Effect of APOE and a polygenic risk score on incident dementia and cognitive decline in a healthy older population

ImportanceFew studies have measured the effect of genetic factors on dementia and cognitive decline in a population of healthy older individuals followed prospectively. ObjectiveTo examine the effect of Apolipoprotein E (APOE) genotypes and a polygenic risk score (PRS) on incident dementia and cognitive decline in a longitudinal cohort of healthy older people. Design, Setting and ParticipantsPost-hoc genetic analysis of a randomized clinical trial population - the ASPirin in Reducing Events in the Elderly (ASPREE) trial. At enrollment, participants had no history of diagnosed dementia, atherothrombotic cardiovascular disease, or permanent physical disability and were without cognitive impairment. Main Outcomes and MeasuresDementia (adjudicated trial endpoint) and cognitive decline, defined as a >1.5 standard deviation decline in test score for either global cognition, episodic memory, language/executive function or psychomotor speed, versus baseline scores. Cumulative incidence curves for all-cause dementia and cognitive decline were calculated with mortality as a competing event, stratified by APOE genotypes and tertiles of a PRS based on 23 common non-APOE variants. Results12,978 participants with European ancestry were included; 54.8% were female, and average age at baseline was 75 years (range 70 to 96). During a median 4.5 years of follow-up, 324 (2.5%) participants developed dementia and 503 (3.8%) died. Cumulative incidence of dementia to age 85 years was estimated to be 7.4% in all participants, 12.6% in APOE {varepsilon}4 heterozygotes, 26.6% in {varepsilon}4 homozygotes, 9.6% in the high PRS tertile, and 7.3% in the low PRS tertile. APOE {varepsilon}4 heterozygosity/homozygosity was associated with a 2.5/6.3-fold increased risk of dementia and a 1.4/1.8-fold increased risk of cognitive decline, versus {varepsilon}3/{varepsilon}3 (P<0.001 for both). A high PRS (top tertile) was associated with a 1.4-fold increase risk of dementia, versus the low tertile (CI 1.04-1.76, P=0.02), but was not associated with cognitive decline risk (CI 0.96-1.22, P = 0.18). Conclusions and RelevanceIncidence of dementia among healthy older individuals is low across all genotypes; however, APOE {varepsilon}4 and high PRS increase relative risk. APOE {varepsilon}4 is associated with cognitive decline, but PRS is not. KEY POINTS QuestionHow do genetic factors influence the risk of dementia and cognitive decline among healthy older individuals? FindingsWe studied cumulative incidence of dementia and cognitive decline in 12,978 healthy older individuals without cardiovascular disease or cognitive impairment at enrollment, stratified by APOE genotype and a polygenic risk score (PRS). APOE {varepsilon}4 and PRS increased the relative risk of dementia, but cumulative incidence was low across all genotypes. APOE genotypes were associated with cognitive decline, but PRS was not. MeaningIncidence of dementia is low among healthy older individuals; however, genetic factors still increase relative risk.