Microglia, the resident immune cells of the central nervous system, play a pivotal role in the pathogenesis of Alzheimer's disease (AD). Recent studies have highlighted various mechanisms through which microglia contribute to synaptic loss and neuroinflammation. For instance, the study by De Schepper et al. demonstrated that SPP1, produced by perivascular cells, modulates microglial phagocytic states, thereby influencing synaptic engulfment in AD mouse models (ref: De Schepper doi.org/10.1038/s41593-023-01257-z/). Furthermore, Zeng et al. introduced STARmap PLUS, a novel method that integrates spatial transcriptomics with protein detection, allowing for a comprehensive understanding of microglial behavior in the context of AD pathology (ref: Zeng doi.org/10.1038/s41593-022-01251-x/). This approach revealed spatiotemporal dynamics of microglial activation and its correlation with synaptic integrity, emphasizing the importance of microglial function in AD progression. Additionally, the pathogenic role of RAGE in tau transmission was explored by Kim et al., who found that RAGE knockout reduced tau propagation and cognitive deficits in transgenic mice, linking microglial activation to tau pathology (ref: Kim doi.org/10.1016/j.biopsych.2022.10.015/). Overall, these findings underscore the multifaceted roles of microglia in AD, from synaptic maintenance to the propagation of neurodegenerative processes, suggesting potential therapeutic targets for modulating microglial activity.

Genetic factors play a crucial role in the susceptibility and progression of Alzheimer's disease (AD). The TREM2 H157Y mutation has been shown to enhance soluble TREM2 production, which in turn accelerates amyloid-beta clearance and reduces amyloid pathology in mouse models (ref: Qiao doi.org/10.1186/s13024-023-00599-3/). This mutation highlights the importance of microglial receptors in modulating amyloid burden and synaptic function. In another study, Li et al. identified a causal variant in the CTSH locus associated with AD, providing insights into the genetic mechanisms underlying the disease (ref: Li doi.org/10.1038/s41386-023-01542-2/). Furthermore, the role of osteocalcin in ameliorating cognitive dysfunctions by reducing amyloid burden and enhancing glycolysis in neuroglia was demonstrated by Shan et al., suggesting metabolic interventions as a potential therapeutic strategy (ref: Shan doi.org/10.1038/s41420-023-01343-y/). These studies collectively emphasize the interplay between genetic factors and metabolic pathways in AD, revealing potential avenues for targeted therapies that address both genetic predispositions and metabolic dysfunctions.

Neuroinflammation is a hallmark of Alzheimer's disease (AD) and significantly contributes to its pathogenesis. Kim et al. elucidated the role of RAGE in tau transmission and memory deficits, demonstrating that RAGE antagonism can mitigate tau propagation and cognitive decline in mouse models (ref: Kim doi.org/10.1016/j.biopsych.2022.10.015/). This finding underscores the importance of inflammatory pathways in AD. Additionally, Xie et al. explored the contribution of Helicobacter pylori-derived outer membrane vesicles to AD pathogenesis, suggesting that gut microbiota may influence neuroinflammatory responses (ref: Xie doi.org/10.1002/jev2.12306/). The study by Arroyo-García et al. further highlighted the role of galectin-3 in amplifying neuroinflammation and disrupting neuronal oscillations, indicating that targeting neuroinflammatory mediators could be a promising therapeutic strategy (ref: Arroyo-García doi.org/10.1186/s40035-023-00338-0/). Collectively, these studies illustrate the complex interplay between neuroinflammation and AD pathology, emphasizing the need for therapeutic approaches that address both immune responses and neuronal health.

Recent advancements in therapeutic strategies targeting microglial function have shown promise in addressing Alzheimer's disease (AD). Zhao et al. developed a multivalent nanobody conjugate designed to simultaneously target amyloid-beta aggregation and oxidative stress, demonstrating its efficacy in mitigating AD pathology (ref: Zhao doi.org/10.1002/adma.202210879/). This innovative approach highlights the potential of multi-target therapies in AD treatment. Additionally, Moutinho et al. investigated the role of TREM2 splice isoforms, revealing that soluble TREM2 species can disrupt long-term potentiation, thereby affecting synaptic plasticity (ref: Moutinho doi.org/10.1186/s13073-023-01160-z/). Furthermore, Fairley et al. identified the translocator protein and hexokinase-2 as critical regulators of microglial metabolism and phagocytosis, suggesting that metabolic modulation could enhance microglial function in AD (ref: Fairley doi.org/10.1073/pnas.2209177120/). These findings collectively underscore the importance of targeting microglial pathways and metabolism as a therapeutic strategy to combat AD.

Extracellular vesicles (EVs) and gut microbiota have emerged as significant players in the pathogenesis of Alzheimer's disease (AD). Xie et al. demonstrated that Helicobacter pylori-derived outer membrane vesicles contribute to AD via C3-C3aR signaling, highlighting the gut-brain axis's role in neurodegeneration (ref: Xie doi.org/10.1002/jev2.12306/). Additionally, Visconte et al. reported increased concentrations of microglial-derived EVs in frail patients with mild cognitive impairment, suggesting a neurotoxic effect that may exacerbate cognitive decline (ref: Visconte doi.org/10.1007/s11357-023-00746-0/). Luo et al. further explored the long RNA profiles of human brain EVs, providing insights into the molecular mechanisms underlying AD pathogenesis (ref: Luo doi.org/10.14336/AD.2022.0607/). These studies collectively emphasize the importance of EVs and gut microbiota in AD, suggesting that targeting these pathways could offer novel therapeutic strategies.

Energy metabolism is critically altered in Alzheimer's disease (AD), contributing to its pathophysiology. Yu et al. reviewed the mechanisms underlying aberrant energy metabolism in AD, emphasizing the potential of therapeutic strategies such as antidiabetic drugs and dietary interventions to restore metabolic balance (ref: Yu doi.org/10.2478/jtim-2022-0024/). Shan et al. provided evidence that osteocalcin can ameliorate cognitive dysfunctions by reducing amyloid-beta burden and enhancing glycolysis in neuroglia, suggesting a metabolic approach to AD treatment (ref: Shan doi.org/10.1038/s41420-023-01343-y/). Furthermore, Cashikar et al. highlighted the role of 25-hydroxycholesterol in regulating astrocyte lipid metabolism and ApoE secretion, linking cholesterol metabolism to neuroinflammation in AD (ref: Cashikar doi.org/10.1016/j.jlr.2023.100350/). These findings underscore the significance of targeting energy metabolism and lipid homeostasis as potential therapeutic strategies for AD.

Sleep disturbances have been increasingly recognized as a contributing factor to the progression of Alzheimer's disease (AD). Liu et al. investigated the effects of REM sleep disturbance on microglial activation in APP/PS1 mice, revealing that both REM and non-REM sleep loss exacerbate AD pathology, albeit through different mechanisms (ref: Liu doi.org/10.1016/j.nlm.2023.107737/). This study highlights the critical role of sleep stages in regulating microglial activity and their subsequent impact on neurodegeneration. The findings suggest that sleep interventions may serve as a novel therapeutic approach to mitigate AD progression by modulating microglial responses. Overall, the interplay between sleep, microglial activation, and neurodegeneration underscores the importance of maintaining healthy sleep patterns as a potential strategy for AD prevention and management.