Sex/gender effects of glial reactivity on preclinical Alzheimer's disease pathology

Abstract

Glial reactivity may contribute to sex/gender differences in Alzheimer's disease (AD) pathophysiology. Here, we investigated the differential effect of cerebrospinal fluid (CSF) glial markers on AD pathology and neurodegeneration by sex/gender among cognitively unimpaired older adults at increased risk of developing AD. We included 397 participants from the ALFA+ cohort with CSF Aβ_42/40, p-tau₁₈₁, sTREM2, YKL40, and GFAP, magnetic resonance imaging-based hippocampal volume (n = 299), and amyloid burden (centiloids) measured with [¹⁸F] flutemetamol positron emission tomography (n = 341). We ran multiple linear regression models to assess the association between glial markers, AD pathology and hippocampal volumes and their interaction with sex/gender, using False Discovery Rate to correct for multiple comparisons. Glial markers significantly contributed to explain amyloid burden, tau pathology, and hippocampal volumes, beyond age and/or primary AD pathology in a sex/gender-specific manner. Compared to men, women showed increased amyloid burden (centiloids) and CSF p-tau₁₈₁ with increasing levels of sTREM2 and YKL40, and YKL40 and GFAP, respectively. Compared to women, men with greater tau burden showed lower hippocampal volumes as CSF YKL40 levels increased. Overall, our findings suggest that glial reactivity may contribute to sex/gender differences in AD progression, mostly, downstream amyloid. Further research identifying sex/gender-specific temporal dynamics in AD development is warranted to inform clinical trials.

Fig. 1. Scatterplots showing the 3-way interactions within the A/T/N framework.

Panels A–C illustrate the 3-way interactions in scatter plots. Aβ_42/40 and p-tau₁₈₁ values were divided by median to the higher (Aβ_42/40 < 0.08; p-tau₁₈₁ > 14.4) vs. lower (Aβ_42/40 ≥ 0.08; p-tau₁₈₁ < 14.4) categories. Aβ_42/40 CSF β-amyloid, p-tau₁₈₁ CSF phosphorylated-tau₁₈₁, GFAP CSF glial fibrillary acidic protein, YKL40 CSF chitinase-3-like protein 1.

Fig. 2. Forest plots with standardized coefficients showing the main and interactive effects of sex/gender and glial markers on the A, T, and N.

Forest plots displaying the standardized regression coefficients (95% confidence intervals) for the multiple regression models with Aβ_42/40 (A), p-tau₁₈₁ (T) and hippocampal volume (N) as the dependent variables. Models with A included age and APOE ε4 as covariates. Models with T included age and Aβ_42/40 as covariates. Models with N included age, Aβ_42/40, and p-tau₁₈₁ as covariates. A amyloid, T tau, N neurodegeneration, sTREM2 CSF soluble triggering receptor expressed on myeloid cells 2, GFAP CSF glial fibrillary acidic protein, YKL40 CSF chitinase-3-like protein 1.