Cognitive endophenotypes in racially- and ethnically-diverse middle-aged adult offspring aggregate with parental magnetic resonance imaging biomarkers of Alzheimer's disease risk

A family history of Alzheimers disease (AD) increases risk for AD in an individual by 1.5-to 3-fold. Heritability of AD risk may be due in part to the aggregation of neurodegeneration and cerebrovascular changes with cognitive endophenotypes within families. The purpose of this study was to determine the extent to which cognitive functioning in middle-aged adults is associated with objectively-measured neurodegenerative and cerebrovascular neuroimaging markers linked to risk for clinical AD in their parents, and the extent to which these associations differ by race/ethnicity and language, as proxy variables for social advantage. Middle-aged children enrolled in the Offspring study (n=356; 53.1{+/-}10.1 years old; 13% Non-Hispanic White, 27% Non-Hispanic Black, 26% Latinx tested in English, 34% Latinx tested in Spanish; 65% women; 13.5{+/-}3.4 years education) were administered the NIH Toolbox, a computerized neuropsychological battery, in their preferred language. Older adults were a subset of the Washington-Heights Inwood Columbia Aging Project (77.3{+/-}6.6 years old; 75% women; 10.0{+/-}4.6 years education) who underwent T1w- and T2w-MRI and who had a child enrolled in the Offspring study. We tested the associations of parental MRI measures reflecting neurodegeneration (hippocampal volume, cortical thickness) and cerebrovascular disease (white matter hyperintensity (WMH) volume, presence of infarct) with cognitive tests scores in Offspring participants. We further stratified the models by race/ethnicity. Better offspring cognitive scores aggregated lower parental neurodegeneration and cerebrovascular disease among Non-Hispanic White and Latinx participants, and with lower parental cerebrovascular disease alone among Non-Hispanic Black participants. Associations were generally strongest in Non-Hispanic White participants compared to the other groups. These results suggest a more consistent link between offspring cognitive endophenotype and parental brain health in intergenerational AD transmission among Non-Hispanic White participants compared to racial/ethnic and minority groups in which other social factors may be adding variance.