title: Cognitive changes preceding clinical symptom onset of mild cognitive impairment and relationship to ApoE genotype.
abstract: BACKGROUND
  This study had two goals (1) to evaluate changes in neuropsychological performance among cognitively normal individuals that might precede the onset of clinical symptoms, and (2) to examine the impact of Apolipoprotein E (ApoE) genotype on these changes.
  
  
  METHODS
  Longitudinal neuropsychological, clinical assessments and consensus diagnoses were completed prospectively in 268 cognitively normal individuals. The mean duration of follow-up was 9.2 years (+/- 3.3). 208 participants remained normal and 60 developed cognitive decline, consistent with a diagnosis of MCI or dementia. Cox regression analyses were completed, for both baseline scores and rate of change in scores, in relation to time to onset of clinical symptoms. Analyses were completed both with and without ApoE-4 status included. Interactions with ApoE-4 status were also examined.
  
  
  RESULTS
  Lower baseline test scores, as well as greater rate of change in test scores, were associated with time to onset of clinical symptoms (p<0.001). The mean time from baseline to onset of clinical symptoms was 6.15 (+/- 3.4) years. The presence of an ApoE-4 allele doubled the risk of progression. The rate of change in two of the test scores was significantly different in ApoE-4 carriers vs. non-carriers.
  
  
  CONCLUSIONS
  Cognitive performance declines prior to the onset of clinical symptoms that are a harbinger of a diagnosis of MCI. Cognitive changes in normal individuals who will subsequently decline may be observed at least 6.5 years prior to symptom onset. In addition, the risk of decline is doubled among individuals with an ApoE-4 allele.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Albert
authors.forename: Anja
authors.initials: A
authors.lastname: Soldan
authors.forename: Rebecca
authors.initials: R
authors.lastname: Gottesman
authors.forename: Guy
authors.initials: G
authors.lastname: McKhann
authors.forename: Ned
authors.initials: N
authors.lastname: Sacktor
authors.forename: Leonie
authors.initials: L
authors.lastname: Farrington
authors.forename: Maura
authors.initials: M
authors.lastname: Grega
authors.forename: Raymond
authors.initials: R
authors.lastname: Turner
authors.forename: Yi
authors.initials: Y
authors.lastname: Lu
authors.forename: Shanshan
authors.initials: S
authors.lastname: Li
authors.forename: Mei-Cheng
authors.initials: MC
authors.lastname: Wang
authors.affiliation: Johns Hopkins School of Medicine - Neurology 1620 McElderry Street Reed Hall West 1 , Baltimore, Maryland 21205 United States. malbert9@jhmi.edu.
authors.forename: Ola
authors.initials: O
authors.lastname: Selnes
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000150:complications; D001057:Apolipoproteins E / Q000235:genetics*; D060825:Cognitive Dysfunction / Q000235:genetics* / Q000503:physiopathology*; D018450:Disease Progression; D005260:Female; D005838:Genotype; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D013997:Time Factors
chemical_list: D001057:Apolipoproteins E