Microglia play a crucial role in the pathogenesis of Alzheimer's disease (AD) through various mechanisms, including autophagy modulation and inflammatory responses. One study demonstrated that microglia-derived nanovesicles synchronize macroautophagy and chaperone-mediated autophagy, both of which are disrupted in AD model mice, leading to disease progression (ref: Li doi.org/10.1038/s41392-025-02453-y/). Another investigation revealed that activated microglia induce astrocyte reactivity in AD, suggesting a complex interplay between these glial cells and amyloid-beta (Aβ) pathology (ref: Ferrari-Souza doi.org/10.1038/s41593-025-02103-0/). Furthermore, the therapeutic antibody Lecanemab was shown to activate microglial effector functions, significantly reducing Aβ pathology and neuritic damage in a human microglia xenograft model, highlighting the potential of targeting microglial mechanisms for AD therapy (ref: Albertini doi.org/10.1038/s41593-025-02125-8/). Contradictory findings emerged regarding genetic factors influencing microglial activation, as a study found that the TMEM106B risk genotype was associated with increased microglial activation and cytokine responses in chronic traumatic encephalopathy, suggesting that genetic variations can modulate microglial responses to neurodegenerative pathology (ref: Hartman doi.org/10.1007/s00401-025-02955-7/). Overall, these studies underscore the multifaceted roles of microglia in AD, from their involvement in autophagy to their interactions with other glial cells and the influence of genetic factors on their activation.

Neuroinflammation is a significant contributor to the progression of Alzheimer's disease, with various studies elucidating its impact on cognitive decline and disease pathology. One study explored the relationship between neuroinflammation, as measured by PET imaging of translocator protein (TSPO), and cognitive outcomes in individuals with symptomatic AD, revealing that neuroinflammation correlates with cognitive decline (ref: Rikken doi.org/10.1186/s13195-025-01915-3/). Another investigation highlighted the role of nobiletin, a flavonoid, in reducing lipopolysaccharide-induced neuroinflammation through TLR4/MyD88/NF-κB signaling pathways in human microglial cells, suggesting potential therapeutic avenues for mitigating neuroinflammation in AD (ref: Kritika doi.org/10.1007/s12035-025-05421-3/). Additionally, the study of syringin demonstrated its ability to attenuate neuroinflammation by inhibiting NLRP3 inflammasome activation, further supporting the idea that targeting neuroinflammatory pathways can ameliorate AD pathology (ref: Xu doi.org/10.1016/j.phymed.2025.157454/). However, the complexity of neuroinflammatory responses is underscored by findings that DDT exposure induces microglial activation and disease-associated signatures, indicating environmental factors can exacerbate neuroinflammation and contribute to AD pathology (ref: Mhatre-Winters doi.org/10.1016/j.neuro.2025.103343/). Collectively, these studies emphasize the critical role of neuroinflammation in AD and the potential for targeted therapies to modulate inflammatory responses.

Genetic and epigenetic factors significantly influence the risk and resilience to Alzheimer's disease, with recent studies uncovering critical insights into these mechanisms. One study identified a myeloid trisomy 21-associated gene variant that appears to confer protection against AD, suggesting that certain genetic backgrounds may enhance microglial resilience in the presence of AD pathology (ref: Jin doi.org/10.1038/s41593-025-02117-8/). Another investigation utilized single-nucleus multi-omics to reveal shared and distinct pathways in Pick's disease and AD, highlighting the importance of understanding transcriptomic and epigenomic variations in neurodegenerative diseases (ref: Shi doi.org/10.1126/sciadv.ads7973/). Furthermore, ATP6V1E1 and NDUFB5 were identified as potential biomarkers for AD through integrative analysis, linking mitochondrial dysfunction to neurodegeneration and emphasizing the role of oxidative phosphorylation-related genes in AD risk (ref: Shao doi.org/10.1016/j.ijbiomac.2025.148733/). These findings collectively underscore the intricate interplay between genetic predispositions and epigenetic modifications in shaping the pathophysiology of Alzheimer's disease, paving the way for future research into targeted interventions.

Innovative therapeutic strategies targeting microglia are emerging as promising avenues for Alzheimer's disease treatment, focusing on modulating microglial activation and neuroinflammation. One study demonstrated that aerobic exercise attenuates microglial activation and neuroinflammation in AD models through the regulation of INPP5D, leading to improved cognitive outcomes (ref: Jiang doi.org/10.1016/j.brainresbull.2025.111633/). Another investigation revealed that TLR4 inhibition can enhance cognitive function in AD models by polarizing microglia and influencing BDNF expression, indicating that targeting specific receptors may provide therapeutic benefits (ref: Ahangaran doi.org/10.1016/j.bbr.2025.115919/). Additionally, the use of low-intensity pulsed ultrasound to open the blood-brain barrier showed promise in mitigating amyloid pathology, suggesting that non-invasive techniques could facilitate drug delivery and enhance therapeutic efficacy (ref: Canney doi.org/10.1016/j.ultrasmedbio.2025.10.008/). Furthermore, engineering microglial exosomes for targeted delivery of microRNA-124-3p presents a novel approach to combinational therapy for AD, highlighting the potential of nanomedicine in addressing complex neurodegenerative processes (ref: Ke doi.org/10.1039/d5bm01080b/). These studies collectively illustrate the potential of microglial-targeted therapies in altering disease trajectories and improving outcomes in Alzheimer's disease.

The response of microglia to amyloid and tau pathologies is a critical area of research in understanding Alzheimer's disease progression. One study found that human microglia exhibit differential responses to β-amyloid and tau pathologies, with the combination of both promoting a distinctive rod microglial phenotype that correlates with neurodegeneration (ref: Coburn doi.org/10.1002/alz.70930/). This highlights the complexity of microglial activation in the context of dual pathologies. Additionally, genetic variation in TMEM106B was shown to alter microglial activation and cytokine responses, suggesting that genetic predispositions can influence how microglia respond to neurodegenerative signals (ref: Hartman doi.org/10.1007/s00401-025-02955-7/). Furthermore, the development of a hydrogen-bonded organic framework-based nanozyme aimed at restoring metabolic homeostasis in AD underscores the potential for innovative therapeutic strategies targeting microglial function (ref: Zhang doi.org/10.1002/smll.202509547/). These findings collectively emphasize the importance of understanding microglial responses to amyloid and tau pathologies, as they may provide insights into therapeutic targets for modulating neuroinflammation and neurodegeneration.

Environmental and lifestyle factors significantly influence the risk and progression of Alzheimer's disease, with recent studies shedding light on their impact on neuroinflammation and cognitive function. One study investigated the effects of CB1 receptor modulation on cognitive deficits and neuropathology in AD mouse models, revealing that both activation and inhibition of this receptor can differentially affect disease outcomes (ref: Ye doi.org/10.1016/j.biopha.2025.118818/). This suggests that the endocannabinoid system may play a role in modulating neuroinflammatory responses associated with AD. Another study examined the relationship between inflammatory alterations, as measured by TSPO PET, and cognitive performance in individuals with Alzheimer's disease and related dementias, indicating that neuroinflammation is linked to domain-specific cognitive deficits (ref: Smith doi.org/10.1097/WAD.0000000000000706/). Additionally, the generation of 3D human iPSC-derived neurospheres for studying neuron, astrocyte, and microglia crosstalk highlights the importance of environmental context in understanding neurodegenerative processes (ref: Wendt doi.org/10.21769/BioProtoc.5493/). These findings underscore the need for a holistic approach to Alzheimer's disease that considers both environmental and lifestyle factors in the development of effective prevention and intervention strategies.

Neurovascular contributions to Alzheimer's disease are increasingly recognized, with studies exploring the interplay between vascular health and neurodegeneration. One study highlighted the association between the brain neurovascular epigenome and dementia, revealing that genes expressed in brain endothelial cells are linked to AD genetic risk, suggesting that vascular factors may influence disease susceptibility (ref: Ziegler doi.org/10.1016/j.neuron.2025.10.001/). Additionally, age-related inflammatory changes and perineuronal net dynamics were examined, indicating that neuroinflammation contributes to cognitive decline and may be influenced by vascular health (ref: Colon doi.org/10.1186/s12974-025-03568-3/). Furthermore, the neuroimaging compendium of microglia, amyloid, tau, and neurodegeneration across clinical variants of Alzheimer's disease provides insights into the spatial and temporal progression of these pathologies, emphasizing the role of vascular contributions in disease manifestation (ref: Houlihan doi.org/10.1097/WAD.0000000000000707/). Collectively, these studies underscore the importance of understanding neurovascular interactions in the context of Alzheimer's disease, as they may reveal novel therapeutic targets and strategies for intervention.