Microglia play a crucial role in the pathophysiology of Alzheimer's disease (AD), acting as both protectors and aggressors in neurodegeneration. Recent studies have highlighted the significance of microglial desynchronization as a potential biomarker for cognitive decline in AD. Zatcepin et al. utilized TSPO-PET imaging to demonstrate that microglial activity is regionally desynchronized in AD models, suggesting a microglia connectome that could be pivotal in understanding disease progression (ref: Zatcepin doi.org/10.1186/s13024-024-00752-6/). Furthermore, Zhong et al. explored the role of TREM2, a microglial receptor, revealing that its absence leads to reduced cerebral amyloid angiopathy despite increased amyloid beta load, indicating a complex interplay between microglial activation and amyloid pathology (ref: Zhong doi.org/10.1002/alz.14222/). In a contrasting study, Zou et al. found that microglia can either promote or restrain excitotoxicity induced by soluble Aβ, emphasizing their dual role in neurodegeneration (ref: Zou doi.org/10.1186/s12974-024-03208-2/). Additionally, Robertson et al. investigated the impact of the iron import gene Slc11a2 on cognitive function, revealing a sex-specific effect on microglial transcriptional landscape in AD models, which further complicates the understanding of microglial roles in disease (ref: Robertson doi.org/10.1186/s12974-024-03238-w/). Together, these studies underscore the multifaceted roles of microglia in AD, highlighting their potential as therapeutic targets.

Neuroinflammation is increasingly recognized as a key factor in cognitive decline associated with various neurodegenerative diseases, including Alzheimer's disease. Kim et al. demonstrated that AIBP regulates TLR4 inflammarafts, which are critical in microglial activation and neuroinflammation, suggesting that targeting these pathways could mitigate cognitive decline (ref: Kim doi.org/10.1186/s12974-024-03214-4/). In a related study, Xue et al. found that a tryptophan-rich diet reversed LPS-induced cognitive impairment in mice, indicating that dietary interventions may influence neuroinflammatory processes and cognitive outcomes (ref: Xue doi.org/10.1186/s12974-024-03239-9/). Furthermore, Zhuang et al. reported that Huang-Lian-Jie-Du Decoction alleviates diabetic encephalopathy by regulating inflammation and pyroptosis, highlighting the potential of traditional medicine in managing neuroinflammatory conditions (ref: Zhuang doi.org/10.1016/j.jep.2024.118787/). These findings collectively suggest that neuroinflammation is a modifiable factor in cognitive decline, and interventions targeting inflammatory pathways may offer therapeutic benefits.

The identification of biomarkers and genetic factors is crucial for understanding Alzheimer's disease and developing targeted therapies. Shen et al. conducted a comprehensive proteomic analysis of cerebrospinal fluid in autosomal dominant Alzheimer's disease, identifying early biomarkers that could aid in disease monitoring (ref: Shen doi.org/10.1016/j.cell.2024.08.049/). Additionally, Simmonds et al. performed an X-chromosome-wide association study, revealing significant genetic variants associated with Alzheimer's disease, which may provide insights into sex-specific risk factors (ref: Simmonds doi.org/10.1038/s41398-024-03058-9/). Guo et al. further elucidated the relationship between BIN1 gene polymorphisms and tau pathology, demonstrating that sTREM2 mediates this association, thereby linking genetic risk factors to neurodegenerative processes (ref: Guo doi.org/10.3233/JAD-240372/). These studies emphasize the importance of genetic and biomarker research in unraveling the complexities of Alzheimer's disease and highlight potential avenues for early diagnosis and intervention.

Innovative therapeutic strategies are being explored to address the challenges posed by Alzheimer's disease. Milazzo et al. investigated the efficacy of hematopoietic stem cell gene therapy in an Alzheimer's disease mouse model, demonstrating that transplantation can lead to the establishment of microglia-like cells in the CNS, potentially offering a novel treatment avenue (ref: Milazzo doi.org/10.1038/s41467-024-52301-w/). Bai et al. developed a zebrafish model of progressive supranuclear palsy, identifying Brd4 as a regulator of microglial synaptic elimination, which could inform future therapeutic targets (ref: Bai doi.org/10.1038/s41467-024-52173-0/). Furthermore, Wang et al. reported that electro-acupuncture significantly improved cognitive functions in Alzheimer's disease models, suggesting non-pharmacological interventions may effectively reduce neuroinflammation and enhance cognitive outcomes (ref: Wang doi.org/10.1002/alz.14260/). These findings highlight the diversity of therapeutic approaches being investigated, from gene therapy to lifestyle interventions, underscoring the need for multifaceted strategies in combating Alzheimer's disease.

Microglia are increasingly recognized for their dual roles in neurodegeneration, particularly in Alzheimer's disease. Zhong et al. highlighted the significance of TREM2 in microglial activation, showing that its loss leads to diminished cerebral amyloid angiopathy despite increased amyloid load, suggesting a complex relationship between microglial function and amyloid pathology (ref: Zhong doi.org/10.1002/alz.14222/). Zou et al. further explored the role of microglia in mediating excitotoxicity from Aβ, revealing that microglia can either protect or exacerbate neurodegeneration depending on the context (ref: Zou doi.org/10.1186/s12974-024-03208-2/). Additionally, Robertson et al. demonstrated that the knockdown of the iron import gene Slc11a2 in microglia worsens cognitive function in a sex-specific manner, indicating that microglial iron metabolism may play a critical role in cognitive outcomes (ref: Robertson doi.org/10.1186/s12974-024-03238-w/). These studies collectively underscore the importance of microglial biology in neurodegeneration and suggest that targeting microglial pathways may offer therapeutic potential.

Environmental factors significantly influence the onset and progression of Alzheimer's disease, with recent studies shedding light on various mechanisms. Zhou et al. demonstrated that noise exposure exacerbates cognitive impairment in APP/PS1 mice through the CD36-mediated ROS/PI3K/AKT signaling pathway, indicating that environmental stressors can have detrimental effects on cognitive function (ref: Zhou doi.org/10.1016/j.scitotenv.2024.175879/). Additionally, Hu et al. reviewed the impact of physical exercise on neuroinflammation, advocating for exercise as a non-pharmacological intervention to mitigate cognitive decline in Alzheimer's disease (ref: Hu doi.org/10.3389/fnagi.2024.1444716/). Zhuang et al. also explored the effects of Huang-Lian-Jie-Du Decoction on diabetic encephalopathy, highlighting the role of traditional medicine in addressing neuroinflammatory processes linked to environmental factors (ref: Zhuang doi.org/10.1016/j.jep.2024.118787/). These findings emphasize the need for a holistic approach to Alzheimer's disease that considers both genetic and environmental influences.

Emerging evidence suggests a significant link between infections and the pathophysiology of Alzheimer's disease, with various studies exploring the mechanisms involved. Onisiforou et al. utilized a systems bioinformatics approach to identify how viral infections, including HSV-1 and SARS-CoV-2, may facilitate Alzheimer's disease pathogenesis through virus-host protein interactions (ref: Onisiforou doi.org/10.1093/infdis/). Ciccotosto et al. demonstrated that chronic oral inoculation of Porphyromonas gingivalis leads to increased brain inflammation and AD-like biomarkers, indicating that oral pathogens may contribute to neurodegenerative processes (ref: Ciccotosto doi.org/10.1093/infdis/). Additionally, Wang et al. highlighted the role of TREM2 in regulating microglial polarization in response to infections, suggesting that targeting these pathways could mitigate neuroinflammation associated with Alzheimer's disease (ref: Wang doi.org/10.1016/j.heliyon.2024.e35800/). Collectively, these studies underscore the importance of understanding infectious contributions to Alzheimer's disease and the potential for therapeutic interventions targeting these pathways.