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Genetic and Social Determinants of Cognitive Decline in Black Older Adults: Exploring the Role of APOE‐TOMM40‐‘523 Haplotypes, Discrimination, and Loneliness

Year: 2025

Type: article

Abstract: BACKGROUND: Social factors such as discrimination and loneliness predict cognitive decline and are commonly reported by Black Americans. TOMM40, a genetic marker adjacent to APOE, is also linked to cognition. Previous work found Black Americans with APOE-ε3/ε3 and with two copies of the short (S) variant of TOMM40-'523 have a faster rate of cognitive decline, while the presence of '523-S in Black APOE-ε4+ carriers is related to slower cognitive decline. The extent to which these social and biological factors may work together to influence cognition in Black older adults is unknown. We investigated whether discrimination and loneliness impact the effect of TOMM40-'523-S on cognitive decline. METHOD: =14.7±3.23; Female=80.7%). Linear mixed effect models examined the effects of TOMM40-'523-S (0, 1, or 2 copies) within APOE genotype (ε3/ε3 or ε4+) and social factors (discrimination, loneliness) on baseline composite measures of global cognition and five cognitive domains. Discrimination was modeled as a dichotomous variable (none vs. presence), while loneliness was continuous. Covariates included age, education (years), and sex/gender, and interactions with time from baseline. Average years of follow-up was 9.5 years. RESULT: Neither discrimination nor loneliness influenced the effect of '523-S on cognitive decline for the global composite or in specific domains. In APOE-ε4+ carriers (N = 220), discrimination was associated with a faster rate of decline in working memory (β=-0.022, S.E.=0.011, p = 0.044) and perceptual speed (β=-0.022, S.E.=0.014, p = 0.047) (Table 1). Loneliness was not associated with cognitive decline in either APOE-stratified model (ε3/ε3: N = 269; ε4+: N = 167) (Table 2). We also observed baseline effects of discrimination in APOE-ε3/ε3 individuals (N = 360, Table 1), and of loneliness in APOE-ε4+ individuals (Table 2). CONCLUSION: Social factors did not influence the effect of TOMM40-'523 on cognitive decline, but the effects of discrimination and loneliness on baseline cognition varied by APOE-genotype, and discrimination predicted cognitive decline in APOE-ε4+ carriers only. These findings suggest that APOE-ε4+ carriers may be vulnerable to the negative effects of discrimination on cognitive decline.

Source: Alzheimer s & Dementia

DOI: 10.1002/alz70855_105774