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Objective: Compared to older Caucasians, older African Americans have higher risks of developing Alzheimer disease (AD) and lower cerebrospinal fluid (CSF) tau biomarker levels. It is not known whether tau-related differences begin earlier in life or whether race modifies other AD-related biomarkers such as inflammatory proteins., Methods: We performed multiplex cytokine analysis in a healthy middle-aged cohort with family history of AD (n = 68) and an older cohort (n = 125) with normal cognition (NC), mild cognitive impairment, or AD dementia. After determining baseline interleukin (IL)-9 level and AD-associated IL-9 change to differ according to race, we performed immunohistochemical analysis for proteins mechanistically linked to IL-9 in brains of African Americans and Caucasians (n = 38), and analyzed postmortem IL-9-related gene expression profiles in the publicly available Mount Sinai cohort (26 African Americans and 180 Caucasians)., Results: Compared to Caucasians with NC, African Americans with NC had lower CSF tau, p-Tau 181 , and IL-9 levels in both living cohorts. Conversely, AD was only correlated with increased CSF IL-9 levels in African Americans but not Caucasians. Immunohistochemical analysis revealed perivascular, neuronal, and glial cells immunoreactive to IL-9, and quantitative analysis in independent US cohorts showed AD to correlate with molecular changes (upstream differentiation marker and downstream effector cell marker) of IL-9 upregulation only in African Americans but not Caucasians., Interpretation: Baseline and AD-associated IL-9 differences between African Americans and Caucasians point to distinct molecular phenotypes for AD according to ancestry. Genetic and nongenetic factors need to be considered in future AD research involving unique populations. ANN NEUROL 2019;86:407-418., (© 2019 American Neurological Association.)

Cerebral amyloid angiopathy (CAA) of the Aβ type is variably present in the brains of patients with Alzheimer's disease (AD). CAA contributes to cognitive decline and increases the risk of lobar hemorrhage; because both AD-typical dementia and lobar hemorrhage are more common in African-Americans than in Caucasians, we postulated that African-Americans with AD might be particularly susceptible to CAA. To test this hypothesis, we analyzed CAA histopathologically in the large vessels and capillaries of autopsy-derived frontal, temporal, parietal, and occipital cortical samples from African-Americans (n = 18) and Caucasians (n = 19) with end-stage AD. In the combined cohort of 37 subjects, 22% of the subjects had severe CAA in large vessels, and 11% had severe CAA in capillaries. However, the prevalence and histopathologic characteristics of CAA were similar in the African-Americans and Caucasians. This conclusion was substantiated in an independent sample from the National Alzheimer's Coordinating Center database, in which the degree of CAA was comparable in 1,554 Caucasians and 68 African-Americans with end-stage AD. These findings support a growing consensus that the fundamental histopathologic features of AD are largely impartial to the race of the afflicted.