Ethnic differences in the effects of apolipoprotein E ɛ4 and vascular risk factors on accelerated brain aging

The frequency of the apolipoprotein E ɛ4 allele and vascular risk factors differs among ethnic groups. We aimed to assess the combined effects of apolipoprotein E ɛ4 and vascular risk factors on brain age in Korean and UK cognitively unimpaired populations. We also aimed to determine the differences in the combined effects between the two populations. We enrolled 2314 cognitively unimpaired individuals aged ≥45 years from Korea and 6942 cognitively unimpaired individuals from the UK, who were matched using propensity scores. Brain age was defined using the brain age index. The apolipoprotein E genotype (ɛ4 carriers, ɛ2 carriers and ɛ3/ɛ3 homozygotes) and vascular risk factors (age, hypertension and diabetes) were considered predictors. Apolipoprotein E ɛ4 carriers in the Korean (β = 0.511, P = 0.012) and UK (β = 0.302, P = 0.006) groups had higher brain age index values. The adverse effects of the apolipoprotein E genotype on brain age index values increased with age in the Korean group alone (ɛ2 carriers × age, β = 0.085, P = 0.009; ɛ4 carriers × age, β = 0.100, P < 0.001). The apolipoprotein E genotype, age and ethnicity showed a three-way interaction with the brain age index (ɛ2 carriers × age × ethnicity, β = 0.091, P = 0.022; ɛ4 carriers × age × ethnicity, β = 0.093, P = 0.003). The effects of apolipoprotein E on the brain age index values were more pronounced in individuals with hypertension in the Korean group alone (ɛ4 carriers × hypertension, β = 0.777, P = 0.038). The apolipoprotein E genotype, age and ethnicity showed a three-way interaction with the brain age index (ɛ4 carriers × hypertension × ethnicity, β=1.091, P = 0.014). We highlight the ethnic differences in the combined effects of the apolipoprotein E ɛ4 genotype and vascular risk factors on accelerated brain age. These findings emphasize the need for ethnicity-specific strategies to mitigate apolipoprotein E ɛ4-related brain aging in cognitively unimpaired individuals.