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.

It is now recognized that understanding how neuroinflammation affects brain function may provide new insights into Alzheimer’s pathophysiology. Tumor necrosis factor (TNF)-α, an inflammatory cytokine marker, has been implicated in Alzheimer’s disease (AD), as it can impair neuronal function through suppression of long-term potentiation. Our study investigated the relationship between cerebrospinal fluid TNF-α and functional connectivity (FC) in a cohort of 64 older adults (μ age = 69.76 years; 30 cognitively normal, 34 mild AD). Higher cerebrospinal fluid TNF-α levels were associated with lower FC among brain regions important for high-level decision-making, inhibitory control, and memory. This effect was moderated by apolipoprotein E-ε4 ( APOE 4) status. Graph theory metrics revealed there were significant differences between APOE 4 carriers at the node level, and by diagnosis at the network level suggesting global brain network dysfunction in participants with AD. These findings suggest proinflammatory mechanisms may contribute to reduced FC in regions important for high-level cognition. Future studies are needed to understand the role of inflammation on brain function and clinical progression, especially in APOE 4 carriers.

Accumulating data suggest that cerebrovascular disease contributes to Alzheimer’s disease pathophysiology and progression toward dementia. Cerebral amyloid angiopathy is a form of cerebrovascular pathology that results from the build-up of β-amyloid in the vessel walls. Cerebral amyloid angiopathy commonly co-occurs with Alzheimer’s disease pathology in the ageing brain and increases the risk of Alzheimer’s disease dementia. In the present study, we examined whether cerebral amyloid angiopathy influences tau deposition and cognitive decline independently or synergistically with parenchymal β-amyloid burden. Secondly, we examined whether tau burden mediates the association between cerebral amyloid angiopathy and cognitive decline. We included data from autopsied subjects recruited from one of three longitudinal clinical–pathological cohort studies: the Rush Memory and Aging Project, the Religious Orders Study and the Minority Aging Research Study. Participants completed annual clinical and cognitive evaluations and underwent brain autopsy. Cerebral amyloid angiopathy pathology was rated as none, mild, moderate or severe. Bielschowsky silver stain was used to visualize neuritic β-amyloid plaques and neurofibrillary tangles. We used linear regression and linear mixed models to test independent versus interactive associations of cerebral amyloid angiopathy and neuritic plaque burden with tau burden and longitudinal cognitive decline, respectively. We used causal mediation models to examine whether tau mediates the association between cerebral amyloid angiopathy and cognitive decline. The study sample included 1722 autopsied subjects (age at baseline = 80.2 ± 7.1 years; age at death = 89.5 ± 6.7 years; 68% females). Cerebral amyloid angiopathy interacted with neuritic plaques to accelerate tau burden and cognitive decline. Specifically, those with more severe cerebral amyloid angiopathy pathology and higher levels of neuritic plaque burden had greater tau burden and faster cognitive decline. We also found that tau mediated the association between cerebral amyloid angiopathy and cognitive decline among participants with higher neuritic plaque burden. In summary, more severe levels of cerebral amyloid angiopathy and higher parenchymal β-amyloid burden interacted to promote cognitive decline indirectly via tau deposition. These results highlight the dynamic interplay between cerebral amyloid angiopathy and Alzheimer’s disease pathology in accelerating progression toward dementia. These findings have implications for Alzheimer’s disease clinical trials and therapeutic development.

Introduction Few studies have investigated how neuroinflammation early in the disease course may affect Alzheimer's disease (AD) progression over time despite evidence that neuroinflammation is associated with AD. Methods Research participants with cerebrospinal fluid (CSF) biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were included in this study. Cox models were used to investigate whether baseline CSF neuroinflammation was associated with incident mild cognitive impairment (MCI) or AD. Moderating effects of sex and apolipoprotein E ( APOE ) ε4 were also examined. Results Elevated levels of tumor necrosis factor α (TNF‐α), interleukin (IL)‐9, and IL‐12p40 at baseline were associated with higher rates of conversion to MCI/AD. Interactions with sex and APOE ε4 were observed, such that women with elevated TNF‐α and all APOE ε4 carriers with elevated IL‐9 levels had shorter times to conversion. In addition, TNF‐α mediated the relationship between elevated IL‐12p40 and IL‐9. Discussion Elevated neuroinflammation markers are associated with incident MCI/AD, and the factors of sex and APOE ε4 status modify the time to conversion.