Microglial activation plays a crucial role in the pathology of Alzheimer's disease (AD), with recent studies highlighting various mechanisms and implications. Huang et al. demonstrated that early AD pathology can be detected in cortical biopsies from patients with Normal Pressure Hydrocephalus, revealing a transition from microglial homeostasis to a disease-associated phenotype as AD pathology progresses. This study identified a restricted set of genes correlating with AD pathology, emphasizing the importance of microglial and non-microglial gene interactions in the early stages of cognitive decline (ref: Huang doi.org/10.1038/s41467-021-25902-y/). Jiang et al. further explored the role of tau pathology, showing that pathological tau aggregates can prime and activate interleukin-1β through myeloid-cell-specific pathways, underscoring the inflammatory response associated with tauopathies (ref: Jiang doi.org/10.1016/j.celrep.2021.109720/). Bhattacherjee et al. focused on CD33, an immunomodulatory receptor linked to AD susceptibility, demonstrating that targeting CD33 with glycan-laden liposomes enhances microglial phagocytosis, suggesting a potential therapeutic avenue for improving microglial function in AD (ref: Bhattacherjee doi.org/10.1016/j.jconrel.2021.09.010/). Additionally, Kim et al. found that transplantation of gut microbiota from AD mouse models led to neuroinflammation and cognitive deficits in recipient mice, indicating that microbiota composition may influence microglial activation and AD pathology (ref: Kim doi.org/10.1016/j.bbi.2021.09.002/). Biechele et al. highlighted the significance of pre-therapeutic microglial activation in determining the efficacy of immunomodulatory therapies, suggesting that the timing and state of microglial activation are critical for therapeutic outcomes (ref: Biechele doi.org/10.7150/thno.64022/). Qiu et al. reported that adult-onset deficiency in CNS myelin sulfatide can induce neuroinflammation and cognitive impairment, linking lipid metabolism and immune response to AD etiology (ref: Qiu doi.org/10.1186/s13024-021-00488-7/). Together, these studies illustrate the multifaceted role of microglia in AD, highlighting both their potential as therapeutic targets and the complexity of their interactions with other cellular and molecular pathways.

Neuroinflammation is a central feature of Alzheimer's disease, with various studies elucidating its mechanisms and consequences. Bassil et al. developed an automated culturing platform for human induced pluripotent stem cell (iPSC) neurons, astrocytes, and microglia, which allows for improved modeling of AD and provides insights into the cellular interactions that drive neuroinflammation (ref: Bassil doi.org/10.1038/s41467-021-25344-6/). Kang et al. investigated the effects of fine particulate matter (PM2.5) on human brain models, demonstrating that PM2.5 exposure induces neuroinflammation and neurodegeneration, thereby linking environmental pollutants to AD pathology (ref: Kang doi.org/10.1002/advs.202101251/). Ma et al. explored the epigenomic features associated with microglial responses in the context of APOE ε4 status, revealing that certain epigenetic modifications may mitigate the risk of AD in some APOE ε4 carriers, suggesting a complex interplay between genetics and neuroinflammation (ref: Ma doi.org/10.1002/alz.12425/). Leyh et al. examined the impact of long-term high-fat diet (HFD) on cognitive functions, finding that while HFD led to health issues, it did not impair learning and memory in adult mice, indicating that dietary factors may influence neuroinflammatory responses differently across contexts (ref: Leyh doi.org/10.1371/journal.pone.0257921/). Gao et al. demonstrated that peony seed oil can ameliorate cognitive deficits associated with neuroinflammation by inhibiting microglial activation, highlighting potential therapeutic strategies targeting neuroinflammatory pathways (ref: Gao doi.org/10.1002/JLB.3MA0821-639RR/). Wu et al. provided evidence that traumatic brain injury (TBI) exacerbates cognitive dysfunction and AD-like pathology by altering microglial phenotypes, suggesting that TBI may serve as a risk factor for AD (ref: Wu doi.org/10.3389/fneur.2021.666430/). Collectively, these studies underscore the critical role of neuroinflammation in AD and the potential for targeted interventions to modulate inflammatory responses.

Advancements in modeling techniques and therapeutic strategies for Alzheimer's disease are crucial for understanding disease mechanisms and developing effective treatments. Bassil et al. established an automated culturing platform for iPSC-derived neurons, astrocytes, and microglia, which enhances the consistency and reliability of AD models, facilitating the study of cellular interactions and neuroinflammatory processes (ref: Bassil doi.org/10.1038/s41467-021-25344-6/). Beebe-Wang et al. introduced a multi-task deep learning framework to analyze gene expression data in relation to AD neuropathologies, revealing complex interrelationships that could inform future therapeutic strategies (ref: Beebe-Wang doi.org/10.1038/s41467-021-25680-7/). Tao et al. explored the use of photobiomodulation with 1070-nm light to modulate microglial activity, demonstrating that this approach can reduce amyloid-beta burden and cognitive impairment in AD mouse models, suggesting a novel non-invasive therapeutic avenue (ref: Tao doi.org/10.1038/s41377-021-00617-3/). Hong et al. investigated the effects of a high-fat, sugar, and salt diet on neurodegeneration and cognitive dysfunction, finding that metformin treatment could ameliorate these effects, indicating potential dietary interventions for AD (ref: Hong doi.org/10.1111/cns.13726/). Wang et al. reported that thioperamide, an H3 receptor antagonist, can reduce neuroinflammation and cognitive impairments in AD models, highlighting the potential of targeting specific receptors to modulate glial responses (ref: Wang doi.org/10.1016/j.expneurol.2021.113870/). These studies collectively emphasize the importance of innovative modeling approaches and targeted therapies in advancing our understanding and treatment of Alzheimer's disease.

Genetic and epigenetic factors significantly influence the risk and progression of Alzheimer's disease, with recent studies shedding light on their roles. Kloske et al. investigated the impact of APOE isoforms on neuroinflammatory responses in AD, revealing that different APOE variants modulate the brain's immune response to AD pathology, which may contribute to the variability in disease progression among individuals (ref: Kloske doi.org/10.1093/jnen/). Gao et al. explored the neuroprotective effects of tetrahydroxy stilbene glycoside (TSG) in APP/PS1 mouse models, identifying its regulatory role on TGF-β and fractalkine signaling pathways, which may provide insights into potential therapeutic targets for AD (ref: Gao doi.org/10.1016/j.npep.2021.102197/). Okuzono et al. reported reduced TREM2 activation in microglia from AD patients, suggesting that impaired TREM2 signaling may hinder the brain's ability to respond to neurodegenerative processes, thus exacerbating AD pathology (ref: Okuzono doi.org/10.1002/2211-5463.13300/). Kang et al. also highlighted the effects of environmental factors, such as PM2.5 exposure, on neuroinflammation and neurodegeneration, indicating that both genetic predispositions and environmental influences interact to shape AD risk (ref: Kang doi.org/10.1002/advs.202101251/). These findings emphasize the complexity of genetic and epigenetic contributions to Alzheimer's disease and the need for integrated approaches to understand their interactions with environmental factors.

Diet and environmental factors play a significant role in the development and progression of Alzheimer's disease, with various studies exploring their impacts. Yanguas-Casás et al. examined the effects of a high-fat diet (HFD) on Tg APP mice, revealing that HFD alters stress behavior and inflammatory parameters in a sex-specific manner, suggesting that dietary composition can influence neuroinflammatory responses and potentially modulate AD risk (ref: Yanguas-Casás doi.org/10.1016/j.nbd.2021.105495/). Hong et al. further investigated the effects of a Western diet high in fat, sugar, and salt, finding that it induces neurodegeneration and sensory dysfunctions in aging mice, while metformin treatment showed ameliorative effects, indicating that dietary interventions may mitigate some adverse outcomes associated with poor nutrition (ref: Hong doi.org/10.1111/cns.13726/). Bhattacherjee et al. focused on the role of CD33 in microglial phagocytosis, demonstrating that targeting CD33 with glycan-laden liposomes enhances microglial function, which may be influenced by dietary factors (ref: Bhattacherjee doi.org/10.1016/j.jconrel.2021.09.010/). Leyh et al. found that long-term HFD did not impair learning and memory in adult mice, suggesting that the relationship between diet and cognitive function may be more complex than previously thought (ref: Leyh doi.org/10.1371/journal.pone.0257921/). These studies collectively highlight the intricate connections between diet, environmental influences, and Alzheimer's disease, emphasizing the need for further research to understand these relationships.

Microglial function and phagocytosis are critical in the context of Alzheimer's disease, with recent research shedding light on their roles in disease progression. Qiu et al. reported that adult-onset deficiency in CNS myelin sulfatide leads to neuroinflammation and cognitive impairment, implicating microglial responses in lipid metabolism and immune regulation as significant factors in AD pathology (ref: Qiu doi.org/10.1186/s13024-021-00488-7/). Kang et al. demonstrated that exposure to PM2.5 induces neuroinflammation and neurodegeneration in human brain models, highlighting the impact of environmental pollutants on microglial function and the potential for impaired phagocytosis in the context of AD (ref: Kang doi.org/10.1002/advs.202101251/). Bhattacherjee et al. explored the enhancement of microglial phagocytosis through CD33-targeted liposomes, providing a potential therapeutic strategy to improve microglial function in AD (ref: Bhattacherjee doi.org/10.1016/j.jconrel.2021.09.010/). Prakash et al. developed a method to monitor phagocytic uptake of amyloid beta into glial cell lysosomes in real time, which is essential for understanding the dynamics of microglial responses during AD progression (ref: Prakash doi.org/10.1039/d1sc03486c/). These studies collectively emphasize the importance of microglial function and phagocytosis in Alzheimer's disease, suggesting that enhancing these processes may offer therapeutic benefits.

Tau pathology is a hallmark of Alzheimer's disease, with recent studies elucidating its role in neurodegeneration. Jiang et al. demonstrated that pathological tau can prime and activate interleukin-1β through specific myeloid cell pathways, linking tau pathology to neuroinflammatory processes that exacerbate AD (ref: Jiang doi.org/10.1016/j.celrep.2021.109720/). Delizannis et al. investigated the effects of microglial depletion and TREM2 deficiency on amyloid-beta plaque burden and tau pathology in 5XFAD mice, revealing that microglial responses are crucial in modulating tau pathology associated with amyloid plaques (ref: Delizannis doi.org/10.1186/s40478-021-01251-1/). Kim et al. found that transplantation of gut microbiota from AD mouse models led to increased neuroinflammation and cognitive deficits, suggesting that microbiota composition may influence tau pathology and overall brain health (ref: Kim doi.org/10.1016/j.bbi.2021.09.002/). Wu et al. provided evidence that traumatic brain injury accelerates cognitive dysfunction and alters microglial phenotypes in AD models, indicating that external injuries may exacerbate tau-related neurodegeneration (ref: Wu doi.org/10.3389/fneur.2021.666430/). These findings highlight the complex interplay between tau pathology, neuroinflammation, and microglial function in the progression of Alzheimer's disease.

Traumatic brain injury (TBI) has been increasingly recognized as a potential risk factor for Alzheimer's disease, with studies exploring its effects on neurodegeneration and cognitive function. Wu et al. demonstrated that TBI accelerates cognitive dysfunction and exacerbates Alzheimer's-like pathology in the hippocampus of APP/PS1 mouse models, suggesting that TBI may alter microglial phenotypes and contribute to the progression of AD (ref: Wu doi.org/10.3389/fneur.2021.666430/). Huang et al. provided insights into early AD pathology by analyzing cortical biopsies from patients with Normal Pressure Hydrocephalus, revealing a transition from microglial homeostasis to a disease-associated phenotype in conjunction with increasing AD pathology (ref: Huang doi.org/10.1038/s41467-021-25902-y/). These findings indicate that TBI may not only serve as a precipitating factor for cognitive decline but also interact with underlying AD pathology, complicating the disease trajectory. The studies collectively emphasize the need for further research to understand the mechanisms by which TBI influences Alzheimer's disease and the potential for targeted interventions to mitigate these effects.