Dataset Information

Polygenic risk scores for Alzheimer's disease are related to dementia risk in APOE ɛ4 negatives.

ABSTRACT:

Introduction

Studies examining the effect of polygenic risk scores (PRS) for Alzheimer's disease (AD) and apolipoprotein E (APOE) genotype on incident dementia in very old individuals are lacking.

Methods

A population-based sample of 2052 individuals ages 70 to 111, from Sweden, was followed in relation to dementia. AD-PRSs including 39, 57, 1333, and 13,942 single nucleotide polymorphisms (SNPs) were used.

Results

AD-PRSs (including 39 or 57 SNPs) were associated with dementia (57-SNPs AD-PRS: hazard ratio 1.09, confidence interval 1.01-1.19, P = .03), particularly in APOE ɛ4 non-carriers (57-SNPs AD-PRS: 1.15, 1.05-1.27, P = 4 × 10^-3, 39-SNPs AD-PRS: 1.22, 1.10-1.35, P = 2 × 10^-4). No association was found with the other AD-PRSs. Further, APOE ɛ4 was associated with increased risk of dementia (1.60, 1.35-1.92, P = 1 × 10^-7). In those aged ≥95 years, the results were similar for the AD-PRSs, while APOE ɛ4 only predicted dementia in the low-risk tertile of AD-PRSs.

Discussion

These results provide information to identify individuals at increased risk of dementia.

SUBMITTER: Najar J

PROVIDER: S-EPMC7821873 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Publications

Polygenic risk scores for Alzheimer's disease are related to dementia risk in APOE ɛ4 negatives.

Najar Jenna J van der Lee Sven J SJ Joas Erik E Wetterberg Hanna H Hardy John J Guerreiro Rita R Bras Jose J Waern Margda M Kern Silke S Zetterberg Henrik H Blennow Kaj K Skoog Ingmar I Zettergren Anna A

Alzheimer's & dementia (Amsterdam, Netherlands) 20210122 1

<h4>Introduction</h4>Studies examining the effect of polygenic risk scores (PRS) for Alzheimer's disease (AD) and apolipoprotein E (<i>APOE</i>) genotype on incident dementia in very old individuals are lacking.<h4>Methods</h4>A population-based sample of 2052 individuals ages 70 to 111, from Sweden, was followed in relation to dementia. AD-PRSs including 39, 57, 1333, and 13,942 single nucleotide polymorphisms (SNPs) were used.<h4>Results</h4>AD-PRSs (including 39 or 57 SNPs) were associated wi ...[more]

PMID: 33532541

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Project description:ObjectiveGenome-wide association studies (GWAS) have identified over 30 susceptibility loci associated with Alzheimer's disease (AD). Using AD GWAS data from the International Genomics of Alzheimer's Project (IGAP), Polygenic Risk Score (PRS) was successfully applied to predict life time risk of AD development. A recently introduced Polygenic Hazard Score (PHS) is able to quantify individuals with age-specific genetic risk for AD. The aim of this study was to quantify the age-specific genetic risk for AD with PRS and compare the results generated by PRS with those from PHS.MethodsQuantification of individual differences in age-specific genetic risk for AD identified by the PRS, was performed with Cox Regression on 9903 (2626 cases and 7277 controls) individuals from the Genetic and Environmental Risk in Alzheimer's Disease consortium (GERAD). Polygenic Hazard Scores were generated for the same individuals. The age-specific genetic risk for AD identified by the PRS was compared with that generated by the PHS. This was repeated using varying SNPs P-value thresholds for disease association.ResultsPolygenic Risk Score significantly predicted the risk associated with age at AD onset when SNPs were preselected for association to AD at P ≤ 0.001. The strongest effect (B = 0.28, SE = 0.04, P = 2.5 × 10-12) was observed for PRS based upon genome-wide significant SNPs (P ≤ 5 × 10-8). The strength of association was weaker with less stringent SNP selection thresholds.InterpretationBoth PRS and PHS can be used to predict an age-specific risk for developing AD. The PHS approach uses SNP effect sizes derived with the Cox Proportional Hazard Regression model. When SNPs were selected based upon AD GWAS case/control P ≤ 10-3, we found no advantage of using SNP effects sizes calculated with the Cox Proportional Hazard Regression model in our study. When SNPs are selected for association with AD risk at P > 10-3, the age-specific risk prediction results are not significant for either PRS or PHS. However PHS could be more advantageous than PRS of age specific AD risk predictions when SNPs are prioritized for association with AD age at onset (i.e., powerful Cox Regression GWAS study).

Dataset Information

Polygenic risk scores for Alzheimer's disease are related to dementia risk in APOE ɛ4 negatives.

Introduction

Methods

Results

Discussion

Publications

Polygenic risk scores for Alzheimer's disease are related to dementia risk in APOE ɛ4 negatives.

Similar Datasets

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