title: Cognitive domain decline in healthy apolipoprotein E epsilon4 homozygotes before the diagnosis of mild cognitive impairment.
abstract: BACKGROUND
  Memory declines more rapidly with age in apolipoprotein E (APOE) epsilon4 carriers than in APOE epsilon4 noncarriers, and APOE epsilon4 homozygotes' cognitive performances correlate with stressors. These changes could represent presymptomatic disease in some, despite their youth.
  
  
  OBJECTIVE
  To show that presymptomatic APOE epsilon4 homozygotes experience greater psychometric decline at a younger age than APOE epsilon4 heterozygotes and noncarriers before the diagnosis of mild cognitive impairment (MCI) and Alzheimer disease (AD).
  
  
  METHODS
  Prospective observational study
  
  
  METHODS
  Academic medical center.
  
  
  METHODS
  A total of 43 APOE epsilon4 homozygotes, 59 APOE epsilon4 heterozygotes, and 112 APOE epsilon4 noncarriers aged 50 to 69 years were cognitively healthy and matched at entry according to age, educational level, and sex.
  
  
  METHODS
  Neuropsychological battery given every 2 years.
  
  
  METHODS
  Predefined test and cognitive domain decline criteria applied to consecutive epochs.
  
  
  RESULTS
  Of 214 participants, 48 showed no decline on any test, 126 showed decline on only 1 test in 1 or more domains, and 40 showed decline on 2 or more tests in 1 or more domains. Cognitive domain decline occurred in 4 of 10 APOE epsilon4 homozygotes 60 years and older at entry (40.0%) compared with 5 of 66 APOE epsilon4 heterozygotes and noncarriers (7.6%) (P = .02) and was more predictive of subsequent decline than nondomain decline (17 of 24 [70.8%] vs 29 of 70 [41.4%]; P = .01). Decline on any memory test was predictive of further decline (P < .001), as was memory domain decline (P = .006) in all genetic subgroups. Seven participants developed MCI (in 6) or AD (in 1), of whom 5 were APOE epsilon4 homozygotes (P = .008). Retrospective comparison showed that those who experienced multidomain, memory, and language domain decline had lower spatial and memory scores at entry than those who experienced no decline.
  
  
  CONCLUSIONS
  APOE epsilon4 homozygotes in their 60s have higher rates of cognitive domain decline than APOE epsilon4 heterozygotes or noncarriers before the diagnosis of MCI and AD, thus confirming and characterizing the existence of a pre-MCI state in this genetic subset.
authors.affiliation: Department of Neurology, Mayo Clinic, 13400 E Shea Blvd, Scottsdale, AZ 85259, USA. caselli.richard@mayo.edu
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Caselli
authors.forename: Eric M
authors.initials: EM
authors.lastname: Reiman
authors.forename: Dona E C
authors.initials: DE
authors.lastname: Locke
authors.forename: Michael L
authors.initials: ML
authors.lastname: Hutton
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Hentz
authors.forename: Charlene
authors.initials: C
authors.lastname: Hoffman-Snyder
authors.forename: Bryan K
authors.initials: BK
authors.lastname: Woodruff
authors.forename: Gene E
authors.initials: GE
authors.lastname: Alexander
authors.forename: David
authors.initials: D
authors.lastname: Osborne
mesh_terms: D000368:Aged; D000375:Aging / Q000502:physiology; D000483:Alleles; D053327:Apolipoprotein E4 / Q000235:genetics*; D003071:Cognition / Q000502:physiology*; D003072:Cognition Disorders / Q000235:genetics* / Q000523:psychology*; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007361:Intelligence Tests; D007807:Language Tests; D008297:Male; D001523:Mental Disorders / Q000523:psychology; D011939:Mental Recall / Q000502:physiology; D008875:Middle Aged; D009483:Neuropsychological Tests; D011569:Psychiatric Status Rating Scales; D011597:Psychomotor Performance / Q000502:physiology; D012306:Risk; D014888:Wechsler Scales
chemical_list: D053327:Apolipoprotein E4