Effect of Alzheimer's disease risk genes on trajectories of cognitive function in the Cardiovascular Health Study.

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. METHOD 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.

[1]  J. Haines,et al.  Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. , 1993, Science.

[2]  B. Devlin,et al.  Psychotic symptoms in Alzheimer disease: evidence for a distinct phenotype , 2003, Molecular Psychiatry.

[3]  Susan M Resnick,et al.  Association of plasma clusterin concentration with severity, pathology, and progression in Alzheimer disease. , 2010, Archives of general psychiatry.

[4]  S. DeKosky,et al.  Synapse loss in frontal cortex biopsies in Alzheimer's disease: Correlation with cognitive severity , 1990, Annals of neurology.

[5]  Katie Hamm,et al.  apoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain. , 2008, The Journal of clinical investigation.

[6]  P. Bosco,et al.  Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease , 2009, Nature Genetics.

[7]  T. Suuronen,et al.  Clusterin: A forgotten player in Alzheimer's disease , 2009, Brain Research Reviews.

[8]  S. Haneuse,et al.  Item response theory facilitated cocalibrating cognitive tests and reduced bias in estimated rates of decline. , 2008, Journal of clinical epidemiology.

[9]  B. Stevens,et al.  The role of the classical complement cascade in synapse loss during development and glaucoma. , 2010, Advances in experimental medicine and biology.

[10]  J. Haines,et al.  Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. , 1997, JAMA.

[11]  Oscar L. Lopez,et al.  Evaluation of Dementia in the Cardiovascular Health Cognition Study , 2003, Neuroepidemiology.

[12]  Eden R Martin,et al.  No gene is an island: the flip-flop phenomenon. , 2007, American journal of human genetics.

[13]  C. Jack,et al.  Evidence for ordering of Alzheimer disease biomarkers. , 2011, Archives of neurology.

[14]  Kyoko Shibata,et al.  Genetic flip-flop without an accompanying change in linkage disequilibrium. , 2008, American journal of human genetics.

[15]  E. Wijsman,et al.  Genome-Wide Association of Familial Late-Onset Alzheimer's Disease Replicates BIN1 and CLU and Nominates CUGBP2 in Interaction with APOE , 2011, PLoS genetics.

[16]  H. Amièva,et al.  Sensitivity of four psychometric tests to measure cognitive changes in brain aging-population-based studies. , 2006, American journal of epidemiology.

[17]  M. Mega,et al.  The Neuropsychiatric Inventory , 1994, Neurology.

[18]  G. Dawson,et al.  Autism and the serotonin transporter: the long and short of it , 2005, Molecular Psychiatry.

[19]  J. Atkinson,et al.  Structure–function relationships of complement receptor type 1 , 2001, Immunological reviews.

[20]  Sudha Seshadri,et al.  Genome-wide analysis of genetic loci associated with Alzheimer disease. , 2010, JAMA.

[21]  J. Haines,et al.  Effects of Age, Sex, and Ethnicity on the Association Between Apolipoprotein E Genotype and Alzheimer Disease: A Meta-analysis , 1997 .

[22]  Sudha Seshadri,et al.  A meta-analysis of four genome-wide association studies of survival to age 90 years or older: the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. , 2010, The journals of gerontology. Series A, Biological sciences and medical sciences.

[23]  D. Bennett,et al.  Terminal Cognitive Decline: Accelerated Loss of Cognition in the Last Years of Life , 2007, Psychosomatic medicine.

[24]  L. Cardon,et al.  Aspects of observing and claiming allele flips in association studies , 2009, Genetic epidemiology.

[25]  Margaret A. Pericak-Vance,et al.  Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease , 1997 .

[26]  L. Fried,et al.  Recruitment of adults 65 years and older as participants in the Cardiovascular Health Study. , 1993, Annals of epidemiology.

[27]  C. Jack,et al.  Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade , 2010, The Lancet Neurology.

[28]  R. Kronmal,et al.  The Cardiovascular Health Study: design and rationale. , 1991, Annals of epidemiology.

[29]  Thomas W. Mühleisen,et al.  Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease , 2013, Nature Genetics.

[30]  Streichenwein Sm,et al.  Am J Psychiatry , 1996 .

[31]  M. Owen,et al.  Distribution and Expression of Picalm in Alzheimer Disease , 2010, Journal of neuropathology and experimental neurology.

[32]  Oscar L Lopez,et al.  Trajectories of cognitive decline in Alzheimer's disease , 2009, International Psychogeriatrics.

[33]  F. Pasquier,et al.  Alzheimer risk associated with a copy number variation in the complement receptor 1 increasing C3b/C4b binding sites , 2011, Molecular Psychiatry.

[34]  D. Ashby.  Bayesian statistics in medicine: a 25 year review , 2006, Statistics in medicine.

[35]  H. Chui,et al.  The Modified Mini-Mental State (3MS) examination. , 1987, The Journal of clinical psychiatry.

[36]  J. Becker,et al.  Trajectory of cognitive decline as a predictor of psychosis in early Alzheimer disease in the cardiovascular health study. , 2011, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[37]  P R Evans,et al.  Simultaneous binding of PtdIns(4,5)P2 and clathrin by AP180 in the nucleation of clathrin lattices on membranes. , 2001, Science.

[38]  Hans Lehrach,et al.  The role of clusterin, complement receptor 1, and phosphatidylinositol binding clathrin assembly protein in Alzheimer disease risk and cerebrospinal fluid biomarker levels. , 2011, Archives of general psychiatry.

[39]  D. Jeste,et al.  Epidemiology of and risk factors for psychosis of Alzheimer's disease: a review of 55 studies published from 1990 to 2003. , 2005, The American journal of psychiatry.