Microglial function plays a crucial role in the pathogenesis of Alzheimer's disease (AD), particularly through mechanisms involving cell senescence, polarization, and neuroinflammation. Recent studies have identified that aging is a significant risk factor for AD, with microglial senescence being a potential therapeutic target. Wood et al. demonstrated that senescence-associated genes are differentially expressed in microglia from AD patients compared to non-demented controls, suggesting that chronic oxidative stress from interactions with beta-amyloid species may trigger these pathways (ref: Wood doi.org/10.1038/s41582-024-00979-3/). Furthermore, Kang et al. found that female microglia exhibit more aging-associated changes than male microglia, indicating a sex-dimorphic response that could influence disease progression (ref: Kang doi.org/10.1186/s12974-024-03130-7/). This highlights the importance of understanding microglial behavior in the context of sex differences and aging in AD pathology. In addition to senescence, microglial polarization is critical for neuronal health. Zhong et al. reported that cordycepin enhances cognitive function in APP/PS1 mice by promoting M2 polarization of microglia, which is associated with metabolic reprogramming that favors neuronal survival (ref: Zhong doi.org/10.1002/advs.202304687/). Conversely, Du et al. identified protein kinase C delta (PKCδ) as a potential biomarker for neuroinflammation in AD, where its upregulation correlates with increased inflammatory cytokines in cerebrospinal fluid (ref: Du doi.org/10.1002/alz.14047/). These findings collectively underscore the dual role of microglia in both neuroprotection and neuroinflammation, emphasizing the need for targeted therapies that can modulate microglial activity effectively.

Neuroinflammation is increasingly recognized as a pivotal factor in the progression of neurodegenerative diseases, particularly Alzheimer's disease (AD). Bajaj et al. explored the role of autophagy in neuroinflammation, revealing that secretory autophagy may facilitate the release of inflammatory mediators, thereby contributing to hippocampal degeneration (ref: Bajaj doi.org/10.1080/15548627.2024.2373675/). This aligns with findings from Ottoy et al., who demonstrated that tau pathology and reactive microglia follow spatial patterns of brain connectivity, suggesting that neuroinflammation may propagate through neural networks (ref: Ottoy doi.org/10.1038/s41467-024-49300-2/). The interconnectedness of these processes highlights the complexity of neurodegeneration, where inflammation can exacerbate tau accumulation and cognitive decline. Moreover, the study by Sweetat et al. introduced a novel animal model that mimics late-onset Alzheimer's disease features, revealing that ovariectomy combined with a high-fat-sugar-salt diet induces metabolic dysregulation and cognitive impairments (ref: Sweetat doi.org/10.14336/AD.2024.03110/). This model provides insights into the metabolic syndrome's role in neurodegeneration, further supported by Peng et al.'s bibliometric analysis, which emphasizes the growing research landscape connecting dementia and metabolic disorders (ref: Peng doi.org/10.3389/fnagi.2024.1400589/). Together, these studies underscore the multifaceted nature of neuroinflammation in AD, suggesting that targeting inflammatory pathways may offer therapeutic benefits.

The search for effective therapeutic targets in Alzheimer's disease (AD) has led to the exploration of various molecular pathways and pharmacological interventions. Etxeberria et al. investigated the effects of TREM2 agonist antibodies, finding that they may disrupt injury resolution in preclinical models, indicating a potential dual role of TREM2 in neurodegeneration (ref: Etxeberria doi.org/10.1523/JNEUROSCI.2347-23.2024/). This complexity is echoed in the findings of Du et al., who identified PKCδ as a promising biomarker and therapeutic target for microglia-mediated neuroinflammation, with elevated levels correlating with inflammatory cytokines in AD patients (ref: Du doi.org/10.1002/alz.14047/). Additionally, the protective effects of melatonin against metabolic disorders and neuropsychiatric injuries in type 2 diabetes mellitus mice were highlighted by Gao et al., suggesting that melatonin may mitigate cognitive decline associated with metabolic dysfunction (ref: Gao doi.org/10.1016/j.phymed.2024.155805/). Furthermore, the study by Dongol et al. demonstrated that olanzapine can attenuate amyloid-beta-induced microglia-mediated neurite lesions, providing evidence for its potential as a therapeutic agent in AD (ref: Dongol doi.org/10.1016/j.intimp.2024.112469/). These findings collectively emphasize the importance of targeting both neuroinflammatory pathways and metabolic dysregulation in developing effective AD therapies.

Understanding the genetic and molecular mechanisms underlying Alzheimer's disease (AD) is crucial for identifying potential therapeutic targets. Recent studies have focused on the role of TREM2, a gene linked to AD risk, with Yin et al. providing a systematic review that highlights the conflicting outcomes from various studies on TREM2's role in neuroinflammation and neurodegeneration (ref: Yin doi.org/10.1097/CM9.0000000000003000/). This complexity is further illustrated by Wang et al., who tracked the trajectory of CSF sTREM2 levels, finding age-related increases that may reflect underlying neurodegenerative processes (ref: Wang doi.org/10.1186/s13195-024-01506-8/). Moreover, Adeoye et al. conducted a systematic analysis of biological processes driving pathway dysregulation in AD, utilizing single-nucleus RNA-sequencing data to reveal intricate gene co-expression modules (ref: Adeoye doi.org/10.14336/AD.2024.0429/). This approach underscores the need for comprehensive analyses that capture the multifactorial nature of AD. Additionally, Xiao et al. demonstrated that epigallocatechin-3-gallate can inhibit neuroinflammation in BV2 cells, suggesting that dietary compounds may influence AD pathology through modulation of inflammatory pathways (ref: Xiao doi.org/10.1007/s11481-024-10131-z/). Collectively, these studies highlight the importance of genetic factors and molecular pathways in AD, paving the way for targeted interventions that address the disease's complex etiology.

Cellular interactions and signaling pathways play a pivotal role in the pathophysiology of Alzheimer's disease (AD), particularly in the context of glia-neuron communication. Soelter et al. reported that altered communication between glia and neurons in AD affects key signaling pathways, including WNT, p53, and NFkB, which may contribute to the disease's progression (ref: Soelter doi.org/10.1186/s12964-024-01686-8/). This disruption in signaling is critical as it may lead to dysregulation of neuronal function and survival, highlighting the importance of understanding these interactions in AD. Additionally, the study by Zhu et al. explored the role of synaptotagmin-7 in promoting M2 polarization of microglia, suggesting that enhancing this polarization could alleviate cognitive impairment in AD models (ref: Zhu doi.org/10.1016/j.brainresbull.2024.110994/). This finding emphasizes the therapeutic potential of targeting microglial polarization to restore homeostasis in the AD brain. Furthermore, the bibliometric analysis by Peng et al. provided insights into the evolving research landscape surrounding dementia and metabolic syndrome, indicating a growing recognition of the interplay between metabolic dysregulation and neurodegeneration (ref: Peng doi.org/10.3389/fnagi.2024.1400589/). Together, these studies underscore the significance of cellular interactions and signaling pathways in AD, offering potential avenues for therapeutic intervention.

Sex differences in Alzheimer's disease (AD) have garnered increasing attention, particularly regarding the distinct responses of male and female microglia to aging and neurodegeneration. Kang et al. found that female microglia exhibit more pronounced aging-associated changes compared to their male counterparts, with a higher abundance of disease-associated microglia (DAM) in older females (ref: Kang doi.org/10.1186/s12974-024-03130-7/). This suggests that sex-specific factors may influence microglial behavior and, consequently, the progression of AD, highlighting the need for tailored therapeutic approaches. Moreover, the study by Wood et al. emphasized the role of microglial senescence as a potential therapeutic target in AD, noting that chronic oxidative stress may trigger senescence pathways in microglia (ref: Wood doi.org/10.1038/s41582-024-00979-3/). Additionally, Wang et al. reported on the trajectory of CSF sTREM2 levels, revealing age-related increments that may differ by sex, further complicating the understanding of AD pathology (ref: Wang doi.org/10.1186/s13195-024-01506-8/). These findings collectively underscore the importance of considering sex differences in AD research, as they may significantly impact disease mechanisms and therapeutic responses.