Sex-specific effects of microglial activation on Alzheimer's disease proteinopathy in older adults - PubMed (original) (raw)

. 2022 Oct 21;145(10):3536-3545.

doi: 10.1093/brain/awac257.

Emma Nichols 2, Vahan Aslanyan 3 4, Stephanie M Simone 5, Jennifer S Rabin 6 7 8, Renaud La Joie 1, Adam M Brickman 9, Kristen Dams-O'Connor 10 11, Priya Palta 12, Raj G Kumar 10, Kristen M George 13, Claudia L Satizabal 14 15, Julie Schneider 16, Judy Pa 17

Affiliations

Sex-specific effects of microglial activation on Alzheimer's disease proteinopathy in older adults

Kaitlin B Casaletto et al. Brain. 2022.

Abstract

Females show a disproportionate burden of Alzheimer's disease pathology and higher Alzheimer's disease dementia prevalences compared to males, yet the mechanisms driving these vulnerabilities are unknown. There is sexual dimorphism in immunological functioning, and neuroimmune processes are implicated in Alzheimer's disease genesis. Using neuropathology indicators from human brain tissue, we examined the mediational role of microglial activation on the relationship between amyloid and tau and how it differs by sex. 187 decedents (64% female; 89 mean age at death; 62% non-demented) from the Rush Memory and Aging Project completed neuropathological evaluations with brain tissue quantified for microglial activation, amyloid-β and tau. Proportion of morphologically activated microglia was determined via immunohistochemistry (HLA-DP-DQ-DR) and morphological staging (stage I, II or III). Amyloid-β and tau burden were quantified via immunohistochemistry (M00872 or AT8, respectively). Using causal counterfactual modelling, we estimated the mediational effect of microglial activation on the amyloid-β to tau relationship in the whole sample and stratified by sex (amyloid-β → microglial activation → tau). Alternative models tested the role of microglia activation as the precipitating event (microglial activation → amyloid-β → tau). Microglial activation significantly mediated 33% [95% confidence interval (CI) 10-67] of the relationship between amyloid-β and tau in the whole sample; stratified analyses suggested this effect was stronger and only statistically significant in females. 57% (95% CI 22-100) of the effect of amyloid-β on tau was mediated through microglial activation in females, compared to 19% (95% CI 0-64) in males. Regional analyses suggested that mediational effects were driven by greater cortical versus subcortical microglial activation. Relationships were independent of cerebrovascular disease indices. Alternative models suggested that in females, microglial activation was a significant exposure both preceding the amyloid-β to tau relationship (mediational effect: 50%, 95% CI 23-90) and directly related to tau burden (microglia direct effect: 50%, 95% CI 10-77). By contrast, in males, only the direct effect of microglial activation to tau reached significance (74%, 95% CI 32-100) (mediational effect: 26%, 95% CI 0-68). Our models suggest a reciprocal, bidirectional relationship between amyloid-β and microglial activation that significantly accounts for tau burden in females. By contrast, in males, direct independent (non-mediational) relationships between microglial activation or amyloid-β with tau were observed. Microglial activation may be disproportionately important for Alzheimer's disease pathogenesis in females. Determining sex-specific vulnerabilities to Alzheimer's disease development both inform fundamental pathophysiology and support precision health approaches for this heterogeneous disease.

Keywords: amyloid-beta; gender; neuroinflammation; tau.

© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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Conflict of interest statement

The authors report no competing interests.

Figures

Figure 1

Figure 1

Added variable plots illustrating the relationship between (A) amyloid-β and microglial activation, (B) microglial activation and tau and (C) amyloid-β and tau, in males versus females. The plots show the sex-stratified relationship in the residuals of amyloid-β burden, microglial activation and tau burden, after regressing out common covariation with age at death, education and APOE4 status. Shaded areas represent 95% CIs. Results indicate positive associations between amyloid-β, microglial activation and tau burden. There was some evidence of a difference by sex in the magnitude of the association between amyloid-β and tau, although differences were not statistically significant. Standardized coefficients (std. coef.) and _P_-values for the interaction by sex are reported in each panel.

Figure 2

Figure 2

Summary of mediation results for the hypothesized model (amyloid-β leads to tau, partially mediated by microglial activation) and the alternative model (microglial activation leads to tau, partially mediated by amyloid-β). Asterisk denotes _P_-values < 0.05. Numbers indicate the proportion of the total effect explained by either the direct or indirect effect. Black arrows correspond to standardized beta estimates >0.30 and grey arrows correspond to standardized beta estimates <0.03. Both (A) indirect (hypothesized model) and (B) direct and indirect (alternative model) effects of microglial activation are observed on the amyloid-β-tau relationship in females, but not males.

Figure 3

Figure 3

The effect of amyloid-β on tau burden via microglial activation (indirect effect) and via other pathways (direct effect) overall (A) and stratified by brain regions (B) from causal mediation analyses. Error bars represent 95% CIs. Results indicate a double dissociation in strength of direct (amyloid-β → tau) versus indirect (amyloid-β → microglia → tau) effects of mediational models in males versus females, which is driven by cortical greater than subcortical microglial activation.

Figure 4

Figure 4

Conceptual summary reflecting study findings from causal counterfactual analytic models. In females, results of the hypothesized and alternative models suggest that there are complex inter-relationships between microglial activation, amyloid-β burden and tau, wherein a reciprocal bidirectional relationship exists between microglial activation and amyloid-β burden, which both then exacerbate tau burden. In contrast, findings in males suggest that the effects of microglial activation and amyloid-β on tau are more independent.

Comment in

References

    1. Nebel RA, Aggarwal NT, Barnes LL, et al. Understanding the impact of sex and gender in Alzheimer’s disease: A call to action. Alzheimer’s Dement. 2018;14:1171–1183. -PMC -PubMed
    1. Ferretti MT, Iulita MF, Cavedo E, et al. Sex differences in Alzheimer disease—The gateway to precision medicine. Nat Rev Neurol. 2018;14:457–469. -PubMed
    1. Buckley RF, Mormino EC, Rabin JS, et al. Sex differences in the association of global amyloid and regional tau deposition measured by positron emission tomography in clinically normal older adults. JAMA Neurol. 2019;76:542. -PMC -PubMed
    1. Hohman TJ, Dumitrescu L, Barnes LL, et al. Sex-specific association of apolipoprotein e with cerebrospinal fluid levels of tau. JAMA Neurol. 2018;75:989. -PMC -PubMed
    1. Edwards L, La Joie R, Iaccarino L, et al. Multimodal neuroimaging of sex differences in cognitively impaired patients on the Alzheimer's continuum: greater tau-PET retention in females. Neurobiol Aging. 2021;105:86–98. -PMC -PubMed

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