Associations of Longitudinal Changes in Blood Biomarkers of Dementia With the Proportion of Genetically Inferred African Ancestry.

Abstract

African American individuals have a higher risk of Alzheimer disease (AD) and related dementia (ADRD) than non-Hispanic White individuals. Some cross-sectional studies with self-reported race and ethnicity have reported racial differences in circulating ADRD biomarkers, including phosphorylated tau181 (p-Tau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL). We aimed to examine the associations of genetically inferred African ancestry proportion with the longitudinal changes in these biomarkers and to evaluate the associations of previously identified ADRD-related genetic factors in European cohorts with these biomarkers in an African American cohort. This study used longitudinal data from the Family and Community Health Study, which was initiated in 1996, recruited and followed 889 African American families residing in Georgia and Iowa. Circulating p-Tau181, GFAP, and NfL were measured in serum samples collected in 2008 (wave 5) and 2019 (wave 8). Closely related individuals, genetically inferred to be third-degree relatives or closer, were excluded. Genetic ancestry proportions were inferred using the ADMIXTURE analysis. Multivariable regression analyses were performed to test the associations of African ancestry proportion with cross-sectional biomarker levels and their longitudinal changes over 11 years. We also tested the associations of selected genetic variants, polygenic scores, and <i>APOE</i> ε4 status with these biomarkers. Our cross-sectional sample included 573 participants (mean age = 55.1 years; 69% female), whereas our longitudinal sample included 225 (57.2 years; 80% female). African ancestry proportion was not associated with cross-sectional biomarker levels but was inversely associated with the longitudinal change in p-Tau181 (β = -14.50 pg/mL, <i>p</i> = 0.02). The significant inverse association was robust to adjustment for age, sex, <i>APOE</i> ε4, socioeconomic status, physical activity, smoking, subjective cognitive decline, and various cardiovascular risk factors and comorbidities. Finally, genetic factors associated with AD and biomarkers in European cohorts were not associated with the 3 biomarkers in our African American cohort. We found suggestive evidence that a higher African ancestry proportion is associated with an attenuated increase in the blood p-Tau181 level over time. More research is needed to characterize the longitudinal dynamics of ADRD biomarkers across ancestry and the driving biological or sociocultural factors.