Microglia play a pivotal role in the neuroinflammatory processes associated with Alzheimer's disease (AD). Recent studies have highlighted the complex interactions between microglia and other glial cells, particularly astrocytes, in regulating synapse remodeling through Wnt signaling pathways (ref: Faust doi.org/10.1016/j.cell.2025.08.023/). This crosstalk is crucial for maintaining synaptic integrity in response to environmental changes, and its dysregulation is implicated in various neurodegenerative conditions. Additionally, the Neurolipid Atlas has been established as a comprehensive resource to explore lipidomic alterations in the brain, which are increasingly recognized as significant contributors to neurodegenerative diseases, including AD (ref: Feringa doi.org/10.1038/s42255-025-01365-z/). The atlas provides a platform for comparative research, facilitating the understanding of lipid metabolism in the context of neuroinflammation and cognitive decline. Moreover, the role of senescent-like border-associated macrophages (BAMs) in cognitive aging has been elucidated, revealing that these cells can induce paracrine senescence in microglia through migrasome-mediated signaling (ref: Hu doi.org/10.1038/s43587-025-00956-5/). This finding underscores the importance of cellular senescence in the aging brain and its potential impact on AD pathology. Therapeutic strategies targeting microglial activation have also gained attention, with studies demonstrating that enhancing microglial antioxidant capacity through the ascorbate transporter SVCT2 can delay disease onset and modify progression in mouse models of AD (ref: Portugal doi.org/10.1016/j.redox.2025.103851/). Collectively, these studies highlight the multifaceted role of microglia in AD, emphasizing the need for targeted interventions that modulate their function to mitigate neuroinflammation and cognitive decline.

The exploration of molecular mechanisms underlying Alzheimer's disease has led to significant insights into potential therapeutic approaches. Single-nucleus RNA sequencing has revealed distinct transcriptional profiles in microglia and endothelial cells, particularly in the context of mixed Alzheimer's and vascular pathology (ref: Olayinka doi.org/10.1016/j.nbd.2025.107128/). This technique allows for a deeper understanding of cell-specific responses to neurodegenerative processes, paving the way for targeted therapies that address the unique contributions of different cell types in AD. Furthermore, the manipulation of microRNA pathways through the deletion of intestinal Dicer1 has been shown to alter gut microbiome composition and influence AD pathology in App-knock-in mice, suggesting a gut-brain axis that could be exploited for therapeutic benefit (ref: Hao doi.org/10.1186/s13195-025-01849-w/). In addition, the role of 14-3-3 proteins in regulating microglial activation via the NF-κB pathway has been highlighted, indicating that these proteins may serve as potential therapeutic targets to modulate neuroinflammation in AD (ref: Stone doi.org/10.1111/jnc.70228/). The study of traditional Chinese medicine has also yielded promising results, with Linggui Zhugan decoction showing potential in modulating microglial ferroptosis through IL-17 and TNF pathways (ref: Tang doi.org/10.1016/j.intimp.2025.115489/). These findings underscore the importance of understanding the molecular underpinnings of AD to develop innovative therapeutic strategies that can effectively target the disease's complex pathology.

Genetic and environmental factors play a crucial role in the development and progression of Alzheimer's disease. Recent research has identified a novel function of the SORLA gene, which is implicated in familial Alzheimer's disease, in regulating the release of neurotrophic exosomes (ref: Juul-Madsen doi.org/10.1002/alz.70591/). This discovery suggests that alterations in exosomal communication may contribute to the pathophysiology of AD, particularly in carriers of SORL1 mutations. Additionally, the impact of LRRK2 kinase activity on NRF2-dependent mitochondrial protection in microglia has been explored, revealing a paradoxical response that may influence neuroinflammatory processes in AD (ref: Weindel doi.org/10.1093/jimmun/). Environmental factors, such as enriched living conditions, have also been shown to alleviate AD pathology by reducing microglial complement signaling in aged APP/PS1 mice (ref: Chen doi.org/10.1096/fj.202501545RR/). This highlights the potential for lifestyle interventions to modify disease progression and cognitive outcomes in individuals at risk for AD. Furthermore, the relationship between sialylation patterns and cerebral amyloid angiopathy has been investigated, revealing significant differences in sialylation levels in AD cases with co-existing conditions (ref: Fastenau doi.org/10.1111/bpa.70042/). These findings emphasize the intricate interplay between genetic predispositions and environmental influences in shaping Alzheimer's pathology.

Microglial activation is intricately linked to aging and the pathogenesis of Alzheimer's disease. Recent studies have demonstrated that senescent-like border-associated macrophages (BAMs) can influence cognitive aging by inducing paracrine senescence in microglia through migrasome-mediated signaling (ref: Hu doi.org/10.1038/s43587-025-00956-5/). This highlights the role of cellular senescence in the aging brain and its potential contribution to neurodegenerative processes. Additionally, enhancing the antioxidant capacity of microglia via the ascorbate transporter SVCT2 has been shown to delay the onset of AD pathology in mouse models, suggesting that targeting microglial function could be a viable therapeutic strategy (ref: Portugal doi.org/10.1016/j.redox.2025.103851/). Moreover, the establishment of the Neurolipid Atlas provides a valuable resource for understanding lipidomic changes associated with neurodegenerative diseases, including the effects of aging on microglial function (ref: Feringa doi.org/10.1038/s42255-025-01365-z/). This resource facilitates comparative research and could lead to novel insights into the role of lipids in microglial activation and aging. Furthermore, environmental factors such as enriched environments have been shown to improve cognitive function and reduce amyloid plaque accumulation in aged APP/PS1 mice, indicating that lifestyle modifications may mitigate the effects of aging on microglial activity and AD progression (ref: Chen doi.org/10.1096/fj.202501545RR/). Collectively, these studies underscore the importance of understanding microglial activation in the context of aging and its implications for Alzheimer's disease.

Lipidomics has emerged as a critical field in understanding the biochemical alterations associated with neurodegenerative diseases, particularly Alzheimer's disease. The establishment of the Neurolipid Atlas serves as a comprehensive resource for lipidomic research, providing valuable data on lipid alterations in various brain diseases (ref: Feringa doi.org/10.1038/s42255-025-01365-z/). This atlas facilitates comparative studies and enhances our understanding of how lipid metabolism influences neurodegeneration. Additionally, the role of senescent-like border-associated macrophages in regulating cognitive aging through lipid signaling pathways has been highlighted, indicating that lipid mediators may play a significant role in microglial function and neuroinflammation (ref: Hu doi.org/10.1038/s43587-025-00956-5/). Furthermore, the relationship between sialylation patterns and cerebral amyloid angiopathy has been explored, revealing that AD cases with co-existing conditions exhibit significantly higher sialylation levels in both parenchymal and leptomeningeal vessels (ref: Fastenau doi.org/10.1111/bpa.70042/). This finding underscores the importance of lipid modifications in the context of amyloid pathology and suggests potential therapeutic targets for modulating lipid metabolism in AD. Overall, the integration of lipidomics into neurodegenerative research provides new avenues for understanding disease mechanisms and developing targeted interventions.

Neuroinflammation is increasingly recognized as a key factor influencing cognitive function in Alzheimer's disease. Recent studies have demonstrated that the P2RX7 receptor modulates the function of human microglia-like cells and mediates the association of IL-18 with Alzheimer's disease traits (ref: Heavener doi.org/10.1016/j.nbd.2025.107106/). This finding highlights the role of purinergic signaling in neuroinflammatory processes and its potential impact on cognitive decline. Additionally, the transition of microglial responses from anti-inflammatory to pro-inflammatory states in the context of hypoxia has been investigated, revealing that mild hypoxic conditions can anticipate this phenotypic switch (ref: Lipari doi.org/10.1186/s12967-025-07044-7/). Moreover, the suppression of neuroinflammation through the administration of protocatechuic acid has been shown to attenuate Alzheimer's disease phenotypes in transgenic mouse models, indicating that targeting neuroinflammatory pathways may offer therapeutic benefits (ref: Kim doi.org/10.1016/j.biopha.2025.118598/). Environmental factors, such as enriched living conditions, have also been associated with improved cognitive function and reduced amyloid plaque accumulation, further emphasizing the interplay between neuroinflammation and cognitive outcomes in AD (ref: Chen doi.org/10.1096/fj.202501545RR/). Collectively, these studies underscore the critical role of neuroinflammation in cognitive function and highlight the potential for therapeutic strategies aimed at modulating inflammatory responses in Alzheimer's disease.

Innovative therapeutic strategies for Alzheimer's disease are being developed to address the complex pathophysiology of the condition. One promising approach involves the use of cleavable antibody-conjugated immune exosomes that specifically target amyloid-beta (Aβ) and neuroinflammatory responses, achieving enhanced efficacy while minimizing side effects associated with traditional antibody therapies (ref: Ma doi.org/10.1002/anie.202517917/). This strategy represents a significant advancement in immunotherapy for AD, aiming to improve pharmacodynamics and clinical outcomes. Additionally, traditional Chinese medicine has shown potential in modulating microglial ferroptosis through IL-17 and TNF pathways, indicating that herbal formulations may offer novel therapeutic avenues for AD management (ref: Tang doi.org/10.1016/j.intimp.2025.115489/). Furthermore, cornuside has been found to ameliorate cognitive dysfunction and inhibit NLRP3 inflammasome activation in LPS-induced models, suggesting that targeting specific inflammatory pathways could provide therapeutic benefits (ref: Lian doi.org/10.1016/j.jep.2025.120615/). Neurotropin, a non-protein extract, has also demonstrated protective effects against AD pathology by improving mitochondrial function and microglial polarization (ref: Huang doi.org/10.5582/bst.2025.01220/). These innovative strategies highlight the importance of exploring diverse therapeutic modalities to effectively combat Alzheimer's disease.