Microglia, the resident immune cells of the central nervous system, play a pivotal role in the pathology of Alzheimer's disease (AD). Recent studies have highlighted the genetic underpinnings of microglial function, particularly the influence of the APOE genotype on microglial activity. For instance, research has shown that APOE4 carriers exhibit increased pro-inflammatory signatures in microglia, which correlates with reduced responses to amyloid-beta pathology (ref: Li doi.org/10.1016/j.neuron.2025.02.017/). Furthermore, the accumulation of lipid droplets in microglia from APOE4 carriers has been linked to neuronal degeneration through the inhibition of lipid droplet autophagy, resulting in elevated levels of phosphorylated tau protein in treated neurons (ref: Mao doi.org/10.1016/j.apsb.2024.10.009/). This interplay between lipid metabolism and inflammation underscores the complex role of microglia in AD pathology. In addition to genetic factors, environmental influences such as cholinergic lesions have been shown to alter microglial activity and density, indicating that microglial responses are not solely dictated by genetic predisposition (ref: Orciani doi.org/10.1016/j.neurobiolaging.2025.03.006/). Moreover, the identification of molecular signatures through cerebrospinal fluid proteomics has revealed dysregulated proteins across the AD continuum, providing potential biomarkers for early diagnosis and therapeutic targets (ref: Ali doi.org/10.1016/j.neuron.2025.02.014/). Collectively, these findings emphasize the multifaceted role of microglia in AD, integrating genetic, environmental, and molecular factors that contribute to disease progression.

The genetic landscape of Alzheimer's disease (AD) is complex, with various studies elucidating the molecular mechanisms underlying its pathogenesis. One significant advancement is the development of Spotiphy, a computational toolkit that enables single-cell spatial whole transcriptomics, providing insights into gene expression patterns within tissue sections (ref: Yang doi.org/10.1038/s41592-025-02622-5/). This approach enhances our understanding of cellular heterogeneity in AD and facilitates the identification of cell-specific gene regulatory networks, as demonstrated by the scMultiomeGRN framework, which integrates single-cell RNA and ATAC sequencing data to infer transcription factor regulatory networks (ref: Xu doi.org/10.1093/nar/). Additionally, the role of specific genes such as Asrij has been investigated, revealing that its depletion can reduce inflammatory microglial activation and ameliorate amyloid-beta pathology in mouse models (ref: Dongre doi.org/10.1186/s12974-025-03415-5/). Moreover, the discovery of somatic mutations in microglia that preferentially target the MAPK pathway highlights the genetic diversity within these cells and its potential implications for AD pathology (ref: Vicario doi.org/10.7554/eLife.96519/). These findings collectively underscore the importance of genetic and molecular mechanisms in shaping the pathological landscape of AD, paving the way for targeted therapeutic strategies.

Neuroinflammation is a critical component of Alzheimer's disease (AD) pathology, with various cytokines and immune responses contributing to disease progression. Recent studies have identified interleukin-12 signaling as a significant driver of AD pathology, disrupting neuronal and oligodendrocyte homeostasis in mouse models (ref: Schneeberger doi.org/10.1038/s43587-025-00816-2/). This highlights the role of specific inflammatory pathways in exacerbating neurodegeneration and suggests that targeting these pathways could be a viable therapeutic strategy. Moreover, the interplay between microglial activation and neuroinflammation has been further elucidated through the development of humanized mouse models for microglia transplantation, which allow for a more accurate study of microglial responses in neurodegenerative diseases (ref: Serneels doi.org/10.1186/s13024-025-00823-2/). Additionally, the impact of IL-17A on exacerbating neuroinflammatory and neurodegenerative biomarkers in amyloid-beta models emphasizes the complex role of cytokines in AD (ref: Gautam doi.org/10.1007/s11481-025-10192-8/). These findings collectively underscore the importance of understanding neuroinflammatory mechanisms in AD, as they may provide insights into novel therapeutic targets.

The complexity of Alzheimer's disease (AD) necessitates innovative therapeutic approaches that target multiple pathways. Recent research has explored the potential of a nasally administered reactive oxygen species-responsive gene delivery nanosystem, which aims to enhance treatment efficacy by addressing both amyloid-beta and microglia-mediated neuroinflammation (ref: Chen doi.org/10.1016/j.jconrel.2025.113604/). This combination therapy approach reflects a growing recognition of the need for multifaceted strategies in AD management. Additionally, the role of natural medicine in AD treatment has been highlighted through the development of SysNatMed, a data-driven approach for discovering natural compounds with potential therapeutic effects (ref: Ye doi.org/10.3389/fphar.2025.1496061/). Furthermore, studies on the effects of parthenolide on microglial and astrocyte function indicate that modulating glial activity can have neuroprotective effects on motor neurons, suggesting that targeting glial cells may be a promising avenue for AD therapy (ref: Thau-Habermann doi.org/10.1371/journal.pone.0319866/). Collectively, these findings emphasize the importance of exploring diverse therapeutic strategies to address the multifactorial nature of AD.

Sex differences play a significant role in the prevalence and manifestation of Alzheimer's disease (AD), with emerging research focusing on the hormonal influences that may contribute to these disparities. Studies have shown that testosterone signaling in microglia, mediated by GPRC6A, may influence the degradation of aggregated amyloid-beta, highlighting a potential mechanism for sex-related differences in AD pathology (ref: Du doi.org/10.1002/advs.202413375/). This suggests that hormonal factors could modulate microglial function and, consequently, the progression of AD. Moreover, the impact of sex chromosomes and gonadal hormones on microglial-mediated pathology has been investigated, revealing that these factors shape immune responses and may contribute to the observed sex bias in AD (ref: Casali doi.org/10.1186/s12974-025-03404-8/). Additionally, the APOE genotype's influence on microglial activity further complicates the understanding of sex differences in AD, as APOE4 carriers exhibit distinct inflammatory profiles compared to other genotypes (ref: Li doi.org/10.1016/j.neuron.2025.02.017/). These findings underscore the need for a nuanced understanding of how sex and hormonal influences intersect with genetic factors in the context of AD.

The development and identity of microglia are shaped by both intrinsic genetic programs and extrinsic environmental signals. Recent research has identified the role of integrin beta 8 (ITGB8) expressed by radial glia in activating TGF-β1 signaling in microglia, which is crucial for their development and identity (ref: McKinsey doi.org/10.1038/s41467-025-57684-y/). This finding highlights the importance of understanding the cellular interactions that govern microglial identity during brain development. Furthermore, the establishment of humanized mouse models for microglia transplantation has opened new avenues for studying microglial responses in neurodegenerative diseases, allowing for a more accurate representation of human microglial behavior (ref: Serneels doi.org/10.1186/s13024-025-00823-2/). Additionally, the impact of the APOE genotype on microglial function and the identification of inflammatory pathways linked to tau propagation further emphasize the complexity of microglial identity in the context of AD (ref: King doi.org/10.1091/mbc.E24-04-0182/). Collectively, these studies underscore the need for continued exploration of microglial development and identity to inform therapeutic strategies in neurodegenerative diseases.