Effect of APOE ε4 and its modification by sociodemographic characteristics on cognitive measures in South Asians from LASI‐DAD

Abstract

AbstractBackgroundThe ε4 allele of the apolipoprotein E (APOE) gene is the most significant genetic risk factor for dementia in nearly all human populations. However, the effects of APOE ε4 on late‐life cognitive function and its potential modification by sociodemographic factors have not been extensively studied in South Asians. We investigated the effects of APOE ε4 and its interaction with sociodemographic characteristics on cognitive measures in 2,607 South Asians from the Diagnostic Assessment of Dementia for the Longitudinal Aging Study of India (LASI‐DAD).MethodWe determined APOE ε4 carrier status from rs429358 and rs7412 genotypes in whole genome sequencing data. We first examined the main effects of APOE ε4 on seven cognitive measures, including five broad cognitive domain scores, a general cognitive function summary score, and the Hindi Mental State Examination (HMSE) score using linear regression models. Model 1 adjusted for age, sex, state of residence, and the first 10 genetic principal components (PCs). Model 2 additionally adjusted for education level, literacy, and urban/rural residence. We then tested for interaction between APOE ε4 and sociodemographic factors (age, sex, and education) through cross‐product terms, and further evaluated significant interactions (p<0.05) using stratified analysis.ResultAPOE ε4 was inversely associated with all cognitive measures except visuospatial function in the full sample in Model 1 after Bonferroni correction (p<0.007), all of which remained nominally significant in Model 2 (p<0.05). For example, APOE ε4 carrier status was associated with a decrease in the HMSE score of 0.77 points (p = 1.6×10−4) and a decrease in general cognitive function score of 0.09 standard deviations (p = 0.001) in Model 2. Furthermore, interaction tests showed that the effect of APOE ε4 was stronger in females than males for memory (ßAPOE ε4_male = ‐0.121, βAPOE ε4_female = ‐0.177) and language/fluency (βAPOE ε4_male = 0.075, βAPOE ε4_female = ‐0.125), and stratified analysis indicated that the APOE ε4 effects were significant only in females (p<0.05).ConclusionAPOE ε4 is associated with lower cognitive function in older South Asians from India. For memory and language/fluency, this association is stronger in females than males.