Microglial cells play a crucial role in the pathogenesis of Alzheimer's disease (AD), particularly in the context of neuroinflammation and amyloid-beta (Aβ) clearance. Recent studies have highlighted innovative strategies to harness microglial functions for therapeutic purposes. For instance, the use of circular RNA aptamers targeting the proinflammatory molecule PKR has shown promise in ameliorating AD phenotypes in mouse models by inhibiting neuroinflammation (ref: Feng doi.org/10.1038/s41587-025-02624-w/). Additionally, research has demonstrated that microglia can drive Aβ clearance in immunized patients, suggesting that active immunization may influence tau accumulation and reduce local tangles in the cerebral cortex (ref: Unknown doi.org/10.1038/s41591-025-03677-9/). Furthermore, the engineering of human iPSC-derived microglia to deliver therapeutic proteins across the CNS has been explored, with promising results indicating enhanced efficacy in targeting Aβ (ref: Chadarevian doi.org/10.1016/j.stem.2025.03.009/). Moreover, the spatial transcriptomic analysis of the hippocampus has revealed significant alterations in gene expression associated with AD, including increased synapse pruning and disrupted microglia-astrocyte communication, which may contribute to synaptic dysfunction (ref: Wang doi.org/10.1016/j.neuron.2025.03.002/). The identification of monoallelic TYROBP deletion as a risk factor for AD underscores the genetic underpinnings of microglial dysfunction in the disease (ref: Martiskainen doi.org/10.1186/s13024-025-00830-3/). Collectively, these findings emphasize the multifaceted role of microglia in AD pathology and highlight potential therapeutic avenues targeting these immune cells.

Neuroinflammation is increasingly recognized as a pivotal factor in the pathogenesis of Alzheimer's disease, particularly in relation to amyloid-beta (Aβ) clearance. Studies have shown that microglia are essential for the clearance of Aβ, with active immunization leading to significant reductions in plaque accumulation and subsequent effects on tau pathology (ref: Unknown doi.org/10.1038/s41591-025-03677-9/). The development of hybrid lipoplexes that enhance neuron-microglia communication has also been proposed as a strategy to boost Aβ clearance through targeted autophagy (ref: Pu doi.org/10.1002/adma.202418560/). Furthermore, the identification of APOE4's role in impairing microglial autophagy and Aβ clearance highlights the genetic factors that exacerbate neuroinflammation in AD (ref: Bassal doi.org/10.1007/s00011-025-02016-5/). In addition, the use of circular RNA aptamers to inhibit neuroinflammation has shown efficacy in mouse models, suggesting that targeting inflammatory pathways may provide therapeutic benefits (ref: Feng doi.org/10.1038/s41587-025-02624-w/). The exploration of microglia-targeting nanomodulators that enhance drug delivery across the blood-brain barrier further illustrates the innovative approaches being developed to mitigate neuroinflammation and improve Aβ clearance (ref: Wei doi.org/10.1016/j.apsb.2025.01.015/). Overall, these studies underscore the complex interplay between neuroinflammation and amyloid clearance, revealing potential therapeutic targets for AD.

Genetic and epigenetic factors play a significant role in the development and progression of Alzheimer's disease. Recent research has identified the SORL1 gene as a critical regulator of lysosomal function in microglia, linking genetic risk factors to cellular dysfunction in AD (ref: Mishra doi.org/10.1002/glia.70009/). Additionally, a genome-wide association study has highlighted the implications of SORL1 in cerebral beta-amyloid deposition, emphasizing the importance of genetic diversity in understanding AD pathology (ref: Kim doi.org/10.1038/s41467-025-57751-4/). The role of environmental factors, such as arsenic exposure, has also been investigated, revealing its potential to activate microglia and induce neuroinflammation, thereby promoting AD-like neurodegeneration (ref: Zhang doi.org/10.1016/j.ecoenv.2025.118251/). Moreover, the therapeutic potential of dietary interventions, such as omega-3 fatty acids, has been explored, with findings suggesting that these compounds can modulate gut microbiota and influence neuroinflammation in AD models (ref: Altendorfer doi.org/10.3390/nu17071108/). The investigation of sex differences in brain iron deposition and microglial activity further highlights the need for tailored approaches in AD treatment, considering the distinct biological responses observed in different sexes (ref: Rahman doi.org/10.1177/00368504251336080/). Collectively, these studies underscore the intricate relationship between genetic, epigenetic, and environmental factors in the pathogenesis of Alzheimer's disease.

Therapeutic strategies targeting microglia have emerged as a promising avenue for the treatment of Alzheimer's disease. Recent advancements include the development of human iPSC-derived microglia capable of delivering disease-modifying proteins throughout the central nervous system, utilizing CRISPR technology to enhance therapeutic efficacy (ref: Chadarevian doi.org/10.1016/j.stem.2025.03.009/). Additionally, the use of circular RNA aptamers to inhibit neuroinflammation has shown potential in ameliorating AD phenotypes in mouse models, indicating a novel approach to modulate microglial activity (ref: Feng doi.org/10.1038/s41587-025-02624-w/). Furthermore, the application of photobiomodulation has been explored as a non-invasive method to enhance mitochondrial function and reduce neurological damage in AD models, suggesting that light-based therapies could be beneficial in modulating microglial responses (ref: Chen doi.org/10.1186/s13195-025-01714-w/). The inhibition of BET proteins has also been investigated for its potential to protect against microglia-mediated neuronal loss, highlighting the role of epigenetic regulation in neuroinflammation (ref: Matuszewska doi.org/10.3390/biom15040528/). These innovative strategies reflect a growing understanding of microglial biology and their therapeutic potential in combating Alzheimer's disease.

Sex differences in Alzheimer's disease pathology have garnered increasing attention, particularly regarding the distinct biological responses observed in males and females. Research has indicated that estrogen receptor beta (ERβ) activation may provide neuroprotective effects that are particularly relevant for females, especially in the context of menopausal changes (ref: Demetriou doi.org/10.1186/s13293-025-00711-w/). This highlights the importance of considering sex-specific mechanisms when developing therapeutic strategies for AD. Additionally, studies examining brain iron deposition and microglial ferritin levels have revealed significant differences between sexes, with implications for disease progression and treatment approaches (ref: Rahman doi.org/10.1177/00368504251336080/). The neuroinvasive potential of SARS-CoV-2 has also been explored, demonstrating increased microglial activation in infected models, which may further complicate sex differences in AD pathology (ref: Benavides doi.org/10.1371/journal.pone.0311449/). Collectively, these findings underscore the necessity of integrating sex as a biological variable in Alzheimer's disease research and treatment.

The gut microbiome has emerged as a significant factor influencing the pathogenesis of Alzheimer's disease, with recent studies highlighting its role in modulating neuroinflammation and microglial activity. Machine learning approaches have been utilized to assess the relationship between gut microbiome profiles and the incidence of AD, suggesting that microbial composition may serve as a predictive biomarker for disease risk (ref: Basgaran doi.org/10.1093/braincomms/). Furthermore, dietary interventions, such as omega-3 EPA supplementation, have been shown to alter gut microbiota composition and reduce neuroinflammatory markers in AD models, indicating a potential therapeutic strategy (ref: Altendorfer doi.org/10.3390/nu17071108/). Additionally, the interplay between the gut microbiome and microglial function has been investigated, revealing that alterations in gut microbial communities can impact neuroinflammation and cognitive outcomes in AD (ref: Chaigneau doi.org/10.1002/glia.70029/). These findings emphasize the importance of the gut-brain axis in Alzheimer's disease and suggest that targeting the microbiome may offer novel avenues for intervention.

Microglial activation is a central feature of neurodegeneration in Alzheimer's disease, with recent studies elucidating the mechanisms underlying this process. Research has shown that chronic activation of microglia can exacerbate neuroinflammation and contribute to neuronal damage, highlighting the need for targeted therapeutic strategies (ref: Zhang doi.org/10.1016/j.ecoenv.2025.118251/). The development of enhanced blood-brain barrier (BBB) penetration strategies, such as microglia-targeting nanomodulators, aims to effectively modulate chronically activated microglia and mitigate neuroinflammation in AD (ref: Wei doi.org/10.1016/j.apsb.2025.01.015/). Moreover, the use of photobiomodulation has been explored as a non-invasive approach to modulate mitochondrial energy metabolism and reduce neurological damage in AD models, indicating potential benefits for microglial function (ref: Chen doi.org/10.1186/s13195-025-01714-w/). The investigation of SGLT2 and DPP4 inhibitors has also revealed their neuroprotective roles in modulating microglial activity and reducing AD-like pathology, further emphasizing the therapeutic potential of targeting microglial activation (ref: Sim doi.org/10.1016/j.expneurol.2025.115271/). Collectively, these studies underscore the critical role of microglial activation in neurodegeneration and highlight potential therapeutic strategies to address this aspect of Alzheimer's disease.