Effect of Alzheimer’s Disease Risk Genes on Trajectories of Cognitive Function in the Cardiovascular Health Study

ObjectiveThe 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 a...

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Bibliographic Details
Published in:The American journal of psychiatry 2012-09, Vol.169 (9), p.954-962
Main Authors: Sweet, Robert A., Seltman, Howard, Emanuel, James E., Lopez, Oscar L., Becker, James T., Bis, Joshua C., Weamer, Elise A., DeMichele-Sweet, Mary Ann A., Kuller, Lewis H.
Format: Article
Language:English
Subjects:
Adult and adolescent clinical studies
Age of Onset
Aged
Alleles
Alzheimer Disease - complications
Alzheimer Disease - genetics
Alzheimer Disease - psychology
Alzheimer's disease
Apolipoprotein E4 - genetics
Bayes Theorem
Biological and medical sciences
Cardiovascular disease
Clusterin - genetics
Cognition & reasoning
Cohort Studies
Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases
Dementia - complications
Dementia - genetics
Dementia - psychology
Disease Progression
Female
Genetic Predisposition to Disease - genetics
Genetics
Humans
Male
Medical sciences
Models, Psychological
Monomeric Clathrin Assembly Proteins - genetics
Neurology
Organic mental disorders. Neuropsychology
Polymorphism, Single Nucleotide - genetics
Psychiatry
Psychology. Psychoanalysis. Psychiatry
Psychopathology. Psychiatry
Receptors, Complement 3b - genetics
Risk Factors
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Summary:ObjectiveThe 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.MethodThe 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.ResultsThe 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.ConclusionsEvaluation of cognitive trajectories provides a powerful approach to dissecting genetic effects on the processes leading to cognitive deterioration and Alzheimer’s disease.
ISSN:0002-953X
1535-7228
DOI:10.1176/appi.ajp.2012.11121815