The etiologies of normative cognitive change and Alzheimer's disease (AD) in late adulthood are not fully understood. Outside of the gene encoding apoE, consistent candidate gene associations are relatively scant. Established effects of genetic variation in APOE, the primary cholesterol transporter in the brain, upon lipid levels, cognitive change, and AD risk suggest the cholesterol pathway may be centrally important. We propose to target genes integral to cholesterol homeostasis and perform multi-tiered association studies to investigate the possible existence and impact of functional genomic sequence variation on plasma lipid parameters, CSF Abeta and tau, measures of longitudinal cognitive performance, and Alzheimer's disease (AD). We have prioritized 502 genetic markers, focusing on HapMap based markers as well as potential functional polymorphisms within 20 cholesterol genes. We hypothesize that functional genetic polymorphism occurs in the selected candidate genes and will explain variance in a variety of cholesterol related phenotypes, with stronger effects upon proximal phenotypes (e.g. cholesterol and Abeta levels) than for cognitive phenotypes and AD risk. Several related longitudinal Swedish twin studies will be combined to test association with serum lipid biomarkers, cognitive decline, total dementia and AD risk. Additionally, we will use a large established Swedish AD case-control sample for testing additional biomarkers (CSF Abeta, tau) and AD risk. Across twin and case-control studies there are 3,858 of individuals (59 percent female) available for analysis of DMA markers, 1,227 with AD diagnoses. Of those with DNA, there are 676 twin pairs with available lipid biomarkers and 729 twin pairs with available cognitive data. Our goals are to move stepwise from anonymous variance components to measured genes in the cholesterol pathway, intermediate biomarkers, and ultimate behavioral and clinical phenotypes. Of principal interest is to: (1) test the association of cholesterol gene markers with serum lipid and CSF biomarkers; (2) test the association of lipid biomarkers and cholesterol gene markers with cognitive decline across verbal, spatial, memory and perceptual speed domains, using longitudinal growth models to quantify change; and (3) test Jhe association of cholesterol gene markers, total dementia and AD risk. We will apply haplotype and multi-locus regression approaches to determine association. Strengths of the study include multiple levels of replication and rich longitudinal data, both for lipid and cognitive traits. The examination of multiple candidate genes in the cholesterol pathway, using both twin-based and case-control methods, will lead to an increased understanding of factors that contribute to cognitive changes, total dementia and AD risk in late-life. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG028555-01A1
Application #
7265691
Study Section
Behavioral Genetics and Epidemiology Study Section (BGES)
Program Officer
Miller, Marilyn
Project Start
2007-06-01
Project End
2011-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
1
Fiscal Year
2007
Total Cost
$406,493
Indirect Cost
Name
University of California Riverside
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
627797426
City
Riverside
State
CA
Country
United States
Zip Code
92521
Svane, Anne Marie; Soerensen, Mette; Lund, Jesper et al. (2018) DNA Methylation and All-Cause Mortality in Middle-Aged and Elderly Danish Twins. Genes (Basel) 9:
Zhan, Yiqiang; Clements, Mark S; Roberts, Rosebud O et al. (2018) Association of telomere length with general cognitive trajectories: a meta-analysis of four prospective cohort studies. Neurobiol Aging 69:111-116
Scott, Robert A; Scott, Laura J; Mägi, Reedik et al. (2017) An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans. Diabetes 66:2888-2902
Jiang, Miao; Foebel, Andrea Dawn; Kuja-Halkola, Ralf et al. (2017) Frailty index as a predictor of all-cause and cause-specific mortality in a Swedish population-based cohort. Aging (Albany NY) 9:2629-2646
Karlsson, I K; Ploner, A; Song, C et al. (2017) Genetic susceptibility to cardiovascular disease and risk of dementia. Transl Psychiatry 7:e1142
Berglund, Kari; Reynolds, Chandra A; Ploner, Alexander et al. (2016) Longitudinal decline of leukocyte telomere length in old age and the association with sex and genetic risk. Aging (Albany NY) 8:1398-415
Ehret, Georg B (see original citation for additional authors) (2016) The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals. Nat Genet 48:1171-1184
Gaulton, Kyle J; Ferreira, Teresa; Lee, Yeji et al. (2015) Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci. Nat Genet 47:1415-25
Carlson, Jesper O E; Gatz, Margaret; Pedersen, Nancy L et al. (2015) Antemortem Prediction of Braak Stage. J Neuropathol Exp Neurol 74:1061-70
Karlsson, Ida K; Bennet, Anna M; Ploner, Alexander et al. (2015) Apolipoprotein E ?4 genotype and the temporal relationship between depression and dementia. Neurobiol Aging 36:1751-1756

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