Impact of sex differences on microglial function in Alzheimer’s disease

Abstract

Aging is the strongest risk factor for Alzheimer’s disease (AD), a multifactorial neurodegenerative disorder characterized by amyloid-β (Aβ) accumulation, tau pathology (hyperphosphorylated tau and neurofibrillary tangles [NFTs]), and associated neuroinflammatory processes. Age-related cellular and molecular stressors, including mitochondrial dysfunction, genomic instability, and chronic low-grade inflammation, progressively increase vulnerability to neurodegeneration. In parallel, sex is increasingly recognized as a biological variable that shapes AD risk, clinical course, and neuropathological burden. Women account for roughly two-thirds of AD cases, a disparity not fully explained by longevity. Multiple factors likely contribute, including hormonal transitions across the lifespan (particularly menopausal estrogen decline), sex chromosome–linked immune regulation, sex-dependent interactions between genetic risk factors (e.g., APOE4 and TREM2) and brain aging, and differences in vascular risk, cognitive reserve, and sociocultural exposures that influence disease expression and detection. Microglia, the brain’s resident immune cells, are sexually dimorphic, and respond to Aβ and tau pathology, modulating inflammatory signaling, synaptic remodeling, and neurovascular dysfunction implicated in AD. Emerging human and experimental evidence indicate that microglial activation states, immunometabolism, and functional responses differ between males and females and may contribute to sex-specific AD trajectories. Here, we synthesize current evidence supporting microglial sexual dimorphism across aging and AD, highlight possible candidates (hormonal signaling, immuno-aging, disease-associated microglial states, and immunometabolic remodeling), and discuss key knowledge gaps toward sex-informed precision approaches for prevention and treatment.

Introduction: why microglial sex differences matter in AD

Alzheimer’s disease (AD) is marked by progressive cognitive decline accompanied by extracellular amyloid-β (Aβ) plaques formation, intracellular neurofibrillary tangles (NFTs), synaptic dysfunction, and prominent neuroinflammatory and neurovascular alterations. Aging amplifies these processes by increasing systemic and central inflammatory tone, impairing cellular stress responses, and reducing overall resilience to neurodegenerative triggers [1, 2]. Importantly, AD is not biologically uniform across sexes.

Women show higher prevalence and lifetime risk, and many studies report sex-dependent differences in neuropathological burden and/or clinical trajectories that cannot be explained by longevity alone [3–5]. These disparities likely reflect complex interactions among endocrine transitions across the lifespan, sex-dependent genetic risk, immune regulation, together with cumulative risk exposures, including vascular profiles, that shape disease expression [6, 7].

Within this landscape, microglia have emerged as key integrators of AD pathophysiology. They detect and respond to Aβ accumulation and NFTs [6, 8–10], remodel synapses and synaptic pruning programs [8, 11–13], regulate inflammatory cytokine networks [14, 15], and interact closely with astrocytes and the neurovascular unit (NVU) [1, 11, 14]. In doing so, microglia adopt diverse context-dependent states that can be protective (e.g., containment and clearance programs) [8, 16] or potentially detrimental when dysregulated (e.g., sustained cytokine signaling [17], excessive reactivation of complement-driven synapse pruning [18], and metabolic dysfunction [19] Importantly, the interaction between microglia and complement signaling in AD is a critical neuroimmune pathway that can contribute to neuroinflammation and neurodegeneration. Complement components that support physiological synaptic pruning during neurodevelopment may become dysregulated in AD, promoting excessive complement-associated synaptic pruning and increasing neuronal vulnerability [11, 18, 20].

Crucially, microglia exhibit sexual dimorphism in baseline features and in their remodeling across aging and disease contexts, suggesting that sex-specific microglial biology contributes to divergent AD trajectories in males and females [10, 19, 21]. Based on current evidence, we advance the conceptual hypothesis that sex influences microglial baseline states, including immune tone, functional capacity, and immunometabolic constraints, and thereby alters the likelihood and timing of transitions into disease-associated microglial (DAM) [8, 12, 19, 22, 23]. In turn, these differences may shape how Aβ and tau pathology relate to synaptic dysfunction, neuroinflammation, and neurodegeneration [24, 25]. Accordingly, we asked what evidence supports sexually dimorphic microglial trajectories across aging and AD, and which biological mechanisms most plausibly explain sex-specific disease patterns?

Despite rapid progress, a critical knowledge gap remains. The field still lacks a clear link between microglial states and sex-dependent clinical and neuropathological outcomes in AD [4, 26]. Moreover, it remains challenging to determine how hormonal status, genetic risk factors, and environmental exposures interact to shape microglial trajectories across the disease progression. Addressing these issues is essential for translating microglial biology into sex-informed strategies for prevention and treatment [5, 27].

Microglial sex differences across aging: baseline vulnerability and immuno-aging

Microglia occupy a continuum of functional states that depend on brain region, age, and local cues, rendering simplistic M1/M2 labels insufficient [28, 29]. This state diversity matters for sex differences because males and females may differ in baseline microglial traits and in the ease with which microglia shift toward reactive or inflammatory programs [15].

Baseline sex differences in microglia

Sex differences in microglia become evident during sexual differentiation in a region- and endpoint-dependent manner [30, 31]. In the preoptic area (POA), males show a more amoeboid phenotype during early postnatal development, consistent with responsiveness to local masculinizing cues [31, 32]. Differences have also been reported across hippocampus, cortex, and amygdala, underscoring regional heterogeneity [31, 33, 34]. Because microglial hormone receptor expression is low/undetectable early postnatally, these effects are thought to be indirect, mediated by hormonally driven changes in the local milieu [30, 35]. Some sex-associated signatures persist beyond development and include cell-intrinsic components, consistent with long-lasting “imprinting” [23, 30].

In adults, baseline sex differences are detectable under physiological conditions but remain region-, age-, and endpoint-dependent. Differences in density, morphology, and inflammatory responsiveness have been reported, suggesting variation across the lifespan that may contribute to sex-biased immune profiles and later-life vulnerability [23, 36–38].

Males can show higher Iba1⁺ microglial density in hippocampus, cortex, and amygdala and stronger antigen-presentation signatures, and region-specific baseline activation has been described [37–39]. Transcriptomic analyses also support sex-biased immune programs, including interferon-associated regulation, and some datasets report larger soma size in males [3, 23, 37, 40]. Together, these findings suggest that males and females may enter aging with distinct baseline microglial profiles that can bias immuno-aging trajectories and responses to neurodegenerative triggers, reinforcing the need to interpret sex effects in light of age, brain region, and methodology [36].

Immuno-aging reshapes microglial phenotype and function

With aging, microglia undergo morphological, transcriptional, and functional remodeling often termed immuno-aging. Aged microglia commonly display dystrophic features (e.g., debranching, fragmented processes, spheroid formations) consistent with impaired surveillance and altered tissue homeostasis [41–43]. Functionally, aging is associated with higher basal production of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6), reduced anti-inflammatory mediators (e.g., IL-10), and decreased motility and phagocytic efficiency [44–48]. These shifts can directly impair synaptic plasticity, for example, excessive IL-1β is linked to reduced hippocampal LTP and impaired memory consolidation [49]. Therefore, immuno-aging establishes a background of increased inflammatory tone and reduced repair capacity that may amplify AD pathology [50].

Sex differences in immuno-aging: inflammatory trajectories in females

Evidence suggests immuno-aging is not identical in males and females. Multiple studies report that females may transition more readily toward activated or inflammatory response states, including greater expression of immune and complement-related pathways in aging female microglia relative to age-matched males [51, 52]. Functionally, aged female microglia have been described as less efficient in phagocytosing neuronal debris under inflammatory conditions, alongside increased expression of microglia-linked risk pathways relevant to AD [52, 53]. These patterns support the idea that female microglia may reach a pre-activated inflammatory state in some contexts, however, the direction and magnitude of sex differences vary with age, brain region, and environmental conditions [23, 33, 37, 54].

Hormonal transitions as modifiers of microglial inflammatory response

A major candidate mechanism for sex differences across the lifespan is the hormonal milieu. Estrogens exert neuroprotective and immunomodulatory effects, including regulation of microglial activation and cytokine production, support of synaptic plasticity, and potential modulation of amyloidogenic processes [55–58]. The menopausal decline in estrogens is widely discussed as a biological transition that increases vulnerability to chronic inflammation and may contribute to the higher AD burden observed in women [56, 59–61]. Although hormone therapy outcomes remain mixed, evidence supports estradiol-mediated modulation of neuroinflammatory signaling and glial responses, suggesting that loss of estrogen signaling can shift microglia toward a more reactive set point [55, 57, 58].

However, hormonal influences alone do not fully explain sex-dependent microglial phenotypes. Evidence from experimental models such as the Four Core Genotype (FCG) system indicates that sex chromosome complement also contributes to shaping microglial function independently of gonadal hormones. Accordingly, both chromosomal and endocrine factors interact to regulate microglial activation states and inflammatory responses, suggesting that hormonal transitions such as the decline in estrogens during menopause could be interpreted within a broader framework that includes sex chromosome–linked mechanisms [62, 63].

Importantly, rodents do not fully model human menopause: the trajectory and timing of age-related estrogen decline in mice differ from the abrupt hormonal transition observed in many women [64]. As a result, experimental findings in aged or ovariectomized rodents should be interpreted as evidence for the effects of reduced estrogen signaling, and translational inferences should be made cautiously and complemented by human data across the menopausal transition.

Sex differences in microglial responses during AD: evidence from animals and human studies

In AD contexts, microglia lie at the intersection of Aβ and tau pathology and play a central role in the inflammatory response, alternating between neuroprotective and neurotoxic phenotypes. On one hand, microglia can support protective functions, including phagocytosis and attempts to clear Aβ aggregates, as well as the release of trophic support that sustains synaptic plasticity [16, 65, 66]. On the other hand, chronic or dysregulated microglial activation can drive sustained production of pro-inflammatory mediators creating a milieu that exacerbate synaptic dysfunction and neuronal vulnerability, and can promote excessive complement-associated synaptic pruning, further compromising synaptic integrity [17, 18, 20].

Increasing evidence indicates that the relative balance between protective and harmful microglial programs is sexually dimorphic, with females in several contexts showing earlier or more pronounced transitions into inflammatory or disease-associated states [8, 67, 68]. In human studies, microglial activation appears to mediate the relationship between Aβ and tau burden in a sex-dependent manner, with greater effects in women, suggesting that this activation may contribute more strongly to AD pathogenesis in females, whereas additional mechanisms may play a relatively larger role in males [25] (Fig. 1).

Fig. 1.

Impact of sex differences on microglial plasticity and AD progression. Schematic comparison of sex-related immune trajectories across aging and AD. While the male pathway (top) exhibits a response oriented towards plaque containment, the female pathway (bottom) is marked by the decline in estrogen-mediated neuroprotection. This may lead to a rapid transition to a pro-inflammatory microglial state, exacerbating tau pathology and synaptic loss

In the following subsections, we examined sex differences in microglial responses to amyloid pathology and DAM-like programs, microglia–tau vulnerability, and genetic risk and immunometabolic contribution to neuron–microglia communication.

Amyloid plaque, DAM-like programs, and inflammatory priming

In amyloid-driven experimental models (e.g., APP/PS1 and related lines), females often show higher Aβ burden and/or plaque pathology compared with age-matched males across ages and regions [67–71]. While model-specific variability exists, these observations frequently coincide with differences in microglial activation dynamics. As aging advances, microglial inflammatory tone increases and microglia may shift toward more cytotoxic/pro-inflammatory phenotypes, reducing adaptive plaque-associated responses [72, 73].

Microglial clustering around plaques involves coordinated chemotaxis, phagocytic activity, and remodeling of the microenvironment, and is linked to key pathways such as TREM2–TYROBP and APOE-associated signaling [74–76]. Transcriptomic studies have identified DAM states enriched near plaques, reflecting a shift from homeostatic surveillance toward programs combining lipid handling, phagocytic signaling, and immune activation. Multiple lines of evidence suggest DAM-like transitions and related inflammatory programs may be more readily engaged in females under AD-like conditions [51, 67, 68].

A critical nuance is that microglial activation is not uniformly beneficial or harmful. Early plaque-associated responses may help contain plaques, whereas prolonged inflammatory signaling can promote synaptic injury and reduce effective clearance. Chronic innate immune activation can impair phagocytosis despite sustained inflammatory markers, potentially leading to inefficient Aβ clearance alongside persistent tissue stress [72, 77]. Complement and inflammatory transcripts (including C1q-related pathways) have been reported to rise with aging and may be more prominent in females in some contexts, supporting a sex-dependent shift toward immune activation coupled to reduced repair efficiency [52, 78, 79].

Tau pathology, synaptic dysfunction, and stage-dependent sex effects

Human studies suggest women may show greater NFT burden than men for a similar Aβ load in some cohorts and/or brain regions, which has been linked to greater brain atrophy and symptom in women [80–82]. Recent evidence indicates that microglial activation can mediate relationships between Aβ accumulation and NFTs more strongly in females than in males, implying sex-specific immune routes to tauopathy and neurodegeneration [25, 51].

From a microglial standpoint, tau-associated degeneration may reflect a “second wave” of immune dysregulation in which sustained cytokine signaling, inflammasome activation, oxidative stress pathways, and complement-associated synaptic remodeling destabilize neural networks and increase vulnerability to tau propagation and toxicity [11, 83, 84]. If females are more likely to enter sustained inflammatory states after estrogen decline or at advanced disease stages, this could strengthen the interaction between microglial activation and tau pathology progression and amplify late-stage cognitive decline [25, 85, 86]. Importantly, clinical patterns may be stage-dependent, some work suggests early cognitive changes may be detected differently across sexes, with divergence later as pathology accumulates, highlighting the need to interpret “sex effects” in a stage-resolved manner [87].

Genetic risk, immunometabolism, and disrupted neuron–microglia communication

Many AD risk pathways converge on microglial biology. TREM2 is a prominent example: via TYROBP/DAP12-dependent signaling, it supports microglial survival, chemotaxis, lipid sensing, and phagocytic responses, and rare variants such as R47H increase AD risk [74, 75], APOE provides a complementary risk axis that also shapes plaque-associated microglial programs. In human cortical tissue, APOE ε4 and TREM2 risk variants are associated with reduced enrichment of CD163⁺ amyloid-responsive microglia (ARM), supporting genotype-dependent differences in microglial engagement with Aβ pathology [76]. In plaque-forming settings, loss of TREM2 signaling disrupts microglial clustering around plaques, and is associated with more diffuse Aβ pathology and altered inflammatory programs [88]. Sex-dependent outcomes have been reported in tau-related settings, where females carrying a TREM2 risk variant (e.g., R47H) show heightened microglial reactivity, worse behavioral performance, and sex-biased induction of DAM-like transcriptional programs [36, 89]. Together, these findings support a model in which genetic risk interacts with sex to shape microglial state transitions and disease expression.

Beyond genetics risk pathways (e.g., TREM2/APOE), metabolic control of microglial activation has emerged as a critical constraint on microglial function. Sex-specific microglial immunometabolic signatures have been reported in AD, including differential enrichment of immune signaling pathways (notably IL-10 and IL-17 signaling) and broader metabolic remodeling in females [14, 90]. Because metabolic state influences microglial functions, such as phagocytosis, lipid handling, and inflammatory output, sex-biased immunometabolic programs could produce qualitative differences in microglial responses even when classical markers of “activation” appear similar [90].

Finally, sex differences may also emerge through altered neuron–microglia communication. In human AD datasets, microglia from females show reductions in pathways related to glutamate/glutamine metabolism, consistent with sex-dependent disruption of neuron–microglia coupling that may limit support for synaptic homeostasis and repair [14]. Together, these findings suggests that sex shapes not only the magnitude of microglial activation but also the quality of microglial state transitions, including metabolic constraints and functional coupling to neuronal networks [14].

Conclusions and future directions

Sex differences in microglia are increasingly recognized as a biologically meaningful dimension of AD. Evidence from aging studies, experimental models, and human datasets supports the view that microglia exhibit sex-dependent trajectories in inflammatory tone, functional capacity, and disease-associated programs, and that these differences may shape how Aβ and tau pathology translate into synaptic dysfunction, neuroinflammation, and neurodegeneration. Estrogen signaling provides a link between endocrine transitions and microglial reactivity, while genetic risk pathways (e.g., TREM2) and immunometabolic remodeling highlight that sex effects likely extend beyond hormones.

Despite this progress, major gaps remain. First, we still lack a stage-resolved map linking specific microglial states (e.g., DAM-like programs, complement-driven pruning, glycolytic shifts) to sex-specific clinical and pathological outcomes. Second, the field shows heterogeneity across studies, reflecting differences in disease stage, sampled regions, and analytic definitions of microglial states. Addressing these limitations will require sex-stratified analyses, standardized staging, and integration of multimodal endpoints (morphology, transcriptomics, metabolism, phagocytosis, and circuit function). Finally, future work should explicitly test whether therapeutic strategies, including immunomodulation and lifestyle interventions such as exercise, produce sex-dependent effects on microglial trajectories and whether such effects are beneficial at specific disease stages. Advancing along these directions is essential for translating microglial biology into sex-informed precision approaches to prevent and treat AD.

Authors' contributions

E.F., C.A., A.P. and B.L. wrote the main manuscript text; E.F., V.P. and V.C. prepared the figure 1 and formated the text. All authors reviewed the manuscript and approved the submitted version.

Funding

This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP grant #2022/00249-8), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brazil (CAPES; Finance Code 001), and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq #312904/2021-5).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.