Microglial activation plays a pivotal role in the pathogenesis of Alzheimer's disease (AD), with studies highlighting both protective and detrimental effects of these immune cells. One study demonstrated that a TREM2-activating antibody, engineered for enhanced blood-brain barrier transport, significantly improved microglial metabolism in AD models, suggesting a potential therapeutic avenue (ref: van Lengerich doi.org/10.1038/s41593-022-01240-0/). Another investigation found that soluble TREM2 (sTREM2) levels in cerebrospinal fluid were associated with amyloid-related increases in phosphorylated tau and glucose hypermetabolism, indicating that microglial activation is influenced by disease stage (ref: Biel doi.org/10.15252/emmm.202216987/). Furthermore, research has shown that microglia utilize SYK signaling to mount neuroprotective responses, emphasizing their dual role in AD pathology (ref: Ennerfelt doi.org/10.1002/ctm2.1178/). In a transgenic rat model, behavioral and proteomic changes correlated with microglial activation, highlighting the importance of TREM2 in neuroinflammation and cognitive function (ref: Bac doi.org/10.1016/j.neurobiolaging.2022.12.015/). Lastly, TREM2 was shown to inhibit tau hyperphosphorylation and neuronal apoptosis via the PI3K/Akt/GSK-3β signaling pathway, further underscoring its protective role in AD (ref: Peng doi.org/10.1007/s12035-023-03217-x/).

Therapeutic strategies targeting microglia have gained attention due to their central role in neurodegenerative diseases. One study revealed that CSF1R inhibitors induced a resilient microglial phenotype in a tauopathy mouse model, suggesting that modulation of microglial activity could reverse pathogenic gene expression patterns (ref: Johnson doi.org/10.1038/s41467-022-35753-w/). In the context of COVID-19, research demonstrated that non-replicating SARS-CoV-2 variants could penetrate the blood-brain barrier and induce neuroinflammation, exacerbating cognitive impairments in AD models (ref: Erickson doi.org/10.1016/j.bbi.2023.01.010/). Additionally, the role of bromodomain and extraterminal (BET) proteins in regulating microglial phagocytosis was explored, indicating that targeting these proteins could enhance microglial function in AD (ref: Matuszewska doi.org/10.3390/ijms24010013/). Another study highlighted the beneficial effects of ACI-24 vaccination on amyloid-β plaque pathology and microglial phenotypes, reinforcing the potential of immunotherapeutic approaches (ref: Rudan Njavro doi.org/10.3390/cells12010079/). Lastly, cortical-blood vessel assembloids exhibited AD phenotypes following SARS-CoV-2 infection, emphasizing the intersection of viral infections and neurodegeneration (ref: Kong doi.org/10.1038/s41420-022-01288-8/).

Neuroinflammation is a critical component of Alzheimer's disease pathogenesis, with various studies elucidating its mechanisms. One investigation linked transposable element (TE) transcription to AD, suggesting that microglia and astrocytes respond to tau protein accumulation through dysregulated TE expression (ref: Evering doi.org/10.1016/j.tins.2022.12.003/). Another study examined the FGF/FGFR signaling in microglial neuroinflammation induced by Borrelia burgdorferi, indicating a potential intersection with other neurological conditions (ref: Parthasarathy doi.org/10.1186/s12974-022-02681-x/). Hypertension was also found to exacerbate neurovascular inflammation in both normal-appearing white matter and white matter hyperintensities, highlighting the vascular contributions to AD pathology (ref: Solé-Guardia doi.org/10.1186/s40478-022-01497-3/). Furthermore, reactive astrocytes induced by ultrafine particulate matter were shown to contribute to neurotoxicity, underscoring the environmental factors influencing neuroinflammation (ref: Li doi.org/10.1016/j.scitotenv.2023.161416/). Lastly, the role of FUT8-catalyzed core fucosylation in microglial activation was investigated, revealing its significance in AD pathogenesis (ref: Jin doi.org/10.1002/glia.24345/).

Biomarkers play a crucial role in understanding and monitoring Alzheimer's disease progression. One study identified soluble TREM2 as a potential biomarker for the severity of primary angiitis of the CNS, suggesting its utility in predicting prognosis (ref: Guo doi.org/10.3389/fimmu.2022.963373/). Additionally, TREM2 was shown to inhibit tau hyperphosphorylation and neuronal apoptosis, further establishing its relevance in AD pathology (ref: Peng doi.org/10.1007/s12035-023-03217-x/). The combination of luteolin and exercise therapy was found to ameliorate cognitive impairment in AD mice, indicating that lifestyle interventions may also serve as biomarkers for therapeutic efficacy (ref: Tao doi.org/10.3233/JAD-220904/). Another study assessed the effects of primary healthy microglia and gap junction blockers on AD neuroinflammation, suggesting early diagnostic potential for AD through localized administration of these agents (ref: Anwar doi.org/10.3389/fnins.2022.1041461/). Collectively, these findings highlight the importance of biomarkers in both understanding disease mechanisms and guiding therapeutic interventions.

Systemic inflammation has been shown to significantly impact neurodegeneration, particularly in Alzheimer's disease. One study demonstrated that systemic inflammation leads to microglial dysfunction, contributing to a vascular phenotype associated with AD (ref: Bathini doi.org/10.1016/j.bbih.2022.100568/). The penetration of SARS-CoV-2 across the blood-brain barrier was also linked to neuroinflammation, suggesting that viral infections may exacerbate cognitive decline in AD patients (ref: Erickson doi.org/10.1016/j.bbi.2023.01.010/). Furthermore, research analyzing Aβ-induced neurotoxicity in human iPSC-derived cortical cultures highlighted the role of microglial responses in AD pathology, emphasizing the need for further exploration of microglial function in neurodegenerative diseases (ref: Takata doi.org/10.1016/j.tice.2023.102023/). These studies collectively underscore the intricate relationship between systemic inflammation and neurodegenerative processes, suggesting that targeting inflammation may offer therapeutic benefits in AD.

Recent research has focused on the genetic and molecular mechanisms underlying microglial function in Alzheimer's disease. One study profiled histone acetylation in brain cell types from AD subjects, revealing that SNPs associated with late-onset AD are often found in microglia-specific regulatory elements, indicating a genetic basis for microglial dysfunction in AD (ref: Ramamurthy doi.org/10.3389/fnmol.2022.948456/). Another investigation identified the role of Ikzf1 as a novel regulator of microglial homeostasis, suggesting that understanding microglial states is essential for unraveling their contributions to neurodegeneration (ref: Ballasch doi.org/10.1016/j.bbi.2023.01.016/). Additionally, studies on Toxoplasma gondii's effects on microglial behavior highlighted the complex interactions between infections and microglial activation, further complicating the understanding of AD pathology (ref: Tao doi.org/10.1186/s13071-022-05618-8/). These findings emphasize the importance of genetic and molecular insights in developing targeted therapies for AD.

Environmental factors have been increasingly recognized as contributors to neurodegeneration, particularly in Alzheimer's disease. One study demonstrated that exposure to ultrafine particulate matter induces reactive astrocytes, which are implicated in neurotoxicity and AD pathology (ref: Li doi.org/10.1016/j.scitotenv.2023.161416/). Another investigation explored the therapeutic potential of natural compounds derived from marine sources, highlighting the need for novel interventions targeting environmental influences on AD (ref: Chen doi.org/10.3390/ijms24020905/). Furthermore, a genome-wide identification of interferon genes in microglial-mediated neuroinflammation provided insights into the role of environmental stressors in modulating microglial responses in AD (ref: Shippy doi.org/10.1016/j.jneuroim.2023.578031/). Collectively, these studies underscore the significance of environmental factors in the etiology of neurodegenerative diseases and the potential for targeted interventions.