Abstract
IntroductionStudies 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.MethodsA 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.ResultsAD‐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.DiscussionThese results provide information to identify individuals at increased risk of dementia.
Highlights
In addition to the apolipoprotein E (APOE) gene, Alzheimer’s disease (AD)-associated single nucleotide polymorphisms (SNPs) have been identified through genome-wide association studies (GWASs).[1,2,3] These variants are usually combined into polygenic risk scores (PRSs), representing the accumulated effect of variants associated with AD.[4]
1243 participants were censored due to death (72.5% women) with a median age at death of 90 years. Compared to those excluded (n = 1131, Figure 1), participants who were followed up (n = 2052) had a higher mean age at baseline (P < .001), were more likely women (P < .001), and had a lower frequency of APOE ɛ4 carriers (P < .001), while no differences were found in AD-PRSs or median age at death. Compared to those with prevalent dementia (n = 266, Figure 1), individuals with incident dementia (n = 605) had a higher age at death (P < .001) and a lower frequency of APOE ɛ4 carriers (P = .049), while no differences were found in sex, the AD-PRSs, or age at baseline
In all individuals with follow-up data (n = 2052), APOE ɛ4 carriership and the 1e–5 AD-PRS were associated with increased risk of dementia, while ɛ2 carriership was associated with reduced risk (HR 0.74; 95% CI 0.59–0.95, P = .02)
Summary
In addition to the apolipoprotein E (APOE) gene, Alzheimer’s disease (AD)-associated single nucleotide polymorphisms (SNPs) have been identified through genome-wide association studies (GWASs).[1,2,3] These variants are usually combined into polygenic risk scores (PRSs), representing the accumulated effect of variants associated with AD.[4]. The 90+ study (hazard ratio [HR] 1.04; 95% confidence interval [CI] 0.71–1.53) and the Vantaa 85+ study (HR 1.78; 95% CI 0.88–3.60) did not find an effect of the APOE ɛ4 allele on dementia risk,[14,16] while the Leiden 85+ study found an increased dementia risk among APOE ɛ4 carriers (odds ratio [OR] 4.1; 95% CI 2.1–8.4).[15] The Rotterdam study reported an effect of AD-PRS (including 23 SNPs) on dementia, with the strongest effects in APOE ɛ4 carriers.[10] none of these studies investigated the effect of AD-PRSs and the possible interaction with APOE genotypes on dementia risk in very old individuals
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