Microglia play a crucial role in the pathophysiology of Alzheimer's disease (AD) through their involvement in synaptic maintenance and immune responses. Recent studies have highlighted the selective clearance of β-amyloid (Aβ) and synapses by microglia, which can be modulated through optogenetic techniques, suggesting a potential therapeutic avenue for enhancing microglial function in AD (ref: Lv doi.org/10.1016/j.neuron.2023.12.003/). Additionally, the inhibition of CD33, a receptor that negatively regulates microglial phagocytosis, has been shown to enhance Aβ clearance in human microglia, indicating that targeting this pathway could improve microglial activity and reduce Aβ burden (ref: Wong doi.org/10.1038/s41380-024-02474-z/). However, the relationship between microglial reactivity and synaptic loss remains complex, as studies have found that increased microglial activation correlates with presynaptic loss independent of Aβ and tau pathology, suggesting that microglial responses may vary in their neuroprotective or detrimental effects (ref: Lan doi.org/10.1002/ana.26885/). Moreover, the role of selenium in modulating microglial functions through SELENOK-dependent mechanisms has been explored, revealing its potential in enhancing Aβ phagocytosis (ref: Ouyang doi.org/10.1016/j.redox.2024.103064/). The identification of truncated GPNMB as a scavenger receptor for oligomeric Aβ further underscores the diverse mechanisms through which microglia interact with Aβ (ref: Kawahara doi.org/10.1111/jnc.16078/). Lastly, cholinergic modulation via agents like choline alphoscerate has shown promise in protecting against Aβ-mediated neurotoxicity, highlighting the interplay between cholinergic signaling and microglial activity in AD (ref: Cantone doi.org/10.3390/cells13040309/).

Neuroinflammation is a critical component of Alzheimer's disease, with emerging evidence linking peripheral immune responses to central nervous system pathology. A study demonstrated that sodium oligomannate alters gut microbiota, leading to reduced cerebral amyloidosis and reactive microglia in a sex-specific manner, suggesting that gut-brain interactions may influence neuroinflammatory processes in AD (ref: Bosch doi.org/10.1186/s13024-023-00700-w/). Furthermore, amyloid-β aggregates have been shown to activate peripheral monocytes in individuals with mild cognitive impairment, indicating that systemic immune activation may precede or accompany neurodegenerative changes (ref: Juul-Madsen doi.org/10.1038/s41467-024-45627-y/). The role of microRNAs in regulating neuroinflammation has also been highlighted, with the miR-25802/KLF4/NF-κB signaling axis identified as a key regulator of microglial activation and inflammatory responses in AD models (ref: Zhao doi.org/10.1016/j.bbi.2024.02.016/). In contrast, a study found that inflammasome signaling is dispensable for Aβ-induced neuropathology, challenging the notion that inflammasome activation is a requisite for neuroinflammation in AD (ref: Srinivasan doi.org/10.3389/fimmu.2024.1323409/). Additionally, environmental factors such as particulate matter from car exhaust have been shown to alter microglial function, linking air pollution to neuroinflammatory responses and cognitive decline (ref: Jäntti doi.org/10.1186/s12989-024-00564-y/).

The accumulation of amyloid-β (Aβ) is a hallmark of Alzheimer's disease, and its impact on synaptic function is a critical area of research. A study utilizing translocator protein (TSPO) positron emission tomography (PET) demonstrated that microglial activation precedes tau pathology and neurodegeneration, suggesting that Aβ accumulation may initiate a cascade of neurodegenerative events leading to cognitive impairment (ref: Rossano doi.org/10.1002/alz.13699/). This aligns with findings that DNA hypomethylation promotes the expression of CASPASE-4, exacerbating inflammation and Aβ deposition, thereby linking epigenetic changes to synaptic dysfunction in AD (ref: Daily doi.org/10.1186/s13195-024-01390-2/). Moreover, the accumulation of neutral lipids in dystrophic neurites surrounding Aβ plaques has been implicated in the pathophysiology of AD, suggesting that lipid metabolism may play a role in synaptic integrity and neuronal health (ref: Huang doi.org/10.1016/j.bbadis.2024.167086/). The dual nature of CD8 T cells in AD has also been explored, with evidence indicating that these cells may contribute to both protective and detrimental effects on synaptic function, highlighting the complexity of immune interactions in the disease (ref: Hu doi.org/10.1186/s13024-024-00706-y/).

Innovative therapeutic strategies targeting neuroinflammation and amyloid pathology are being explored in the context of Alzheimer's disease. Hecubine, a natural alkaloid, has been identified as a TREM2 activator that alleviates lipopolysaccharide-induced neuroinflammation, suggesting its potential as a therapeutic agent for neuroinflammatory conditions (ref: Li doi.org/10.1016/j.redox.2024.103057/). Additionally, dimethyl fumarate has shown promise in improving cognitive impairment and reducing neuroinflammation in AD mouse models, indicating that Nrf2 pathway activation may be a viable therapeutic target (ref: Wang doi.org/10.1186/s12974-024-03046-2/). The efficacy of 4-octyl itaconate has also been demonstrated, with RNA-seq analyses revealing its therapeutic effects on cognitive deficits in AD models, further supporting the exploration of metabolic modulators in AD treatment (ref: Liu doi.org/10.1016/j.ejphar.2024.176432/). Furthermore, polygalacic acid has been shown to attenuate cognitive impairment by regulating inflammation through the PPARγ/NF-κB signaling pathway, highlighting the importance of inflammatory modulation in AD therapy (ref: Zhao doi.org/10.1111/cns.14581/). Early intervention strategies, such as glatiramer acetate treatment in transgenic mice, have demonstrated the potential to delay pathological development and cognitive decline, emphasizing the need for timely therapeutic approaches in AD management (ref: Huang doi.org/10.3389/fnagi.2024.1267780/).

Genetic and molecular mechanisms underpinning Alzheimer's disease are critical for understanding its pathogenesis and developing targeted therapies. Recent research has identified CD8 T cells as significant neuroimmune responders in AD, with effector memory CD8 T cells enriched in the brains of individuals with AD dementia, suggesting their role in mediating neuroinflammation (ref: Yamakawa doi.org/10.3390/biomedicines12020308/). Additionally, studies have focused on the role of sTGFBR3 in microglial polarization and its impact on Aβ and tau pathology, indicating that dysregulation of this pathway may contribute to AD progression (ref: Chen doi.org/10.2174/0113816128278324240115104615/). Moreover, the inhibition of ribonucleotide reductase has been proposed as a potential therapeutic strategy, with gemcitabine emerging as a candidate drug against AD, highlighting the importance of targeting metabolic pathways in AD treatment (ref: Brokate-Llanos doi.org/10.1093/g3journal/). A neuroimaging-based deep learning approach has also been utilized to disentangle accelerated cognitive decline from normal aging, revealing genetic components associated with AD progression (ref: Dai doi.org/10.3233/JAD-231020/). These findings underscore the multifaceted genetic landscape of AD and the potential for precision medicine approaches in its management.

Microglial heterogeneity and its implications for aging and neurodegeneration are gaining attention in Alzheimer's disease research. A study identified S100A8-enriched microglia in tau-seeded and accelerated aging mouse models, suggesting that specific microglial subsets may contribute to neurodegenerative processes (ref: Gruel doi.org/10.1111/acel.14120/). This highlights the need to understand the functional diversity of microglia in different pathological contexts, particularly in relation to aging. Additionally, the impact of environmental factors, such as particulate matter from car exhaust, on microglial function has been explored, linking air pollution to altered microglial activity and potential exacerbation of neurodegenerative diseases (ref: Jäntti doi.org/10.1186/s12989-024-00564-y/). Furthermore, the role of DNA hypomethylation in promoting CASPASE-4 expression has been implicated in exacerbating inflammation and Aβ deposition, indicating that epigenetic changes may influence microglial behavior and contribute to aging-related neurodegeneration (ref: Daily doi.org/10.1186/s13195-024-01390-2/). Understanding these mechanisms is crucial for developing interventions that target microglial function and improve outcomes in aging populations.

Environmental factors are increasingly recognized as significant contributors to the pathogenesis of Alzheimer's disease. Research has shown that exposure to particulate matter from car exhaust can alter the function of human iPSC-derived microglia, suggesting a direct link between air pollution and neuroinflammatory processes associated with AD (ref: Jäntti doi.org/10.1186/s12989-024-00564-y/). This aligns with findings that highlight the role of cholinergic dysfunction in AD, where agents like choline alphoscerate have been shown to protect against Aβ-mediated neurotoxicity, indicating that environmental factors may interact with cholinergic signaling pathways (ref: Cantone doi.org/10.3390/cells13040309/). Moreover, the influence of gut microbiota on neuroinflammation and Aβ accumulation has been explored, with sodium oligomannate demonstrating the ability to modify gut microbiota and reduce cerebral amyloidosis in a sex-specific manner, further emphasizing the complex interplay between environmental exposures and neurodegenerative processes (ref: Bosch doi.org/10.1186/s13024-023-00700-w/). These findings underscore the importance of considering environmental factors in the development of therapeutic strategies for Alzheimer's disease.