title: APOEε2 is associated with milder clinical and pathological Alzheimer disease.
abstract: OBJECTIVE
  The Alzheimer disease (AD) APOEε4 risk allele associates with an earlier age at onset and increased amyloid-β deposition, whereas the protective APOEε2 allele delays the onset and appears to prevent amyloid-β deposition. Yet the clinical and pathological effects of APOEε2 remain uncertain because of its relative rarity. We investigated the effects of APOEε2 and ε4 alleles on AD pathology and cognition in a large US data set of well-characterized AD patients.
  
  
  METHODS
  We studied individuals from the National Alzheimer's Coordinating Center autopsy cohort across the entire clinicopathological continuum of AD. Multivariate models were built to examine the associations between APOE alleles and AD neuropathological changes, using the APOEε3/ε3 group as comparator. Mediation analysis was used to estimate the direct and indirect effects of APOE alleles on AD pathology and cognition (Clinical Dementia Rating Sum of Boxes and Mini-Mental State Examination).
  
  
  RESULTS
  Compared to APOEε3/ε3, APOEε2 is independently associated with lower Braak neurofibrillary tangle (NFT) stages and possibly fewer neuritic plaques, but has no direct effect on cerebral amyloid angiopathy (CAA) severity, whereas APOEε4 is associated with more neuritic plaques and CAA, but has no independent effect on Braak NFT stage. Unadjusted analyses showed marked differences among APOE genotypes with respect to cognitive performance (ε2 > ε3 > ε4). Mediation analysis suggests that this is largely explained through effects on pathology.
  
  
  CONCLUSIONS
  Even when adjusted for age at onset, symptom duration, and other demographic variables, APOEε2 is associated with milder AD pathology and less severe antemortem cognitive impairment compared to APOEε3 and ε4 alleles, suggesting a relative neuroprotective effect of APOEε2 in AD.
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Boston, MA.|Massachusetts Alzheimer Disease Research Center, Charlestown, MA.|Department of Neurology, University of Iowa Hospitals and Clinics, Iowa City, IA.
authors.forename: Alberto
authors.initials: A
authors.lastname: Serrano-Pozo
authors.affiliation: Division of Biostatistics and Epidemiology, University of Massachusetts, Amherst, MA.
authors.forename: Jing
authors.initials: J
authors.lastname: Qian
authors.affiliation: National Alzheimer's Coordinating Center and Department of Epidemiology, University of Washington, Seattle, WA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Monsell
authors.affiliation: Massachusetts Alzheimer Disease Research Center, Charlestown, MA.|Department of Biostatistics, Harvard School of Public Health, Boston, MA.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Betensky
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Boston, MA.|Massachusetts Alzheimer Disease Research Center, Charlestown, MA.
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D053329:Apolipoprotein E2 / Q000235:genetics*; D053318:Apolipoprotein E3 / Q000235:genetics; D053327:Apolipoprotein E4 / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D012720:Severity of Illness Index
chemical_list: D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4