Interleukin 9 alterations linked to alzheimer disease in african americans

Abstract

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-Tau₁₈₁ , 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.

Figure 1.

CSF AD biomarker and cytokine levels in middle-aged African Americans and Caucasians with normal cognition. Compared to Caucasians (open circles), African Americans (filled circles) had lower t-Tau (A, *) and p-Tau₁₈₁ (B, *) levels, but similar Aβ42 (C) levels. The relationship between CSF IL-9 and t-Tau (D) or p-Tau₁₈₁ (E) also differed according to race (top panels, blue lines for African Americans, green lines for Caucasians), and segmental linear analysis showed similar relationship between races at low t-Tau and p-Tau₁₈₁ concentrations but possible divergence at higher concentrations. Shaded areas represent 95% CI of the regression curves.

Figure 2.

CSF cytokine levels in older African Americans and Caucasians according to diagnosis (A, C, E) or a continuous measure of cognition (B, D, F). CSF IL-9 levels were lower in cognitively normal African Americans (closed circles) than Caucasians (open circles), and were associated with increases in MCI and AD dementia only in African Americans (A, B). Analysis of the balance between IL-9 and IP-10 showed similar AD-associated Th1-to-Th9 bias, with Caucasians showing a greater overall bias than African Americans.

Figure 3.

IHC of protein markers related to Th9 in post-mortem brain tissue. In AD, there was intense staining of IL-9 in perivascular cells (A) which are also immunoreactive to a T-cell marker CD3 (B) in adjacent slides suggesting these to be IL-9-containing T cells (higher magnification in C). There was also modest immunoreactivity to IL-9 in non-perivascular parenchymal neurons and glia (D), associated with increased PU.1 immunoreactivity (same magnification as IL-9) and strongly tryptase-positive cells (black arrow).

Figure 4.

Mean superior frontal IL-9 (A), PU.1 (B), and mast cell tryptase (C) immunoreactive areas in a post-mortem cohort from Emory. For each marker, immunoreactivity was normalized to the mean of Caucasian NC subjects. Greater PU.1 was associated with AD (†), while greater tryptase was only associated with African Americans with AD (*; bars represent median values.

Figure 5.

Relationship between neuritic plaque density, race, and IL-9 related transcripts in the Mount Sinai cohort. For two genes involved in Th9 differentiation, race modified the relationship between plaque density and IL4RA (A) but not TGFBR2 (Caucasians: open circles, dashed line; African Americans: filled circles, solid line). Analyzing the ratio of TGFBR2 to IL4RA (TGFBR2/IL4RA) as a marker of Th9 differentiation showed a strong positive correlation with plaque density only in African Americans but not Caucasians (B). Examination of a mast cell (effector of Th9 cells) surface marker KIT/CD117 revealed the same changes as TGFBR2/IL4RA ratio (C).