Microglia play a crucial role in the pathogenesis of Alzheimer's disease (AD), particularly through their involvement in neuroinflammation and lipid metabolism. Recent studies have highlighted the significance of specific molecular pathways in microglial activation and their implications for AD. For instance, research by Gao et al. demonstrated that the multifunctional enzyme type 2 (MFE-2) is downregulated in microglia from AD patients, leading to impaired lipid homeostasis and increased neuroinflammation, which subsequently drives amyloid-beta (Aβ) deposition (ref: Gao doi.org/10.1038/s43587-025-00976-1/). In another study, Zhang et al. found that conditional knockout of Rack1 in microglia reduced Aβ aggregation and alleviated cognitive impairments in AD model mice, indicating that microglial dysfunction can exacerbate AD pathology (ref: Zhang doi.org/10.1002/advs.202515877/). Furthermore, Xu et al. revealed that microglia selectively regulate lipid accumulation associated with AD pathology, underscoring the importance of lipid metabolism in microglial function (ref: Xu doi.org/10.1038/s41467-025-64161-z/). These findings collectively suggest that targeting microglial pathways could offer new therapeutic avenues for AD treatment. The interplay between microglial activation and neuroinflammation is further emphasized by studies exploring the role of specific receptors and signaling pathways. For example, the study by Xu et al. on microglial deletion of Hrh4 demonstrated enhanced phagocytosis of Aβ and tau, which alleviated AD pathologies (ref: Xu doi.org/10.1002/advs.202505421/). Additionally, the research by Oh et al. identified PLXDC2 as a key regulator of Aβ phagocytosis and inflammatory responses in microglia, highlighting the need for further exploration of microglial receptors in AD (ref: Oh doi.org/10.4062/biomolther.2025.150/). Overall, these studies illustrate the complex roles of microglia in AD, revealing potential targets for therapeutic intervention aimed at modulating their function to mitigate disease progression.

Neuroinflammation is a critical component of Alzheimer's disease (AD) pathology, particularly in relation to amyloid-beta (Aβ) accumulation and tau hyperphosphorylation. La Barbera et al. highlighted that midbrain degeneration correlates with increased astrocyte reactivity and tau pathology, suggesting that neuroinflammation may serve as a predictor for the progression from mild cognitive impairment (MCI) to dementia (ref: La Barbera doi.org/10.1186/s13024-025-00893-2/). This relationship underscores the importance of understanding how neuroinflammatory processes contribute to the development of AD. Additionally, Xie et al. demonstrated that uric acid, an endogenous modulator, can enhance microglial function and reduce amyloid plaque burden in AD models, indicating a potential protective role against neuroinflammation (ref: Xie doi.org/10.1002/advs.202510270/). Moreover, the study by Zhao et al. explored the role of amyloid precursor protein (APP) in microglial activation, revealing that APP and its cleaved fragment C99 enhance inflammatory mediator release in human microglia (ref: Zhao doi.org/10.1073/pnas.2509903122/). This finding suggests that APP processing may exacerbate neuroinflammation in AD. Complementing these insights, Ding et al. developed a nanolipid carrier targeting complement component C1q, which is upregulated in AD, to deliver therapeutic agents for synaptic protection (ref: Ding doi.org/10.1021/acs.nanolett.5c04420/). Collectively, these studies illustrate the intricate relationship between neuroinflammation and amyloid pathology, emphasizing the need for targeted therapeutic strategies that address both aspects to effectively combat AD.

Circadian rhythms significantly influence neurodegenerative processes, including Alzheimer's disease (AD). Sheehan et al. provided a comprehensive analysis of circadian gene expression in glial cells, revealing that aging and amyloid pathology induce cell-type-specific reprogramming of circadian translatomes (ref: Sheehan doi.org/10.1038/s41593-025-02067-1/). This study highlights how disruptions in circadian rhythms may contribute to the progression of neurodegenerative diseases by affecting glial function and neuroinflammation. Furthermore, the findings by Gertie et al. on ZBP1-RIPK1 signaling in microglia suggest that circadian regulation may also play a role in modulating neuroinflammatory responses in AD (ref: Gertie doi.org/10.1016/j.immuni.2025.09.010/). Additionally, the research by Masrori et al. on C9orf72 hexanucleotide repeat expansions indicates that genetic factors influencing circadian rhythms may impair microglial responses in neurodegenerative contexts (ref: Masrori doi.org/10.1038/s41593-025-02075-1/). This connection between circadian biology and microglial function underscores the potential for circadian modulation as a therapeutic strategy in AD. Overall, these studies emphasize the need for further exploration of circadian mechanisms in neurodegeneration, as they may reveal novel insights into the timing and regulation of neuroinflammatory processes in AD.

Lipid metabolism is increasingly recognized as a critical factor in microglial function and its implications for Alzheimer's disease (AD). Gao et al. demonstrated that the downregulation of multifunctional enzyme type 2 (MFE-2) in microglia leads to impaired lipid homeostasis and promotes neuroinflammation, thereby contributing to AD pathogenesis (ref: Gao doi.org/10.1038/s43587-025-00976-1/). This study highlights the importance of lipid metabolism in maintaining microglial health and suggests that targeting lipid pathways could be a viable therapeutic strategy. Similarly, Xu et al. found that microglia selectively regulate lipid accumulation associated with AD pathology, indicating that dysregulated lipid processing may exacerbate disease progression (ref: Xu doi.org/10.1038/s41467-025-64161-z/). Moreover, the research by Zhang et al. on Rack1 deficiency in microglia revealed that enhancing astrocytic phagocytosis through IGF1 signaling can alleviate AD pathology, further linking lipid metabolism to microglial function (ref: Zhang doi.org/10.1002/advs.202515877/). These findings collectively underscore the intricate relationship between lipid metabolism and microglial activation, suggesting that interventions aimed at restoring lipid homeostasis may have therapeutic potential in AD.

Recent advancements in therapeutic strategies for Alzheimer's disease (AD) have focused on modulating neuroinflammation and amyloid pathology. Wang et al. developed a nanotherapeutic platform that co-delivers a TREM2 agonist and a glutamate modulator, addressing the dual challenges of Aβ clearance and neuronal hyperexcitability (ref: Wang doi.org/10.1021/acsnano.5c08317/). This innovative approach highlights the importance of targeting multiple pathways simultaneously to enhance therapeutic efficacy. Additionally, the study by Xu et al. demonstrated that low-dose ionizing radiation can promote microglial phagocytosis of Aβ and tau, suggesting a novel intervention for AD pathology (ref: Xu doi.org/10.1002/advs.202505421/). Furthermore, the identification of PLCG2 variants associated with AD risk by Bedford et al. underscores the potential for genetic insights to inform therapeutic development (ref: Bedford doi.org/10.1002/alz.70772/). The exploration of complement-targeted therapies, as demonstrated by Ding et al., also represents a promising avenue for synaptic protection in AD (ref: Ding doi.org/10.1021/acs.nanolett.5c04420/). Collectively, these studies illustrate the dynamic landscape of AD therapeutics, emphasizing the need for innovative approaches that integrate genetic, molecular, and pharmacological strategies to effectively combat the disease.

Genetic and molecular research has provided significant insights into the mechanisms underlying Alzheimer's disease (AD). The study by Kumar et al. utilized single-cell RNA sequencing to derive cell-weighted polygenic risk scores, revealing associations with β-amyloid and tau biomarkers (ref: Kumar doi.org/10.1093/braincomms/). This approach highlights the importance of considering cellular heterogeneity in understanding AD pathology and suggests that genetic predispositions may influence the accumulation of toxic proteins. Additionally, Bedford et al. explored the impact of PLCG2 variants on microglial function, demonstrating that risk-associated variants alter the transcriptional profile and immune responses of microglia (ref: Bedford doi.org/10.1002/alz.70772/). Moreover, the research by Hsieh et al. on quercetin's anti-inflammatory effects in microglia emphasizes the potential for dietary compounds to modulate neuroinflammation in AD (ref: Hsieh doi.org/10.2174/0109298673395813250901012530/). These findings collectively underscore the intricate interplay between genetic factors and molecular pathways in AD, suggesting that targeted interventions may be developed based on individual genetic profiles to mitigate disease progression.

Inflammatory pathways play a pivotal role in the activation of microglia and the progression of Alzheimer's disease (AD). Recent studies have elucidated various mechanisms through which inflammation contributes to neurodegeneration. For instance, Rong et al. demonstrated that dual inhibition of phosphodiesterases 4 and 10 restores CREB1 function, enhancing neuronal resilience in AD models (ref: Rong doi.org/10.1186/s13195-025-01869-6/). This finding highlights the importance of targeting inflammatory signaling pathways to promote neuroprotection. Additionally, Kim et al. showed that ROE treatment in BV-2 microglial cells suppresses the MAPK and NF-κB signaling pathways, reducing neuroinflammation in response to LPS stimulation (ref: Kim doi.org/10.3390/ph18101557/). Furthermore, Wang et al. investigated the effects of probenecid on LPS-induced neuroinflammation, revealing its potential to modulate the NLRP1 inflammasome pathway in BV2 cells (ref: Wang doi.org/10.1038/s41598-025-19015-5/). These studies collectively emphasize the critical role of inflammatory pathways in microglial activation and suggest that targeting these pathways may offer therapeutic opportunities to mitigate neuroinflammation and its detrimental effects in AD.

Environmental and dietary factors have emerged as significant contributors to the risk and progression of Alzheimer's disease (AD). Pan et al. investigated the effects of chronic ethanol exposure on cognitive function and neuroinflammation in an APP/PS1 mouse model, demonstrating that N-acetylcysteine (NAC) supplementation can ameliorate ethanol-induced oxidative stress and cognitive dysfunction (ref: Pan doi.org/10.1038/s41398-025-03496-z/). This study highlights the potential for dietary interventions to mitigate the adverse effects of environmental factors on AD pathology. Additionally, the research by Li et al. on the β2-adrenergic pathway suggests that pharmacological activation of this pathway can restore cognitive function and synaptic integrity in preclinical models of AD (ref: Li doi.org/10.4103/NRR.NRR-D-25-00529/). These findings underscore the importance of considering lifestyle and dietary factors in the context of AD prevention and treatment. By understanding how environmental influences interact with genetic predispositions, researchers can develop more effective strategies to combat the disease. Overall, these studies emphasize the need for a holistic approach to AD that incorporates both genetic and environmental considerations.