A polygenic risk score for Alzheimer’s disease determines the risk of incident dementia in APOE ɛ4 negative individuals over the age of 95: A population‐based cohort study

Abstract

AbstractBackgroundThe combined effect of common genetic variants (SNPs) into polygenic risk scores (AD‐PRS) have been shown to have a strong influence on incident AD between ages 60 and 95 years, especially in carriers of the APOE ϵ4 genotype. However, few studies have investigated the effect of AD‐PRS on incident dementia in the general population and among the oldest old (≥ 95 years).MethodA population‐based sample of 2053 participants aged 70‐108 years, from the Gothenburg H70 Birth Cohort Studies, Sweden, was followed for incident dementia. An AD‐PRS (39 SNPs) were constructed using effect sizes from large genome‐wide association studies. Dementia was diagnosed according to DSM‐III‐R based on information from neuropsychiatric examinations and close informant interviews. Cox regression models adjusted for sex, birth year, age at blood sampling, and APOE ϵ4 status, were used to analyse the associations between AD‐PRS and incident dementia in the total sample and in the oldest old (n = 338). Additionally, we stratified the analysis by APOE ϵ4 carriership and tertiles of the AD‐PRS.ResultDuring mean follow‐up of 7.19 years (SD 4.68; 14,775.25 person‐years), 607 participants developed dementia (220 over the age of 95 years). In the total sample, AD‐PRS was associated with incident dementia (HR per increased point of the score 1.38; 95%CI 1.12‐1.73, p = 0.003), especially among APOE ϵ4 non‐carriers (HR 1.72; 95%CI 1.33‐2.23, p < 0.0001). Among the oldest old, AD‐PRS was associated with incident dementia in APOE ϵ4 non‐carriers only (HR 1.80; 95%CI 1.20‐2.69, p = 0.004). Further, in this age group, APOE ϵ4 carriership was associated with increased risk of dementia only among those in the low‐risk tertile of AD‐PRS (HR 1.84; 95%CI 1.08‐3.12, p = 0.004).ConclusionWe found an association between AD‐PRS and dementia in the general population up to very old ages, especially among APOE ϵ4 non‐carriers. In the oldest old, an effect of APOE ϵ4 carriership on dementia risk was observed among individuals in the low‐risk tertile of the AD‐PRS. These results could provide additional information to identify individuals at risk for dementia.