Microglia, the resident immune cells of the brain, play a crucial role in the pathogenesis of Alzheimer's disease (AD). Recent studies have highlighted the importance of the microglial transcriptome in understanding genetic risks associated with AD. For instance, Lopes et al. conducted a comprehensive analysis of 255 primary human microglial samples, revealing significant variations in gene expression across different brain regions and in relation to aging and disease pathologies (ref: Lopes doi.org/10.1038/s41588-021-00976-y/). This study underscores the potential of microglial gene expression profiles as biomarkers for AD risk. Additionally, the work by Qureshi et al. demonstrated that the neuronal retromer regulates both neuronal and microglial phenotypes in AD, linking endosomal trafficking disruptions to microglial morphology changes, which are characteristic of AD pathology (ref: Qureshi doi.org/10.1016/j.celrep.2021.110262/). These findings collectively suggest that microglial dysfunction is intricately tied to the progression of AD, highlighting the need for targeted therapeutic strategies that address microglial health. Moreover, the role of microglia in AD extends to their interaction with other cell types and the extracellular environment. Cakir et al. developed human cortical organoids to study microglial functions in health and disease, providing a novel model for investigating microglial roles in neurodevelopmental and neurodegenerative disorders (ref: Cakir doi.org/10.1038/s41467-022-28043-y/). Furthermore, the study by You et al. identified disease-related molecules in extracellular vesicles from activated astrocytes, suggesting that microglial interactions with astrocytes may influence AD progression (ref: You doi.org/10.1002/jev2.12183/). Together, these studies emphasize the multifaceted roles of microglia in AD, from their genetic underpinnings to their interactions with other glial cells, paving the way for future research focused on microglial-targeted therapies.

The interplay between gut microbiota and neuroinflammation has emerged as a significant area of research in Alzheimer's disease (AD). Chen et al. demonstrated that gut microbiota composition influences AD pathologies, showing that germ-free 3xTg mice exhibited reduced cerebral amyloid-β plaques and neurofibrillary tangles compared to specific-pathogen-free mice (ref: Chen doi.org/10.1136/gutjnl-2021-326269/). This suggests that gut microbiota may modulate neuroinflammatory responses and cognitive functions in AD. The study highlights the potential of microbiota-targeted interventions as a therapeutic strategy for AD. In addition, Qu et al. investigated the effects of Nano-Honokiol on cognitive deficits in TgCRND8 mice, revealing that it not only inhibited tau hyperphosphorylation but also modulated gut microbiota, indicating a dual mechanism of action involving both neuroprotection and microbiota regulation (ref: Qu doi.org/10.1016/j.jare.2021.03.012/). Furthermore, the work by Li et al. on the DPP-4 inhibitor Gramcyclin A showed significant reductions in Aβ plaques and neuroinflammation in APP/PS1/tau mice, further supporting the role of neuroinflammation in AD pathology (ref: Li doi.org/10.1002/ptr.7387/). These findings collectively underscore the importance of gut-brain interactions and neuroinflammation in AD, suggesting that therapeutic strategies targeting both the gut microbiome and neuroinflammatory pathways may hold promise for AD treatment.

Genetic and molecular mechanisms play a pivotal role in the development and progression of Alzheimer's disease (AD). Nuytemans et al. explored the differential regulatory control of the APOE ε4 allele, identifying single nucleotide polymorphisms that may influence APOE expression and contribute to AD risk, particularly in African populations (ref: Nuytemans doi.org/10.1002/alz.12534/). This study highlights the importance of genetic diversity in understanding AD susceptibility and potential therapeutic targets. Moreover, Zamolodchikov et al. reported increased levels of high molecular weight kininogen in the brains of AD patients, suggesting its involvement in microglial function and phagocytosis (ref: Zamolodchikov doi.org/10.1002/alz.12531/). This finding emphasizes the need to investigate how various proteins and genetic factors interact within the neuroinflammatory milieu of AD. Additionally, Fang et al. developed an artificial intelligence framework to identify druggable targets from multi-omics data, aiming to repurpose existing drugs for AD treatment (ref: Fang doi.org/10.1186/s13195-021-00951-z/). This innovative approach could accelerate the discovery of effective therapies by leveraging genetic insights into AD pathology. Collectively, these studies underscore the complexity of genetic and molecular interactions in AD, paving the way for personalized medicine approaches in treatment.

Recent advancements in therapeutic approaches for Alzheimer's disease (AD) have focused on innovative drug development strategies. Li et al. investigated the effects of Gramcyclin A, a DPP-4 inhibitor, which demonstrated significant cognitive improvements in APP/PS1/tau triple transgenic mice by enhancing GLP-1 signaling and reducing Aβ plaques (ref: Li doi.org/10.1002/ptr.7387/). This study highlights the potential of targeting metabolic pathways as a therapeutic strategy in AD. Furthermore, Kamei et al. explored the efficacy of anti-amyloid β antibodies delivered via different routes, revealing that nose-to-brain administration significantly improved cognitive outcomes compared to intravenous delivery (ref: Kamei doi.org/10.1007/s13346-022-01117-6/). This finding suggests that optimizing delivery methods could enhance the therapeutic potential of existing antibody treatments. Additionally, Xiang et al. examined the neuroprotective effects of GPR55 activation in a streptozotocin-induced AD mouse model, demonstrating reductions in cognitive impairment and neuroinflammation (ref: Xiang doi.org/10.1016/j.pbb.2022.173340/). This study indicates that targeting GPR55 may offer a novel approach to mitigate AD-related neurodegeneration. Moreover, Zhu et al. reported that silencing the Crry protein alleviated neuroinflammatory responses and tau pathology in a tauopathy model, suggesting that modulating complement pathways could be a viable therapeutic strategy (ref: Zhu doi.org/10.4103/1673-5374.332160/). Together, these studies illustrate the diverse therapeutic avenues being explored in AD, emphasizing the importance of innovative drug development and targeted interventions.

The identification of pathological features and biomarkers in Alzheimer's disease (AD) is crucial for early diagnosis and treatment. Hermann et al. investigated plasma Lipocalin-2 as a potential biomarker, finding significantly lower levels in AD patients compared to healthy controls, which could aid in differential diagnosis (ref: Hermann doi.org/10.1186/s13195-021-00955-9/). This study underscores the need for reliable biomarkers that can reflect disease progression and facilitate clinical decision-making. Additionally, Oyeleke et al. explored the antioxidant and anti-inflammatory effects of Bacopa floribunda extracts in an AD mouse model, providing insights into the potential therapeutic benefits of natural compounds in managing AD symptoms (ref: Oyeleke doi.org/10.1016/j.jep.2022.114997/). Furthermore, Monoranu et al. examined the involvement of monocytes in AD pathology, suggesting that their recruitment to the brain may be impaired in older individuals, which could contribute to the inefficacy of neuroinflammatory responses (ref: Monoranu doi.org/10.3233/ADR-210052/). These findings collectively highlight the complexity of AD pathology and the importance of identifying reliable biomarkers and understanding cellular interactions to develop effective therapeutic strategies.

Cellular and molecular interactions are fundamental to understanding the neurodegenerative processes in Alzheimer's disease (AD). Qureshi et al. demonstrated that the neuronal retromer regulates both neuronal and microglial phenotypes, linking endosomal trafficking disruptions to AD pathology (ref: Qureshi doi.org/10.1016/j.celrep.2021.110262/). This study emphasizes the importance of cellular mechanisms in AD, particularly how alterations in one cell type can affect others in the brain's microenvironment. Moreover, You et al. identified disease-related molecules in extracellular vesicles derived from activated astrocytes, suggesting that these vesicles play a significant role in AD progression by mediating intercellular communication (ref: You doi.org/10.1002/jev2.12183/). Additionally, Belsare et al. explored the role of soluble TREM2 in inhibiting amyloid-β fibrillization and enhancing its uptake by microglia, further illustrating the complex interactions between amyloid pathology and microglial function (ref: Belsare doi.org/10.1073/pnas.2114486119/). These studies collectively highlight the intricate cellular and molecular networks involved in AD, emphasizing the need for a holistic understanding of these interactions to inform therapeutic strategies.

Apolipoprotein E (APOE) plays a critical role in the pathogenesis of Alzheimer's disease (AD), particularly the ε4 allele, which is associated with increased risk. Machlovi et al. demonstrated that APOE4 confers significant transcriptomic and functional alterations to primary mouse microglia, suggesting that this genetic variant may influence microglial responses in AD (ref: Machlovi doi.org/10.1016/j.nbd.2022.105615/). This finding underscores the importance of understanding how genetic factors modulate immune responses in the brain. Furthermore, Hu et al. reported that a fragment of the cell adhesion molecule L1 reduced amyloid-β plaques in a mouse model of AD, indicating that L1 may interact with APOE-related pathways to influence amyloid pathology (ref: Hu doi.org/10.1038/s41419-021-04348-6/). Additionally, Fernandes et al. examined immune-related gene expression in 3xTg-AD mice, revealing temporal and regional differences that may be influenced by APOE genotype (ref: Fernandes doi.org/10.3390/cells11010137/). These studies collectively highlight the multifaceted role of APOE in AD, emphasizing its impact on microglial function and the broader immune landscape in the brain.