Microglia play a pivotal role in the pathogenesis of Alzheimer's disease (AD), particularly through their interactions with amyloid-beta (Aβ) and tau proteins. A study identified a tetravalent TREM2 agonistic antibody (Ab18) that significantly reduced amyloid pathology in a mouse model of AD, highlighting the importance of TREM2 in regulating microglial migration and phagocytosis of oligomeric Aβ and amyloid plaques (ref: Zhao doi.org/10.1126/scitranslmed.abq0095/). Another study demonstrated that elevating TREM2 levels in microglia not only reduced amyloid seeding but also suppressed disease-associated microglial activation, suggesting that enhancing TREM2 signaling could be a viable therapeutic strategy, although the optimal therapeutic window remains uncertain (ref: Zhao doi.org/10.1084/jem.20212479/). Furthermore, research indicated that Trem2 deletion exacerbated tau pathology and impaired cognitive functions, emphasizing the dual role of microglia in both amyloid and tau pathologies (ref: Zhu doi.org/10.1186/s13024-022-00562-8/). Additionally, the characterization of dark microglia, which exhibit signs of cellular stress, has revealed their presence in aging brains and their potential implications in AD pathology (ref: St-Pierre doi.org/10.1186/s12974-022-02595-8/). Overall, these findings underscore the complex dynamics of microglial activation and their critical involvement in AD progression.

The triggering receptor expressed on myeloid cells 2 (TREM2) has emerged as a significant factor in Alzheimer's disease pathology. Studies have shown that TREM2 variants are associated with atypical clinical presentations of AD, characterized by a distinct distribution of neurofibrillary tangles and lower hippocampal NFT burden compared to neocortical accumulation (ref: Kim doi.org/10.1007/s00401-022-02495-4/). Additionally, a tetravalent TREM2 agonistic antibody was found to reduce amyloid pathology in mouse models, reinforcing the receptor's role in modulating microglial responses to amyloid deposits (ref: Zhao doi.org/10.1126/scitranslmed.abq0095/). Elevating TREM2 expression in microglia has been shown to decrease amyloid seeding and mitigate the activation of disease-associated microglia, suggesting that TREM2 signaling could be a promising target for therapeutic interventions (ref: Zhao doi.org/10.1084/jem.20212479/). Moreover, comparative analyses of plaque-associated and plaque-distant microglia have revealed distinct transcriptomic profiles, indicating that these subpopulations contribute differently to AD progression (ref: Hemonnot-Girard doi.org/10.1186/s12974-022-02581-0/). Collectively, these studies highlight the multifaceted role of TREM2 in AD pathology and its potential as a therapeutic target.

Neuroinflammation is increasingly recognized as a critical factor in cognitive decline associated with Alzheimer's disease. Research has demonstrated that the human antimicrobial peptide LL-37 promotes microglial activation, which is linked to AD progression through mechanisms involving chloride intracellular channel 1 (CLIC1) (ref: Chen doi.org/10.1038/s41380-022-01790-6/). Additionally, fasting-mimicking diet cycles have been shown to reduce neuroinflammation and cognitive decline in mouse models of AD, with significant reductions in Aβ load and hyperphosphorylated tau, alongside decreased microglial numbers and neuroinflammatory gene expression (ref: Rangan doi.org/10.1016/j.celrep.2022.111417/). Conversely, exposure to traffic-related air pollution has been linked to impaired cognitive function and increased neuroinflammation, suggesting environmental factors play a role in AD pathology (ref: Xu doi.org/10.1016/j.envres.2022.114181/). Furthermore, novel compounds such as akebia saponin D have shown promise in protecting against microglia-mediated inflammation and cognitive impairment, indicating potential therapeutic avenues for mitigating neuroinflammation in AD (ref: Liu doi.org/10.3389/fphar.2022.927419/). These findings collectively emphasize the intricate relationship between neuroinflammation and cognitive decline in Alzheimer's disease.

Genetic and epigenetic factors play a crucial role in the development and progression of Alzheimer's disease. A comprehensive study profiling DNA methylation across cortical regions identified 334 differentially methylated positions associated with AD pathology, revealing that non-neuronal cell types primarily drive these epigenetic changes (ref: Shireby doi.org/10.1038/s41467-022-33394-7/). Additionally, a sex-stratified analysis of neuroimmune gene expression signatures in AD brains highlighted the differential activation of chitinases, which are biomarkers for microglial and astrocytic activation, suggesting that sex may influence neuroinflammatory responses in AD (ref: Sanfilippo doi.org/10.1007/s11357-022-00664-7/). Furthermore, gliovascular alterations in both sporadic and familial AD have been linked to the APOE genotype, indicating that genetic variations can affect neurovascular integrity and contribute to disease pathology (ref: Henao-Restrepo doi.org/10.1111/bpa.13119/). These studies underscore the importance of understanding genetic and epigenetic mechanisms in the context of AD, as they may provide insights into potential therapeutic targets and biomarkers for disease progression.

Dietary and environmental factors significantly influence the risk and progression of Alzheimer's disease. Research has shown that fasting-mimicking diet cycles can reduce neuroinflammation and cognitive decline in AD mouse models, outperforming traditional protein restriction diets in terms of reducing Aβ load and enhancing neurogenesis (ref: Rangan doi.org/10.1016/j.celrep.2022.111417/). Conversely, exposure to traffic-related air pollution has been associated with cognitive impairment and increased neuroinflammation, highlighting the detrimental effects of environmental toxins on brain health (ref: Xu doi.org/10.1016/j.envres.2022.114181/). Additionally, compounds like akebia saponin D have demonstrated protective effects against microglia-mediated inflammation, suggesting that dietary interventions may mitigate the impact of neuroinflammation on cognitive function (ref: Liu doi.org/10.3389/fphar.2022.927419/). These findings indicate that both dietary choices and environmental exposures play critical roles in modulating the neuroinflammatory processes underlying Alzheimer's disease.

Microglial dynamics are crucial in understanding the progression of Alzheimer's disease. Recent studies have shown that microglial activation is preferentially distributed along highly connected brain regions, mirroring the spread of tau pathology, suggesting that microglial responses may follow similar patterns of neurodegeneration (ref: Rauchmann doi.org/10.1002/ana.26465/). The characterization of dark microglia, which exhibit signs of stress, has revealed their presence in both mouse models and aging human brains, indicating a potential link between microglial states and AD pathology (ref: St-Pierre doi.org/10.1186/s12974-022-02595-8/). Furthermore, chronic alcohol consumption has been shown to influence microglial dynamics and Aβ clearance, raising questions about the interplay between lifestyle factors and neuroinflammatory processes in AD (ref: Marsland doi.org/10.1016/j.alcohol.2022.08.013/). These insights into microglial behavior and their interactions with neurodegenerative processes are essential for developing targeted therapeutic strategies in Alzheimer's disease.

Therapeutic strategies targeting microglia are gaining attention in the context of Alzheimer's disease. Recent research has explored the transplantation of nasal olfactory mucosa mesenchymal stem cells as a potential treatment to ameliorate cognitive impairment associated with AD, highlighting the need for innovative approaches to neural regeneration (ref: Hong doi.org/10.1007/s12035-022-03044-6/). Additionally, studies have shown that sex and APOE genotype significantly influence the inflammatory responses of primary microglia, with APOE4 carriers exhibiting heightened inflammatory profiles, suggesting that personalized approaches may be necessary for effective treatment (ref: Mhatre-Winters doi.org/10.3390/ijms23179829/). Furthermore, compounds like akebia saponin D have demonstrated protective effects against microglia-mediated inflammation, indicating their potential as therapeutic agents in mitigating neuroinflammatory damage (ref: Liu doi.org/10.3389/fphar.2022.927419/). These findings underscore the importance of targeting microglial dynamics and inflammatory pathways in developing effective therapies for Alzheimer's disease.