Few studies have measured the effect of genetic factors on
dementia and
cognitive decline in healthy older individuals followed prospectively. We studied cumulative incidence of
dementia and
cognitive decline, stratified by
APOE genotypes and
polygenic risk score (PRS) tertiles, in 12,978 participants of the
ASPirin in Reducing Events in the Elderly (ASPREE) trial. At enrolment, participants had no history of diagnosed
dementia,
cardiovascular disease, physical disability or
cognitive impairment.
Dementia (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 for all-cause
dementia and
cognitive decline was calculated with mortality as a competing event, stratified by
APOE genotypes and tertiles of a PRS based on 23 common non-
APOE variants. During a median 4.5 years of follow-up, 324 participants developed
dementia, 503 died. Cumulative incidence of
dementia to age 85 years was 7.4% in all participants, 12.6% in
APOE ε3/ε4 and 26.6% in ε4/ε4.
APOE ε4 heterozygosity/homozygosity was associated with a 2.5/6.3-fold increased
dementia risk and 1.4/1.8-fold
cognitive decline risk, versus ε3/ε3 (p < 0.001 for both). High PRS tertile was associated with a 1.4-fold
dementia risk versus low (CI 1.04-1.76, p = 0.02), but was not associated with
cognitive decline (CI 0.96-1.22, p = 0.18). Incidence of
dementia among healthy older individuals is low across all genotypes; however,
APOE ε4 and high PRS increase relative risk.
APOE ε4 is associated with
cognitive decline, but PRS is not.