Association of genetic risk of Alzheimer’s disease and cognitive function in two European populations

Although there is some evidence of an association between Alzheimer's disease polygenic risk score (AD PRS) and cognitive function, limited validations have been performed in large populations. We investigated the relationship between AD PRS and cognitive function in the UK Biobank in over 276,000 participants and further validated the association in the Alzheimer's Disease Neuroimaging Initiative (ADNI) sample. We developed the AD PRS (excluded the APOE variants) in the middle age UK Biobank participants (age ranged 39-72, mean age 57 years) of European ancestries by LDpred2. To validate the association of AD PRS and cognitive function internally in the UK Biobank, we linearly regressed standardized cognitive function on continuous standardized AD PRS with age at cognitive test, sex, genotyping array, first 10 principal components of genotyping, smoking, education in years, body mass index, and apolipoprotein E gene ε4 (APOE4) risk allele dosages. To validate the associations externally, we ran the linear mixed effects model in the ADNI sample free of dementia (age ranged 55-91, mean age 73), including similar covariates as fixed effects and participants' IDs as the random effect. Stratification by age, APOE4 carrier status, and cognitive status (cognitively normal or mild cognitive impairment) was also investigated. Our study validated the associations of AD PRS and cognitive function in both midlife and late-life observational cohorts. Although not all of the cognitive measures were significantly associated with AD PRS, non-verbal fluid reasoning (matrix pattern completion, β = - 0.022, P = 0.003), processing speed (such as symbol digit substitution, β = - 0.017, P = 1.08E-05), short-term memory and attention (such as pairs matching, β = - 0.014, P = 1.66E-10), and reaction time (β = - 0.010, P = 1.19E-06) were inversely associated with increasing AD PRS in the UK Biobank. Higher likelihood of cognitive impairment was also associated with higher AD PRS in the ADNI cognitive normal individuals (AD assessment scale β = 0.079, P = 0.02). In summary, we confirmed that poorer cognitive function was associated with a higher polygenic AD risk, and suggested the potential utility of the AD PRS in identifying those who may be at risk for further cognitive decline.