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A Network of Genetic Effects on Non-Demented Cognitive Aging: Alzheimer's Genetic Risk (CLU + CR1?+?PICALM) Intensifies Cognitive Aging Genetic Risk (COMT + BDNF) Selectively for APOE?4 Carriers.

ABSTRACT: BACKGROUND:Trajectories of complex neurocognitive phenotypes in preclinical aging may be produced differentially through selective and interactive combinations of genetic risk. OBJECTIVE:We organize three possible combinations into a "network" of genetic risk indices derived from polymorphisms associated with normal and impaired cognitive aging, as well as Alzheimer's disease (AD). Specifically, we assemble and examine three genetic clusters relevant to non-demented cognitive trajectories: 1) Apolipoprotein E (APOE), 2) a Cognitive Aging Genetic Risk Score (CA-GRS; Catechol-O-methyltransferase + Brain-derived neurotrophic factor), and 3) an AD-Genetic Risk Score (AD-GRS; Clusterin + Complement receptor 1?+?Phosphatidylinositol-binding clathrin assembly protein). METHOD:We use an accelerated longitudinal design (n?=?634; age range?=?55-95 years) to test whether AD-GRS (low versus high) moderates the effect of increasing CA-GRS risk on executive function (EF) performance and change as stratified by APOE status (?4+ versus ?4-). RESULTS:APOE?4 carriers with high AD-GRS had poorer EF performance at the centering age (75 years) and steeper 9-year decline with increasing CA-GRS but this association was not present in APOE?4 carriers with low AD-GRS. CONCLUSIONS:APOE?4 carriers with high AD-GRS are at elevated risk of cognitive decline when they also possess higher CA-GRS risk. Genetic risk from both common cognitive aging and AD-related indices may interact in intensification networks to differentially predict (1) level and trajectories of EF decline and (2) potential selective vulnerability for transitions into impairment and dementia.

SUBMITTER: Sapkota S

PROVIDER: S-EPMC5830167 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Publications

A Network of Genetic Effects on Non-Demented Cognitive Aging: Alzheimer's Genetic Risk (CLU + CR1 + PICALM) Intensifies Cognitive Aging Genetic Risk (COMT + BDNF) Selectively for APOEɛ4 Carriers.

Sapkota Shraddha S Dixon Roger A RA

Journal of Alzheimer's disease : JAD 20180101 2

<h4>Background</h4>Trajectories of complex neurocognitive phenotypes in preclinical aging may be produced differentially through selective and interactive combinations of genetic risk.<h4>Objective</h4>We organize three possible combinations into a "network" of genetic risk indices derived from polymorphisms associated with normal and impaired cognitive aging, as well as Alzheimer's disease (AD). Specifically, we assemble and examine three genetic clusters relevant to non-demented cognitive traj ...[more]

PMID: 29480189

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Project description:BackgroundGenetic variants at the CLU, CR1, and PICALM loci associate with risk for late-onset Alzheimer's disease (LOAD) in genomewide association studies. In this study, our aim was to determine whether the LOAD risk variants at these three loci influence memory endophenotypes in black and white subjects.MethodsWe pursued an association study between single nucleotide polymorphism genotypes at the CLU, CR1, and PICALM loci and memory endophenotypes. We assessed black subjects (AA series: 44 with LOAD and 224 control subjects) recruited at Mayo Clinic Florida and whites recruited at Mayo Clinic Minnesota (RS series: 372 with LOAD and 1690 control subjects) and Florida (JS series: 60 with LOAD and 529 control subjects). Single nucleotide polymorphisms at the LOAD risk loci CLU (rs11136000), CR1 (rs6656401, rs3818361), and PICALM (rs3851179) were genotyped and tested for association with Logical Memory immediate recall, Logical Memory delayed recall, Logical Memory percent retention, Visual Reproduction immediate recall, Visual Reproduction delayed recall, and Visual Reproduction percent retention scores from the Wechsler Memory Scale-Revised using multivariable linear regression analysis, adjusting for age at exam, sex, education, and apolipoprotein E ε4 dosage.ResultsWe identified nominally significant or suggestive associations between the LOAD-risky CR1 variants and worse Logical Memory immediate recall scores in blacks (P = .068-.046, β = -2.7 to -1.2). The LOAD-protective CLU variant is associated with better logical memory endophenotypes in white subjects (P = .099-.027, β = 0.31-0.93). The CR1 associations persisted when the control subjects from the AA series were assessed separately. The CLU associations appeared to be driven by one of the white series (RS) and were also observed when the control subset from RS was analyzed.ConclusionThese results suggest for the first time that LOAD risk variants at CR1 may influence memory endophenotypes in blacks. In addition, the CLU LOAD-protective variant may confer enhanced memory in whites. Although these results would not remain significant after stringent corrections for multiple testing, they need to be considered in the context of the LOAD associations with which they have biological consistency. They also provide estimates for effect sizes on memory endophenotypes that could guide future studies. The detection of memory effects for these variants in clinically normal subjects, implies that these LOAD risk loci might modify memory prior to clinical diagnosis of AD.

Dataset Information

A Network of Genetic Effects on Non-Demented Cognitive Aging: Alzheimer's Genetic Risk (CLU + CR1?+?PICALM) Intensifies Cognitive Aging Genetic Risk (COMT + BDNF) Selectively for APOE?4 Carriers.

Publications

A Network of Genetic Effects on Non-Demented Cognitive Aging: Alzheimer's Genetic Risk (CLU + CR1 + PICALM) Intensifies Cognitive Aging Genetic Risk (COMT + BDNF) Selectively for APOEɛ4 Carriers.

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