Recent studies have underscored the critical role of microglia in Alzheimer's disease (AD) pathogenesis, particularly in relation to apolipoprotein E4 (APOE4) and amyloid-beta (Aβ) accumulation. For instance, Rao et al. demonstrated that microglial depletion in a chimeric model with human neurons significantly reduced APOE4-related pathologies, suggesting a concerted interaction between microglia and neuronal APOE in AD progression (ref: Rao doi.org/10.1016/j.stem.2024.10.005/). Similarly, Arber et al. highlighted that microglia contribute to the production of the amyloidogenic ABri peptide in familial British dementia, indicating that microglial activity is not only pivotal in AD but also in other amyloid-related disorders (ref: Arber doi.org/10.1007/s00401-024-02820-z/). Furthermore, Pan et al. identified that microglial Lyzl4 facilitates the clearance of Aβ aggregates, emphasizing the importance of microglial phagocytic functions in maintaining brain homeostasis and mitigating AD pathology (ref: Pan doi.org/10.1002/advs.202412184/). These findings collectively highlight the dual role of microglia in both promoting and alleviating AD pathogenesis, depending on their activation state and the surrounding microenvironment. In addition to their roles in amyloid clearance, microglia are also implicated in neuroinflammation associated with AD. Sobue et al. explored the effects of cannabinoid receptor type II stimulation on cognitive impairment and neuroinflammation in AD mice, revealing that modulation of microglial activity can improve cognitive outcomes by controlling astrocyte activation (ref: Sobue doi.org/10.1038/s41419-024-07249-6/). Wei et al. further contributed to this narrative by demonstrating that AD-derived outer membrane vesicles exacerbate cognitive dysfunction and increase neuroinflammation, suggesting that microglial responses to extracellular signals are crucial in the disease's progression (ref: Wei doi.org/10.1007/s12035-024-04579-6/). Together, these studies illustrate the complex interplay between microglial function and AD pathogenesis, highlighting both their protective and detrimental roles in the disease.

Neuroinflammation is increasingly recognized as a central feature of Alzheimer's disease (AD), with microglia playing a pivotal role in mediating immune responses. Koskeridis et al. conducted a multi-trait association analysis that revealed shared genetic loci between AD and cardiovascular traits, suggesting that neuroinflammatory pathways may intersect with cardiovascular health (ref: Koskeridis doi.org/10.1038/s41467-024-53452-6/). This connection is further supported by findings from Pomara et al., who highlighted the role of TREM2 in enhancing microglial phagocytic activity and modulating inflammatory signaling, indicating that microglial activation is crucial for maintaining neuroimmune balance (ref: Pomara doi.org/10.1073/pnas.2417472121/). Additionally, Preman et al. provided insights into the differential roles of APOE expressed in astrocytes versus microglia, revealing that astrocytic APOE is central to amyloid plaque pathology and influences microglial responses, thus emphasizing the importance of cellular context in neuroinflammatory processes (ref: Preman doi.org/10.1038/s44321-024-00162-7/). Moreover, the study by Deshpande et al. on cerebral small vessel disease highlighted that microglial activation occurs without peripheral immune cell infiltration, suggesting that local neuroinflammatory responses are critical in the context of vascular pathology associated with cognitive deficits (ref: Deshpande doi.org/10.1111/nan.13015/). This finding aligns with the work of Alami et al., which investigated the neuroprotective effects of pomegranate polyphenols against oxidative stress and inflammation, further supporting the notion that modulating neuroinflammatory pathways can have therapeutic implications for AD (ref: Alami doi.org/10.3390/nu16213667/). Collectively, these studies underscore the multifaceted role of neuroinflammation in AD, revealing both genetic and environmental factors that influence microglial activation and immune responses.

The genetic and molecular underpinnings of Alzheimer's disease (AD) have been a focal point of recent research, particularly concerning sex differences and the role of specific genes in disease pathology. Lopez-Lee et al. utilized single-nuclei transcriptomics to explore the contributions of sex chromosomes and gonads in demyelination and AD, revealing that these factors significantly modify microglial and oligodendrocyte responses, thus highlighting the importance of sex in AD pathology (ref: Lopez-Lee doi.org/10.1126/science.adk7844/). This study complements findings from Wen et al., who reported altered immune responses associated with sex differences in vulnerability to AD, suggesting that females may exhibit distinct pathophysiological characteristics compared to males (ref: Wen doi.org/10.1111/bpa.13318/). In addition to sex differences, the role of specific genes such as BACE1 and APOE in AD has been extensively studied. Ishii et al. focused on the contribution of oligodendrocytes to amyloid deposition, emphasizing the need for targeted therapies that consider the complex interactions between different cell types in the brain (ref: Ishii doi.org/10.1186/s13024-024-00759-z/). Furthermore, Günaydin et al. demonstrated that the delivery of the APOE2-Christchurch variant via AAV vectors effectively suppressed amyloid and tau pathology in AD mice, suggesting that genetic interventions may offer promising therapeutic avenues (ref: Günaydin doi.org/10.1016/j.ymthe.2024.11.003/). These findings collectively underscore the intricate genetic landscape of AD and the potential for targeted therapies that address both genetic predispositions and sex-specific responses.

Therapeutic strategies targeting microglia have gained traction in the quest to mitigate Alzheimer's disease (AD) pathology, with recent studies exploring various interventions. Yan et al. introduced a polymer-formulated nerve growth factor that effectively reduced oxidative stress and neuronal apoptosis in a mouse model of cerebral microinfarcts, reshaping microglial polarization and leading to improved cognitive outcomes (ref: Yan doi.org/10.1002/adma.202412843/). This highlights the potential of microglial modulation as a therapeutic strategy in AD, particularly in the context of ischemic brain injury. Additionally, Sobue et al. investigated the effects of cannabinoid receptor type II stimulation on cognitive impairment and neuroinflammation in AD mice, revealing that such modulation can control astrocyte activation and improve cognitive function (ref: Sobue doi.org/10.1038/s41419-024-07249-6/). This aligns with Kerschbaum et al.'s findings on lipid-nanoparticle-induced vacuolization in microglia, suggesting that understanding microglial metabolism and activation states is crucial for developing effective therapies (ref: Kerschbaum doi.org/10.1038/s42003-024-07271-6/). Furthermore, Nairuz et al. examined differential glial responses in various hippocampal regions of 5XFAD mice, emphasizing the need for region-specific therapeutic approaches that consider the heterogeneous nature of microglial activation in AD (ref: Nairuz doi.org/10.3390/ijms252212156/). Collectively, these studies illustrate the promise of targeting microglial function and activation states as a multifaceted approach to AD treatment.

The interplay between amyloid-beta (Aβ) and tau proteins remains a central focus in Alzheimer's disease (AD) research, with recent studies elucidating their roles in neurodegeneration. Buonfiglioli et al. developed a microglia-containing cerebral organoid model to study the effects of early life immune challenges on neurodevelopment, highlighting the importance of the immune environment in shaping the pathogenesis of AD (ref: Buonfiglioli doi.org/10.1016/j.bbi.2024.11.008/). This model allows for the exploration of how Aβ and tau pathology may interact with immune responses during critical developmental windows. Nagata et al. further contributed to this understanding by demonstrating that tau accumulation induces alterations in microglial states in AD model mice, suggesting that tau pathology may directly influence microglial activation and function (ref: Nagata doi.org/10.1523/ENEURO.0260-24.2024/). This finding is complemented by Sobue et al.'s work on cannabinoid receptor modulation, which showed that controlling neuroinflammation can improve cognitive outcomes in the context of Aβ and tau accumulation (ref: Sobue doi.org/10.1038/s41419-024-07249-6/). Additionally, Wei et al. explored the impact of AD-derived outer membrane vesicles on cognitive dysfunction and neuroinflammation, further emphasizing the complex interactions between amyloid, tau, and the neuroimmune environment (ref: Wei doi.org/10.1007/s12035-024-04579-6/). Together, these studies underscore the intricate relationship between amyloid and tau in AD, highlighting their roles in modulating neuroinflammation and cognitive decline.

Sex differences in Alzheimer's disease (AD) have emerged as a significant area of research, with evidence suggesting that females may be more vulnerable to the disease than males. Lopez-Lee et al. utilized single-nuclei transcriptomics to dissect the roles of sex chromosomes and gonads in modulating microglial and oligodendrocyte responses in a mouse model of demyelination and AD, revealing that these factors significantly influence disease pathology (ref: Lopez-Lee doi.org/10.1126/science.adk7844/). This study highlights the necessity of considering sex as a biological variable in AD research and therapeutic development. Wen et al. further explored the immune response differences between sexes in human prefrontal cortex samples, identifying altered immune pathways that may contribute to the higher incidence of AD in females (ref: Wen doi.org/10.1111/bpa.13318/). This aligns with findings from Wei et al., who reported that AD-derived outer membrane vesicles exacerbate cognitive dysfunction and neuroinflammation, suggesting that sex-specific responses to these vesicles may play a role in disease progression (ref: Wei doi.org/10.1007/s12035-024-04579-6/). Collectively, these studies underscore the importance of understanding sex differences in AD, as they may inform targeted interventions and improve outcomes for affected individuals.

Natural products and traditional medicine are gaining attention as potential therapeutic avenues for Alzheimer's disease (AD), with recent studies highlighting their multifaceted benefits. Moreira et al. investigated bioactive extracts from Eucalyptus globulus leaves, demonstrating protective properties against AD in experimental models, which may offer novel disease-modifying strategies (ref: Moreira doi.org/10.1016/j.biopha.2024.117652/). This study emphasizes the potential of natural compounds to target multiple pathways involved in AD pathology. Temviriyanukul et al. examined the neuroprotective effects of Phikud Navakot, a Thai traditional medicine, against oxidative stress and neuroinflammation, indicating that multi-targeted agents may be preferable to single-target therapies in AD treatment (ref: Temviriyanukul doi.org/10.1016/j.heliyon.2024.e39700/). Additionally, Zhou et al. focused on the structural optimization of ar-turmerone, a compound derived from turmeric, which has shown promise in suppressing neuroinflammation in AD models (ref: Zhou doi.org/10.1016/j.bmc.2024.118014/). These findings collectively highlight the potential of natural products and traditional medicine in developing effective therapeutic strategies for AD, underscoring the need for further exploration of their mechanisms of action and clinical efficacy.

Microglial activation is a critical factor in the neurodegenerative processes associated with Alzheimer's disease (AD), with recent studies elucidating the patterns of glial response in various brain regions. Nairuz et al. examined the differential glial responses and neurodegenerative patterns in the CA1, CA3, and dentate gyrus regions of 5XFAD mice, revealing significant Aβ deposition and highlighting the non-uniform nature of glial and neuronal responses to amyloid plaque deposition (ref: Nairuz doi.org/10.3390/ijms252212156/). This study underscores the importance of regional differences in microglial activation and their implications for cognitive deficits in AD. Wang et al. explored the effects of electroacupuncture on microglial phenotype and epigenetic modulation in SAMP8 mice, demonstrating that promoting the transition of microglia from an M1 to an M2 phenotype can inhibit neuroinflammatory responses, offering new insights into potential therapeutic strategies for AD (ref: Wang doi.org/10.1016/j.brainres.2024.149339/). Furthermore, Preman et al. investigated the role of astrocytic APOE in modulating microglial responses to amyloid pathology, indicating that astrocytes play a central role in influencing microglial activation and neurodegeneration (ref: Preman doi.org/10.1038/s44321-024-00162-7/). Together, these studies highlight the complex interplay between microglial activation and neurodegeneration in AD, emphasizing the need for targeted interventions that consider the diverse roles of glial cells in disease progression.