Recent studies have highlighted the critical role of microglia in the pathogenesis of Alzheimer's disease (AD), particularly in relation to amyloid and tau pathologies. For instance, the ApoE3 R136S variant has been shown to bind to tau, inhibiting its propagation and reducing neurodegeneration in mouse models (ref: Chen doi.org/10.1016/j.neuron.2024.12.015/). This protective effect contrasts with findings that demyelination-derived lysophosphatidylserine promotes microglial dysfunction, exacerbating AD pathology (ref: Zhou doi.org/10.1038/s41423-024-01235-w/). Moreover, the APOE Christchurch variant enhances microglial responses to amyloid plaques while suppressing responses to tau pathology, indicating a nuanced role of genetic factors in microglial activation (ref: Tran doi.org/10.1186/s13024-024-00793-x/). The Human Microglia Atlas has further elucidated the diversity of microglial populations across neurodegenerative conditions, revealing distinct activation states associated with AD (ref: Martins-Ferreira doi.org/10.1038/s41467-025-56124-1/). Additionally, genetic studies have identified that variants such as ABCA7 p.A696S can disrupt microglial responses to amyloid pathology, suggesting that genetic predispositions significantly influence microglial function in AD (ref: Ma doi.org/10.1016/j.nbd.2025.106813/). The accumulation of lipid droplets in microglia, linked to neuroinflammation, has been observed in aging brains, indicating that metabolic changes may also contribute to microglial dysfunction (ref: Sha doi.org/10.1038/s41419-024-07328-8/). These findings collectively underscore the complex interplay between genetic factors, microglial activation, and neuroinflammatory processes in the context of Alzheimer's disease.

Neuroinflammation plays a pivotal role in the progression of Alzheimer's disease, with recent research focusing on the immune response mechanisms involved. A comprehensive analysis of cerebrospinal fluid (CSF) has identified disease-associated immune cell populations, providing insights into the cellular landscape relevant to neurodegenerative diseases (ref: Cantoni doi.org/10.1172/JCI177793/). Furthermore, studies have demonstrated that cigarette smoke exposure accelerates Alzheimer-like pathology through mechanisms involving NLRP3 inflammasome activation and microglial dysfunction (ref: Wang doi.org/10.1016/j.jhazmat.2025.137310/). This highlights environmental factors as significant contributors to neuroinflammatory processes in AD. Moreover, the role of oxidative stress in AD has been emphasized, with findings indicating that Aβ oligomers induce oxidative damage in glial cells, which can be mitigated by protective agents like carnosine (ref: Cardaci doi.org/10.1016/j.freeradbiomed.2025.01.030/). The modulation of neuroinflammation through various pathways, including the TLR4-mediated MyD88/NF-κB signaling, has been shown to alleviate cognitive deficits in AD models (ref: Chen doi.org/10.2174/0118715273337232241121113048/). These studies collectively illustrate the intricate relationship between neuroinflammation, immune responses, and the pathophysiology of Alzheimer's disease.

The genetic landscape of Alzheimer's disease is becoming increasingly complex, with studies revealing significant insights into the molecular mechanisms underlying the disease. Research has shown that regional brain iron accumulation correlates with transcriptional changes in AD, implicating processes such as protein phosphorylation and metal ion transport in disease pathology (ref: Yang doi.org/10.1002/alz.14459/). Additionally, the regulation of microglial function by neuraminidase 1 has been identified as a crucial factor in neuropathogenesis, influencing microglial survival and cytokine production through modulation of Trem2 sialylation (ref: Fremuth doi.org/10.1016/j.celrep.2024.115204/). Furthermore, intermittent fasting has been shown to ameliorate β-amyloid deposition and cognitive impairment in AD models, suggesting that dietary interventions may influence genetic expression related to neurodegeneration (ref: Wu doi.org/10.1002/mnfr.202400660/). The identification of PANoptosis-related genes associated with immune dysregulation in AD highlights the importance of programmed cell death mechanisms in the disease (ref: Liu doi.org/10.1007/s11011-025-01540-x/). These findings underscore the interplay between genetic factors, molecular pathways, and environmental influences in the development and progression of Alzheimer's disease.

The search for effective therapeutic strategies for Alzheimer's disease has intensified, with recent studies exploring various pharmacological interventions. Research has demonstrated that chitinase 1 (CHIT1) plays a significant role in modulating neuroinflammation and phagocytosis in microglia, thereby reducing Aβ plaque deposition in AD models (ref: Yuan doi.org/10.1002/path.6387/). Additionally, the identification of potential ERK1 inhibitors from natural products presents a promising avenue for therapeutic targeting, with compounds showing higher affinity than existing treatments (ref: Taufeeq doi.org/10.1177/13872877241309592/). Moreover, the development of novel nanocomplexes combining aronia bioactive fractions with alginic acid has shown potential in enhancing neuroinflammation modulation and inhibiting Aβ aggregation (ref: Jang doi.org/10.3390/pharmaceutics17010013/). The investigation of DAG-MAG-βHB as a ketone diester that modulates NLRP3 inflammasome activation further illustrates the diverse approaches being explored to address neuroinflammatory pathways in AD (ref: Gentili doi.org/10.3390/nu17010149/). These advancements reflect a multifaceted approach to drug development, focusing on both neuroinflammation and cognitive function in the context of Alzheimer's disease.

Understanding the pathological mechanisms underlying Alzheimer's disease is crucial for developing effective biomarkers and therapeutic strategies. Recent findings have shown that microglia modulate cerebrovascular reactivity through ectonucleotidase CD39, which is essential for regulating cerebral blood flow and responses to stimuli (ref: Fu doi.org/10.1038/s41467-025-56093-5/). This highlights the importance of microglial function in maintaining vascular health in the context of neurodegeneration. Additionally, network pharmacology studies have identified heparan sulfate as a potential modulator of neuroinflammation in AD, suggesting that targeting specific molecular pathways may offer therapeutic benefits (ref: Kim doi.org/10.3390/biomedicines13010103/). The ABCA7 p.A696S variant has been implicated in disrupting microglial responses to amyloid pathology, providing insights into genetic susceptibility factors in AD (ref: Ma doi.org/10.1016/j.nbd.2025.106813/). These studies collectively emphasize the need for a comprehensive understanding of the molecular and cellular mechanisms involved in Alzheimer's disease to facilitate the identification of reliable biomarkers and therapeutic targets.

Environmental and lifestyle factors are increasingly recognized as significant contributors to the risk and progression of Alzheimer's disease. Recent research has demonstrated that exposure to cigarette smoke accelerates Alzheimer-like pathology through mechanisms involving NLRP3 inflammasome activation and microglial dysfunction (ref: Wang doi.org/10.1016/j.jhazmat.2025.137310/). This underscores the impact of environmental pollutants on neuroinflammatory processes associated with AD. Moreover, dietary interventions such as intermittent fasting have shown promise in ameliorating β-amyloid deposition and cognitive impairment in transgenic mouse models of AD (ref: Wu doi.org/10.1002/mnfr.202400660/). The modulation of neuroinflammation through lifestyle changes highlights the potential for non-pharmacological approaches to influence disease outcomes. These findings suggest that addressing environmental and lifestyle factors may play a crucial role in the prevention and management of Alzheimer's disease.

The interplay between neurodegeneration and aging is a critical area of research in understanding Alzheimer's disease. Recent studies have explored the effects of environmental factors, such as dietary habits, on the incidence of neurodegenerative diseases like multiple sclerosis, indicating a potential link between lifestyle and neurodegeneration (ref: Van Gaever doi.org/10.3389/fimmu.2024.1500697/). Additionally, research on blast-induced brain injuries has revealed early pathological changes, such as intramural hematomas and astrocytic infiltration, that precede neuroinflammation, suggesting that environmental stressors can exacerbate neurodegenerative processes (ref: Gama Sosa doi.org/10.1093/jnen/). Furthermore, the role of SERPINA3 as a neuroinflammatory modulator has been highlighted, showing its expression is linked to microglial and astrocytic markers, which may influence neuroinflammatory responses in AD (ref: Sanfilippo doi.org/10.1007/s11011-024-01523-4/). These findings emphasize the importance of understanding the aging process and environmental influences on neurodegeneration to develop effective interventions for Alzheimer's disease.

Microglial activation is a key factor in the neuroinflammatory response associated with Alzheimer's disease, and recent studies have focused on understanding its role in neuroprotection. The TRPV1-PKM2-SREBP1 axis has been identified as crucial for maintaining microglial lipid homeostasis, with implications for phagocytic dysfunction in AD (ref: Sha doi.org/10.1038/s41419-024-07328-8/). This highlights the importance of lipid metabolism in microglial function and its potential impact on neuroprotection. Additionally, the ABCA7 p.A696S variant has been shown to compromise microglial responses to amyloid pathology, suggesting that genetic factors can influence the efficacy of microglial activation in AD (ref: Ma doi.org/10.1016/j.nbd.2025.106813/). The exploration of potential ERK1 inhibitors from natural products also points to novel therapeutic strategies aimed at enhancing microglial function and neuroprotection (ref: Taufeeq doi.org/10.1177/13872877241309592/). These insights into microglial activation and neuroprotection underscore the potential for targeted therapies that enhance microglial function in the context of Alzheimer's disease.