Microglial cells play a crucial role in the pathogenesis of Alzheimer's disease (AD), particularly through their interactions with amyloid-beta (Aβ) and their response to neuroinflammation. Recent studies have highlighted the significance of the triggering receptor expressed on myeloid cells 2 (TREM2) in maintaining neuronal bioenergetics during development, with findings indicating that TREM2 regulates the metabolic fitness of neurons in a region-specific manner (ref: Tagliatti doi.org/10.1016/j.immuni.2023.12.002/). Additionally, an exhausted-like microglial population has been identified in aged brains, particularly those with the APOE4 genotype, suggesting that aging and genetic factors significantly alter microglial function and contribute to neuroinflammatory processes (ref: Millet doi.org/10.1016/j.immuni.2023.12.001/). This exhausted microglial state is further confirmed by longitudinal studies that show its enrichment in very elderly and APOE4 AD brains, reinforcing the connection between age, genetics, and microglial dysfunction in AD (ref: Li doi.org/10.1016/j.immuni.2023.12.015/). Moreover, therapeutic approaches targeting microglial activation, such as aducanumab, have demonstrated the ability to induce sustained microglial alterations and amyloid clearance, although the long-term effects of such treatments remain to be fully elucidated (ref: Cadiz doi.org/10.1084/jem.20231363/). The role of cysteinyl-tRNA synthetase (CARS) in driving neuroinflammation has also been highlighted, with increased levels observed in the temporal cortex of AD patients, suggesting a potential target for therapeutic intervention (ref: Qi doi.org/10.1186/s40035-023-00394-6/). Overall, these findings underscore the complex interplay between microglial function, neuroinflammation, and the progression of Alzheimer's disease, paving the way for future research into targeted therapies.

Genetic factors significantly influence the risk and progression of Alzheimer's disease (AD), with particular emphasis on the APOE4 allele and TREM2 variants. The APOE4 genotype has been shown to correlate with an exhausted-like microglial population in aged brains, indicating that genetic predisposition can alter neuroimmune function and contribute to AD pathology (ref: Millet doi.org/10.1016/j.immuni.2023.12.001/). This association is further supported by studies demonstrating that aging exacerbates the reactive microglial state, which is enriched in individuals carrying the APOE4 allele (ref: Li doi.org/10.1016/j.immuni.2023.12.015/). Additionally, loss-of-function variants in TREM2 have been linked to early-onset dementia and increased risk for late-onset AD, with recent findings revealing that these variants affect gene splicing, thereby influencing the pathogenesis of neurodegenerative disorders (ref: Kiianitsa doi.org/10.1093/brain/). Moreover, novel genetic modifiers of soluble TREM2 have been identified through extensive genome-wide association studies, highlighting the complexity of genetic interactions in AD (ref: Wang doi.org/10.1186/s13024-023-00687-4/). The interplay between genetic factors and environmental influences, such as gut microbiome alterations due to hormonal changes, further complicates the understanding of AD risk, particularly in women (ref: Saha doi.org/10.1038/s41598-024-52246-6/). Collectively, these studies illustrate the multifaceted role of genetic factors in Alzheimer's disease, emphasizing the need for continued research into their mechanisms and potential therapeutic targets.

Neuroinflammation is a critical component of Alzheimer's disease pathology, with various immune responses contributing to disease progression. Recent studies have identified increased levels of cysteinyl-tRNA synthetase (CARS) in the temporal cortex of AD patients, suggesting its role in driving neuroinflammation (ref: Qi doi.org/10.1186/s40035-023-00394-6/). Additionally, the association between sex, body mass index (BMI), and microglial responses has been explored, revealing that women with AD exhibit a stronger Aβ-plaque-independent microglial response compared to men (ref: Biechele doi.org/10.1186/s12974-024-03020-y/). This finding underscores the importance of considering sex differences in neuroinflammatory responses when studying AD. Furthermore, the role of interferon regulatory factor 5 (IRF5) in regulating microglial phagocytosis and alleviating Aβ-induced neuroinflammation has been highlighted, indicating potential therapeutic avenues for modulating immune responses in AD (ref: Fan doi.org/10.1093/gerona/). The emerging role of galectin-3 in neuroinflammation also suggests that it may serve as a detrimental factor in neurodegenerative diseases, warranting further investigation into its mechanisms (ref: Lozinski doi.org/10.4103/1673-5374.391181/). Overall, these findings emphasize the complex interplay between neuroinflammation and immune responses in Alzheimer's disease, highlighting the potential for targeted interventions to modulate these processes.

Therapeutic strategies for Alzheimer's disease (AD) are increasingly focusing on innovative approaches to overcome barriers to effective treatment delivery and to modulate neuroinflammation. One promising strategy involves the development of mannose-integrated nanoparticles designed to enhance oral delivery of therapeutic agents across the blood-brain barrier (BBB) (ref: Lei doi.org/10.1021/acsnano.3c09715/). This approach aims to improve the bioavailability of drugs targeting AD pathology, potentially leading to better clinical outcomes. Additionally, the standardized extract of Centella asiatica has shown antioxidative and anti-neuroinflammatory effects on microglial cells, suggesting its potential as a therapeutic agent in managing AD (ref: Hambali doi.org/10.3233/JAD-230875/). Moreover, the modulation of neuroinflammation through compounds such as Andrographolide derivatives has demonstrated efficacy in attenuating neuropathological changes in AD models by targeting key signaling pathways (ref: Hu doi.org/10.1016/j.ejphar.2023.176305/). Other studies have explored the effects of dietary factors, such as high salt intake, on cognitive deficits and neurovascular abnormalities in AD models, indicating that lifestyle modifications may also play a role in disease management (ref: Chen doi.org/10.1016/j.jnutbio.2024.109570/). Collectively, these therapeutic approaches highlight the importance of targeting neuroinflammation and enhancing drug delivery systems to improve treatment efficacy in Alzheimer's disease.

Sex differences in Alzheimer's disease (AD) are becoming increasingly recognized as critical factors influencing disease onset and progression. Studies have shown that late-onset Alzheimer's disease disproportionately affects women, with female-enriched microglial populations identified as contributing to this disparity (ref: Wu doi.org/10.1186/s12974-023-02987-4/). The characterization of disease-associated microglia (DAM) in females reveals distinct metabolic and inflammatory profiles that may influence disease severity and progression. Furthermore, research indicates that the Aβ-plaque-independent microglial response is significantly associated with tau pathology in females, suggesting that sex-specific mechanisms may underlie neuroinflammatory responses in AD (ref: Biechele doi.org/10.1186/s12974-024-03020-y/). Additionally, hormonal influences on the gut microbiome have been shown to alter amyloid pathology and microglial function, highlighting the interplay between sex hormones and neuroinflammation (ref: Saha doi.org/10.1038/s41598-024-52246-6/). Transcriptomic analyses further reveal that aged female brains exhibit increased expression of DAM genes and altered metabolic pathways, suggesting that aging may exacerbate sex differences in AD pathology (ref: Cleland doi.org/10.1016/j.brainres.2024.148772/). These findings underscore the necessity of considering sex as a biological variable in Alzheimer's research and therapeutic development.

The microglial response to amyloid-beta (Aβ) is a pivotal aspect of Alzheimer's disease pathology, influencing both neuroinflammation and cognitive decline. Recent studies have demonstrated that the Aβ-plaque-independent microglial response is significantly associated with tau pathology in females, indicating a sex-specific response to Aβ accumulation (ref: Biechele doi.org/10.1186/s12974-024-03020-y/). Furthermore, vascular endothelial growth factor (VEGF) has been shown to regulate microglial phagocytic responses to Aβ, suggesting that targeting this pathway may enhance microglial clearance of toxic Aβ aggregates (ref: de Gea doi.org/10.3389/fncel.2023.1264402/). Additionally, the role of C-C chemokine receptor 5 (CCR5) in cognitive deficits associated with Aβ has been explored, revealing its potential involvement in the neuroinflammatory processes that characterize AD (ref: Huang doi.org/10.1016/j.nlm.2024.107890/). The emerging role of galectin-3 in modulating neuroinflammation and neurodegeneration further emphasizes the complexity of microglial responses to Aβ and their implications for disease progression (ref: Lozinski doi.org/10.4103/1673-5374.391181/). Collectively, these findings highlight the critical role of microglia in responding to Aβ and the potential for therapeutic strategies aimed at enhancing microglial function to mitigate Alzheimer's disease pathology.

Aging is a significant risk factor for Alzheimer's disease (AD), influencing both the onset and progression of the disease. Recent research has shown that age-related changes in the brain, such as the accumulation of extracellular elastin-derived peptides (EDPs), can disrupt neuronal morphology and impair neuron-microglia interactions, contributing to AD pathology (ref: Ma doi.org/10.1111/jnc.16039/). Additionally, age-dependent alterations in the subcellular localization of high mobility group box 1 (HMGB1) have been observed, with significant reductions in nuclear HMGB1 levels in aged AD models compared to age-matched controls (ref: Seol doi.org/10.3390/cells13020189/). Furthermore, the effects of anti-Aβ monoclonal antibodies on microglial activation and neuroinflammation have been investigated, revealing that higher levels of soluble TREM2 in cerebrospinal fluid are associated with increased neuroinflammatory responses in the context of aging and AD (ref: Pomara doi.org/10.1002/alz.13684/). These findings underscore the complex interplay between aging, neuroinflammation, and Alzheimer's disease, highlighting the need for targeted interventions that address age-related changes in the brain to mitigate disease progression.