds or microhemorrhages; EFAD mice; Karolinska Imaging Dementia Study (KIDS); Microbleeds; Sex bias