title: Effect of Alzheimer's disease risk genes on trajectories of cognitive function in the Cardiovascular Health Study.
abstract: OBJECTIVE
  The trajectory of cognitive decline in patients with late-onset Alzheimer's disease varies widely. Genetic variations in CLU, PICALM, and CR1 are associated with Alzheimer's disease, but it is unknown whether they exert their effects by altering cognitive trajectory in elderly individuals at risk for the disease.
  
  
  METHODS
  The authors developed a Bayesian model to fit cognitive trajectories in a cohort of elderly subjects and test for genetic effects. They first validated the model's ability to detect the previously established effects of APOE ε4 alleles on age at cognitive decline and of psychosis on the rate of cognitive decline in 802 subjects from the Cardiovascular Health Cognition Study who did not have dementia at study entry and developed incident dementia during follow-up. The authors then evaluated the effects of CLU, PICALM, and CR1 on age and rate of decline in 1,831 subjects who did not have dementia at study entry and then did or did not develop incident dementia by study's end.
  
  
  RESULTS
  The model generated robust fits to the observed cognitive trajectory data, and validation analysis supported the model's utility. CLU and CR1 were associated with more rapid cognitive decline. PICALM was associated with an earlier age at midpoint of cognitive decline. Associations remained after accounting for the effects of APOE and demographic factors.
  
  
  CONCLUSIONS
  Evaluation of cognitive trajectories provides a powerful approach to dissecting genetic effects on the processes leading to cognitive deterioration and Alzheimer's disease.
authors.affiliation: Department of Psychiatry, University of Pittsburgh, Pittsburgh, USA. sweetra@upmc.edu
authors.forename: Robert A
authors.initials: RA
authors.lastname: Sweet
authors.forename: Howard
authors.initials: H
authors.lastname: Seltman
authors.forename: James E
authors.initials: JE
authors.lastname: Emanuel
authors.forename: Oscar L
authors.initials: OL
authors.lastname: Lopez
authors.forename: James T
authors.initials: JT
authors.lastname: Becker
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Bis
authors.forename: Elise A
authors.initials: EA
authors.lastname: Weamer
authors.forename: Mary Ann A
authors.initials: MA
authors.lastname: DeMichele-Sweet
authors.forename: Lewis H
authors.initials: LH
authors.lastname: Kuller
mesh_terms: D017668:Age of Onset; D000368:Aged; D000483:Alleles; D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics* / Q000523:psychology*; D053327:Apolipoprotein E4 / Q000235:genetics; D001499:Bayes Theorem; D051152:Clusterin / Q000235:genetics*; D015331:Cohort Studies; D003704:Dementia / Q000150:complications / Q000235:genetics* / Q000523:psychology*; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008297:Male; D008960:Models, Psychological; D034041:Monomeric Clathrin Assembly Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017463:Receptors, Complement 3b / Q000235:genetics*; D012307:Risk Factors
chemical_list: D053327:Apolipoprotein E4; C495242:CLU protein, human; C509991:CR1 protein, human; D051152:Clusterin; D034041:Monomeric Clathrin Assembly Proteins; C439003:PICALM protein, human; D017463:Receptors, Complement 3b