Microglial activation plays a pivotal role in the pathology of Alzheimer's disease (AD), with recent studies highlighting the diverse transcriptomic states of microglia in response to amyloid-beta pathology. Mancuso et al. generated over 138,000 single-cell expression profiles from human stem cell-derived microglia xenotransplanted into the brains of APP mice, revealing varied activation states that could inform therapeutic strategies (ref: Mancuso doi.org/10.1038/s41593-024-01600-y/). In a mouse model of tauopathy, Toral-Rios et al. demonstrated that cholesterol 25-hydroxylase mediates neuroinflammation and neurodegeneration, suggesting that lipid metabolism is intricately linked to microglial function in AD (ref: Toral-Rios doi.org/10.1084/jem.20232000/). Furthermore, Shin proposed that rejuvenating aged microglia through cell cycle regulation could enhance their phagocytic capacity, potentially mitigating amyloid accumulation (ref: Shin doi.org/10.1186/s13024-024-00715-x/). Contradictory findings emerged from Kim's study, which indicated that thyroid hormone deficiency impairs microglial immune responses, exacerbating AD pathology (ref: Kim doi.org/10.1126/sciadv.adi1863/). This highlights the complex interplay between microglial activation and neuroinflammation in AD, where both rejuvenation and dysfunction can influence disease progression. Additionally, Zhang's work on tau-induced inflammasome activation revealed that tau protein can exacerbate microglial activation and cognitive decline, emphasizing the need for targeted interventions to modulate these pathways (ref: Zhang doi.org/10.1002/ctm2.1623/). Recent findings by Yu showed that microglial ApoD-induced NLRC4 inflammasome activation promotes AD progression, further underscoring the role of chronic neuroinflammation in the disease (ref: Yu doi.org/10.1002/ame2.12361/). Lastly, Kim's research on probiotics demonstrated that oral administration can alleviate tau phosphorylation and microglial activation, suggesting a novel therapeutic avenue through modulation of the gut-brain axis (ref: Kim doi.org/10.3390/brainsci14030208/).

The genetic landscape of Alzheimer's disease (AD) is complex, with recent studies elucidating the interplay between genetic variation and gene expression in brain cell types. Fujita et al. conducted single-nucleus RNA sequencing on the neocortex of 424 individuals, identifying over 10,000 eGenes, which highlights the significant impact of genetic variants on cellular function in AD (ref: Fujita doi.org/10.1038/s41588-024-01685-y/). In a broader context, Enduru's atlas of shared genetic determinants between AD and immune-mediated diseases revealed a substantial genetic overlap, suggesting a shared but non-causal genetic architecture that could influence disease susceptibility (ref: Enduru doi.org/10.1038/s41380-024-02510-y/). The role of specific alleles, particularly APOE2 and APOE4, was further explored by Jackson, who demonstrated that APOE2 gene therapy reduces amyloid deposition and neuroinflammation in a mouse model, contrasting sharply with the detrimental effects associated with APOE4 (ref: Jackson doi.org/10.1016/j.ymthe.2024.03.024/). Additionally, Bar's study on Gtf2i deletion in a Williams syndrome model revealed developmental microglial alterations, indicating that genetic factors can influence microglial behavior and potentially contribute to neurodegenerative processes (ref: Bar doi.org/10.1002/glia.24519/). Creus-Muncunill's work on TYROBP/DAP12 knockout in Huntington's disease mice further emphasized the role of immune activation in neurodegeneration, linking genetic mechanisms to microglial responses (ref: Creus-Muncunill doi.org/10.1186/s12974-024-03052-4/). Huang's characterization of a preclinical AD model in type 2 diabetic monkeys also provided insights into the genetic and environmental interactions that may exacerbate AD pathology (ref: Huang doi.org/10.1186/s13195-024-01416-9/). Lastly, García-Alberca's investigation into a germline variant in SIRPα1 highlighted its dual effect on cognitive decline and microglial response, underscoring the intricate relationship between genetic factors and AD pathology (ref: García-Alberca doi.org/10.3233/JAD-231150/).

The interplay between amyloid and tau pathology is central to understanding Alzheimer's disease (AD). Rodriguez-Rodriguez identified DEK as a cell-autonomous regulator of tau in vulnerable neurons, suggesting that specific molecular pathways may be targeted to mitigate tau pathology (ref: Rodriguez-Rodriguez doi.org/10.1093/brain/). In a broader context, Enduru's research on genetic overlap between AD and immune-mediated diseases revealed significant shared genetic determinants, indicating that immune responses may also influence tau pathology (ref: Enduru doi.org/10.1038/s41380-024-02510-y/). Zhang's study highlighted the role of tau in inducing inflammasome activation and microgliosis, demonstrating that tau pathology can exacerbate neuroinflammation and cognitive decline (ref: Zhang doi.org/10.1002/ctm2.1623/). Kapasi's investigation into the relationship between hippocampal microglia and cognitive decline found that tau tangles were independently associated with microglial activation, reinforcing the notion that tau pathology drives neuroinflammatory responses (ref: Kapasi doi.org/10.1002/alz.13780/). Ceyzériat's work on low-dose radiation therapy showed that while it impacts microglial inflammatory responses, it does not modulate amyloid load, suggesting that therapeutic strategies may need to differentiate between amyloid and tau-targeted interventions (ref: Ceyzériat doi.org/10.3233/JAD-231153/). Kumari's research on COX-2 levels in AD patients proposed a potential blood-based biomarker for early diagnosis, linking neuroinflammation to amyloid deposition (ref: Kumari doi.org/10.3233/JAD-231445/). Lastly, Iemmolo's study on cerebrospinal fluid effects on neurons-astrocytes-microglia co-cultures indicated that AD patient-derived CSF could destabilize neurofilaments, further implicating the role of amyloid and tau in neurodegeneration (ref: Iemmolo doi.org/10.3390/ijms25052510/).

Recent advancements in therapeutic strategies for Alzheimer's disease (AD) have focused on targeting neuroinflammation and neurodegeneration. Pak's comprehensive analysis of brain cell types revealed that distinct whole-brain cell types can predict tissue damage patterns across various neurodegenerative conditions, including AD, suggesting that understanding cellular contributions could inform treatment approaches (ref: Pak doi.org/10.7554/eLife.89368/). Huang's characterization of a preclinical AD model in type 2 diabetic monkeys demonstrated the potential for targeting systemic inflammation to mitigate AD-like pathology, emphasizing the importance of environmental factors in therapeutic interventions (ref: Huang doi.org/10.1186/s13195-024-01416-9/). Abd-Elrahman's work on a positive allosteric modulator of M1 muscarinic acetylcholine receptors showed promise in reducing neurogliosis and improving cognitive function in female AD mice, highlighting the potential for sex-specific therapies (ref: Abd-Elrahman doi.org/10.1016/j.biopha.2024.116388/). Ng's research on liver-specific adiponectin gene therapy indicated that it could suppress microglial NLRP3 inflammasome activation, presenting a novel approach to modulating neuroinflammation in AD (ref: Ng doi.org/10.1186/s12974-024-03066-y/). Kumari's study on COX-2 levels proposed a potential blood-based biomarker for early diagnosis and therapeutic targeting, linking inflammation to AD pathology (ref: Kumari doi.org/10.3233/JAD-231445/). Ahmed's findings on taurine's effects on microglial activation suggested that dietary interventions could also play a role in AD treatment (ref: Ahmed doi.org/10.1038/s41598-024-57973-4/). Singh's exploration of multifunctional ligands targeting the NLRP3 inflammasome emphasized the need for innovative drug design to address multiple pathological features of AD (ref: Singh doi.org/10.1021/acschemneuro.3c00679/). Collectively, these studies underscore the importance of a multifaceted approach to AD therapy, integrating genetic, molecular, and lifestyle factors.

Environmental and lifestyle factors significantly influence the progression of Alzheimer's disease (AD). Tsay's research demonstrated that reducing brain amyloid-beta burden can ameliorate high-fat diet-induced fatty liver disease in APP/PS1 mice, suggesting that dietary interventions may have a dual benefit in managing both metabolic and neurodegenerative aspects of AD (ref: Tsay doi.org/10.1016/j.biopha.2024.116404/). Kumari's study on COX-2 levels proposed a potential blood-based biomarker for early diagnosis, linking neuroinflammation to lifestyle factors such as diet (ref: Kumari doi.org/10.3233/JAD-231445/). Ochi's investigation into the effects of early tooth loss on chronic stress and neuropathogenesis in AD models highlighted the potential impact of oral health on cognitive decline, suggesting that maintaining dental health may be a preventive strategy against AD (ref: Ochi doi.org/10.3389/fnagi.2024.1361847/). Gao's analysis of N6-methyladenosine modification dynamics during AD development indicated that environmental factors could influence gene expression and contribute to disease progression (ref: Gao doi.org/10.1016/j.heliyon.2024.e26911/). Majkutewicz's work on dimethyl fumarate's efficacy in alleviating cognitive impairment in a rat model of AD emphasized the importance of pharmacological interventions that consider environmental influences (ref: Majkutewicz doi.org/10.1007/s12035-024-04024-8/). Collectively, these studies underscore the need for a holistic approach to AD prevention and treatment, integrating lifestyle modifications with pharmacological strategies to address the multifactorial nature of the disease.

Microglial subtypes play a crucial role in the neurodegenerative processes associated with Alzheimer's disease (AD). Podleśny-Drabiniok's research identified BHLHE40/41 as regulators of microglial and macrophage responses, linking genetic risk factors to altered immune responses in lipid-rich tissues like the brain (ref: Podleśny-Drabiniok doi.org/10.1038/s41467-024-46315-7/). Nguyen's study on protein changes in the human hippocampus revealed a consistent rise in specific proteins associated with AD, indicating that microglial activation may be linked to these biochemical changes (ref: Nguyen doi.org/10.1016/j.mad.2024.111930/). Olešová's investigation into lipid metabolism changes during tauopathies demonstrated that tau can deregulate lipid metabolism in microglia, suggesting that targeting lipid pathways may provide therapeutic benefits (ref: Olešová doi.org/10.1186/s12974-024-03060-4/). Fujita's work on genetic variation in brain cell types highlighted the importance of understanding microglial responses at the cellular level, identifying thousands of eGenes that could influence microglial function in AD (ref: Fujita doi.org/10.1038/s41588-024-01685-y/). Fernández-Blanco's research on microglial transcriptomic states in Down syndrome indicated that intermediate activation states may precede full activation, suggesting a more nuanced understanding of microglial roles in neurodegeneration (ref: Fernández-Blanco doi.org/10.3390/ijms25063289/). Collectively, these findings emphasize the importance of characterizing microglial subtypes and their functional states to develop targeted therapies for AD.

Neurodegenerative disease models are essential for understanding the mechanisms underlying Alzheimer's disease (AD) and developing effective therapies. Abd-Elrahman's work on a positive allosteric modulator targeting M1 muscarinic acetylcholine receptors demonstrated significant reductions in neurogliosis and improvements in cognitive function in female AD mice, highlighting the relevance of sex-specific responses in therapeutic development (ref: Abd-Elrahman doi.org/10.1016/j.biopha.2024.116388/). Bar's study on Gtf2i deletion in a Williams syndrome model revealed developmental alterations in microglia, suggesting that genetic factors can influence neuroinflammatory responses and contribute to neurodegeneration (ref: Bar doi.org/10.1002/glia.24519/). Creus-Muncunill's research on TYROBP/DAP12 knockout in Huntington's disease mice emphasized the role of immune activation in neurodegeneration, linking genetic mechanisms to microglial behavior (ref: Creus-Muncunill doi.org/10.1186/s12974-024-03052-4/). Huang's characterization of a preclinical AD model in type 2 diabetic monkeys provided insights into the interactions between metabolic disorders and neurodegenerative processes, reinforcing the need for comprehensive models that reflect human disease complexity (ref: Huang doi.org/10.1186/s13195-024-01416-9/). García-Alberca's investigation into a germline variant in SIRPα1 highlighted its dual effect on cognitive decline and microglial response, underscoring the intricate relationship between genetic factors and AD pathology (ref: García-Alberca doi.org/10.3233/JAD-231150/). Collectively, these studies underscore the importance of diverse neurodegenerative models in elucidating disease mechanisms and guiding therapeutic strategies.