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

Abstract

Women show disproportionate burden of Alzheimer’s disease (AD) pathology and higher AD dementia prevalences compared to men, yet the mechanisms driving these vulnerabilities are unknown. There is sexual dimorphism in immunologic functioning, and neuroimmune processes are implicated in AD 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 modeling, 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%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 women. 57% (95%CI 22-100) of the effect of amyloid-β on tau was mediated through microglial activation in women, compared to 19% (95%CI 0-64) in men. 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 women, 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). In contrast, in men, 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 women. In contrast, in men, direct independent (non-mediational) relationships between microglial activation or amyloid-β with tau were observed. Microglial activation may be disproportionately important for AD pathogenesis in women. Determining sex-specific vulnerabilities to AD development both inform fundamental pathophysiology and support precision health approaches for this heterogeneous disease.

sTREM2 is associated with amyloid‐related p‐tau increases and glucose hypermetabolism in Alzheimer's disease

“…These findings support the view that earliest Aβ fibrillization induces an sTREM2‐related activation of microglia, which is in turn associated with p‐tau 181 increases, while sTREM2 increases may uncouple from Aβ severity at later stages. Our findings of microglial activation as a mediator of soluble p‐tau 181 increases is in line with a recent post‐mortem study in older adults showing that activated microglia partly mediated the relationship between Aβ and tau (Casaletto et al , 2022 ). In addition, several preclinical studies showed that activated microglia can enhance tau phosphorylation in animal models of AD and other tauopathies (Bhaskar et al , 2010 ; Lee et al , 2014 ; Maphis et al , 2015 ; Ising et al , 2019 ).…”

“…Similarly, studies in sporadic AD patients found that a TREM2‐related microglial response is strongly correlated with soluble p‐tau but not with Aβ levels (Suárez‐Calvet et al , 2019 ) and that a TREM2‐related microglial response may promote the development of aggregated tau pathology in AD, as measured via tau‐PET (Vogels et al , 2019 ; Pascoal et al , 2021 ). Indeed, a recent post‐mortem study investigating the mediating effect of microglial activation on the Aβ to tau association in brain tissue revealed a mediation effect of 33% of microglia for the relationship between Aβ and tau (Casaletto et al , 2022 ). This suggests that microglial activation may be associated with tau hyperphosphorylation and therefore contribute to the development of tau pathology in AD.…”

Soluble TREM2 mediates earliest amyloid-associated p-tau increases and cerebral glucose hypermetabolism in Alzheimer’s disease

“…These findings support the view that earliest Aβ fibrillization induces a sTREM2-related activation of microglia, which is in turn associated with p-tau increases, while sTREM2 increases may uncouple from Aβ severity at later stages. Our findings of microglial activation as a mediator of soluble p-tau increases is in line with a recent post mortem study in older adults showing that activated microglia partly mediated the relationship between Aβ and tau (15). In addition, several preclinical studies showed that activated microglia can enhance tau phosphorylation in animal models of AD and other tauopathies (11, 42–44).…”

“…Similarly, studies in sporadic AD patients found that microglial activation is strongly correlated with fluid p-tau but not with Aβ levels (13) and that microglial activation may promote the development of aggregated tau pathology in AD, as measured via tau-PET (10, 14). Indeed, a recent post mortem study investigating the mediating effect of microglial activation on the Aβ to tau association in brain tissue revealed a mediation effect of 33% of microglia for the relationship between Aβ and tau (15). This suggests that microglial activation may be associated with tau hyperphosphorylation and therefore contribute to the development of tau pathology in AD.…”

Molecular insights into sex-specific metabolic alterations in Alzheimer’s mouse brain using multi-omics approach

“…We can therefore speculate on the possibility of sex-biased phenotypes within reactive astrocytes which have recently been placed in the center of AD pathology as an early event (i.e., reactive astrogliosis) in AD progression [91,92]. This would not be so surprising, since sex differences in glial cells have been previously described, reviewed elsewhere [93], and were recently also reported in microglial cells in AD [94].…”