Microglia, the resident immune cells of the brain, play a critical role in the pathology of Alzheimer's disease (AD). Recent studies have focused on the identification and characterization of specific microglial populations, particularly those expressing the TREM2 gene, which is associated with increased risk for AD. Rachmian et al. utilized high-throughput mass cytometry to identify senescent microglia in the 5×FAD mouse model, revealing that these cells exhibit a distinct signature compared to disease-associated microglia (DAM), suggesting a complex role in AD pathology (ref: Rachmian doi.org/10.1038/s41593-024-01620-8/). Additionally, Hou et al. demonstrated that targeting the inhibitory receptor LILRB4 on microglia can attenuate amyloid pathology, highlighting the potential for therapeutic interventions that modulate microglial responses (ref: Hou doi.org/10.1126/scitranslmed.adj9052/). The regulation of microglial gene expression through innovative approaches, such as RNAase-H active antisense oligonucleotides, has also been explored by Vandermeulen et al., who showed that these oligonucleotides can modify microglial responses to amyloid-β plaques in vivo (ref: Vandermeulen doi.org/10.1186/s13024-024-00725-9/). These findings collectively underscore the heterogeneity of microglial functions in AD and the potential for targeted therapies that harness these cells' capabilities to mitigate disease progression. Furthermore, the clinicopathologic heterogeneity of AD has been examined through the lens of glial activation patterns. Kouri et al. analyzed a large cohort of autopsied individuals to explore the spatial distribution of neurofibrillary tangles and their correlation with glial activation, using a novel corticolimbic index (CLix) to quantify disease heterogeneity (ref: Kouri doi.org/10.1001/jamaneurol.2024.0784/). The development of an integrated toolkit for human microglial functional genomics by Haq et al. offers researchers new avenues to study microglial functions in AD, incorporating a CRISPR-ON/OFF system for controlled gene expression (ref: Haq doi.org/10.1186/s13287-024-03700-9/). Lastly, Ramakrishnan et al. elucidated the role of SHIP1 in mediating TREM2-induced microglial functions, providing insights into the molecular mechanisms that govern microglial activation and their neuroprotective roles in AD (ref: Ramakrishnan doi.org/10.1016/j.molimm.2024.04.002/).

Neuroinflammation plays a pivotal role in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD) and frontotemporal dementia (FTD). Al-Dalahmah et al. investigated the role of osteopontin in driving neuroinflammation and cell loss in MAPT-N279K FTD patient neurons, revealing that this protein exacerbates neurodegenerative processes (ref: Al-Dalahmah doi.org/10.1016/j.stem.2024.03.013/). This study emphasizes the need to understand the inflammatory mechanisms that underlie neurodegeneration, as they may offer potential therapeutic targets. In a related context, Guerrero-Carrasco et al. explored how low-grade systemic inflammation can stimulate microglial turnover and accelerate the onset of AD-like pathology, suggesting that chronic low-grade inflammation may predispose individuals to neurodegenerative diseases (ref: Guerrero-Carrasco doi.org/10.1002/glia.24532/). Moreover, Jaisa-Aad et al. characterized monoamine oxidase-B (MAO-B) as a biomarker of reactive astrogliosis in AD, finding that its expression correlates with cortical atrophy and local measures of reactive astrocytes and microglia (ref: Jaisa-Aad doi.org/10.1007/s00401-024-02712-2/). This highlights the complex interplay between different glial cell types in response to neurodegenerative pathology. Bathe et al. further contributed to this understanding by examining disease- and brain region-specific immune response profiles in neurodegenerative diseases, emphasizing the intricate immune interactions that occur in the presence of mixed protein pathologies (ref: Bathe doi.org/10.1186/s40478-024-01770-7/). Fritze et al. also reported that microglia undergo disease-associated transcriptional activation, which regulates neurogenesis in the aged brain, indicating that aging and neurodegeneration significantly impact microglial function (ref: Fritze doi.org/10.1002/dneu.22939/). Collectively, these studies underscore the critical role of neuroinflammation in neurodegeneration and the potential for targeting immune responses in therapeutic strategies.

Therapeutic strategies targeting microglia are gaining attention as potential interventions for Alzheimer's disease (AD). Wang et al. investigated the effects of Gegen Qinlian tablets, a traditional Chinese medicine, on AD progression, demonstrating that these tablets inhibit glial neuroinflammation and help restore gut microbiota homeostasis, thereby delaying disease progression (ref: Wang doi.org/10.1016/j.phymed.2024.155394/). This study highlights the promise of integrating traditional medicine with modern therapeutic approaches to address complex diseases like AD. Additionally, Jiang et al. reported on biomimetic nanovesicles designed for dual gene delivery, which can modulate microglial function and intervene in amyloid-β anabolism, presenting a novel gene therapy strategy for AD (ref: Jiang doi.org/10.1021/acsnano.3c13150/). Moreover, Shan et al. explored the neuroprotective effects of Kai-Xin-San, showing that it ameliorates neuropathology and cognitive impairment in APP/PS1 mice through the mitochondrial autophagy-NLRP3 inflammasome pathway, further supporting the role of microglial modulation in therapeutic contexts (ref: Shan doi.org/10.1016/j.jep.2024.118145/). Liang et al. provided insights into the regulation of NLRP3-mediated IL-1β production in human macrophages and microglia, identifying UCH-L1 as a key regulator, which could be targeted to enhance microglial responses in neuroinflammation (ref: Liang doi.org/10.1016/j.celrep.2024.114152/). Lastly, Wu et al. demonstrated the neuroprotective potential of tanshinone IIA-modified mesenchymal stem cells in a model of LPS-induced neuroinflammation, indicating that stem cell therapies may also offer a route to modulate microglial activity and improve cognitive outcomes (ref: Wu doi.org/10.1016/j.heliyon.2024.e29424/). Together, these studies illustrate the diverse strategies being explored to harness microglial functions for therapeutic benefit in AD.

The exploration of genetic and molecular mechanisms underlying Alzheimer's disease (AD) has revealed critical insights into disease pathology. Liang et al. utilized proximity proteomics to identify UCH-L1 as an essential regulator of NLRP3-mediated IL-1β production in human macrophages and microglia, providing a detailed molecular map of inflammasome activation that could inform therapeutic strategies targeting neuroinflammation (ref: Liang doi.org/10.1016/j.celrep.2024.114152/). Furthermore, Schrader et al. conducted a longitudinal proteomic analysis in the rTg-DI rat model of cerebral amyloid angiopathy, identifying several differentially expressed proteins that may serve as biomarkers for disease progression, thus enhancing our understanding of the molecular changes associated with AD (ref: Schrader doi.org/10.1038/s41598-024-59013-7/). Additionally, Patel et al. investigated the neurobiological impacts of obesity on the cerebral cortex, revealing that diet-induced obesity leads to decreased cortical volume in both mice and humans, thereby linking metabolic factors to neurodegenerative processes (ref: Patel doi.org/10.1016/j.bbi.2024.04.033/). Haq et al. contributed to the field by developing an integrated toolkit for human microglial functional genomics, which incorporates a CRISPR-ON/OFF system for controlled gene expression, thus facilitating the study of microglial roles in AD (ref: Haq doi.org/10.1186/s13287-024-03700-9/). These findings collectively underscore the importance of genetic and molecular investigations in elucidating the complex mechanisms of AD and highlight potential avenues for targeted interventions.

Extracellular vesicles (EVs) have emerged as significant players in the pathophysiology of Alzheimer's disease (AD), particularly in the context of intercellular communication and the spread of neurodegenerative pathology. Ransom et al. focused on small extracellular vesicles (sEVs) derived from human brain tissue, demonstrating that these vesicles contain selectively packaged, full-length mRNA. Their findings suggest that sEVs may facilitate the spread of pathological changes in the brain, potentially contributing to the progression of AD (ref: Ransom doi.org/10.1016/j.celrep.2024.114061/). This highlights the role of EVs in mediating molecular signals that could influence neuroinflammatory responses and neuronal health. In parallel, Fritze et al. examined how microglia undergo transcriptional activation in response to aging and neurodegeneration, revealing that CX3C motif chemokine receptor 1 expression regulates neurogenesis in the aged brain. This suggests that microglial responses to EVs may be critical in maintaining neurogenesis and overall brain health (ref: Fritze doi.org/10.1002/dneu.22939/). The interplay between EVs and microglial function represents a promising area for further research, as understanding these interactions could unveil novel therapeutic targets for AD.

Lifestyle factors significantly influence the risk and progression of Alzheimer's disease (AD), with emerging research highlighting the role of obesity and systemic inflammation. Patel et al. demonstrated that diet-induced obesity leads to decreased cortical volume in both mice and humans, establishing a link between obesity and neurodegenerative changes in the brain (ref: Patel doi.org/10.1016/j.bbi.2024.04.033/). This finding underscores the importance of maintaining a healthy weight as a modifiable risk factor for AD. Additionally, Guerrero-Carrasco et al. explored how low-grade systemic inflammation can stimulate microglial turnover and accelerate the onset of AD-like pathology, suggesting that chronic inflammation may predispose individuals to neurodegenerative diseases (ref: Guerrero-Carrasco doi.org/10.1002/glia.24532/). Moreover, Bathe et al. characterized disease- and brain region-specific immune response profiles in neurodegenerative diseases, emphasizing the complexity of immune interactions in the presence of mixed protein pathologies (ref: Bathe doi.org/10.1186/s40478-024-01770-7/). These studies collectively highlight the intricate relationship between lifestyle factors, immune responses, and the pathogenesis of AD, suggesting that interventions aimed at lifestyle modifications could play a crucial role in mitigating disease risk and progression.

The clinical and pathological heterogeneity of Alzheimer's disease (AD) presents significant challenges for diagnosis and treatment. Kouri et al. examined the clinicopathologic characteristics of AD using a large cohort of autopsied individuals, employing a corticolimbic index (CLix) to quantify disease heterogeneity and assess the spatial distribution of neurofibrillary tangles (ref: Kouri doi.org/10.1001/jamaneurol.2024.0784/). This study highlights the variability in disease presentation and progression among individuals, suggesting that personalized approaches may be necessary for effective management. In the context of frontotemporal dementia (FTD), Al-Dalahmah et al. investigated the role of osteopontin in driving neuroinflammation and cell loss in patient neurons, revealing mechanisms that contribute to neurodegeneration in this early-onset dementia (ref: Al-Dalahmah doi.org/10.1016/j.stem.2024.03.013/). Furthermore, Hou et al. focused on the inhibitory receptor LILRB4 in microglia, demonstrating its high expression in AD patients and its potential role in modulating amyloid pathology (ref: Hou doi.org/10.1126/scitranslmed.adj9052/). These findings collectively underscore the importance of understanding the diverse clinical presentations and underlying mechanisms of AD and related dementias, paving the way for targeted therapeutic strategies.