Microglial dysfunction is increasingly recognized as a critical factor in the pathogenesis of Alzheimer's disease (AD). Recent studies have demonstrated that exposure to amyloid-beta (Aβ) leads to the formation of lipid droplets (LDs) in microglia, which correlates with impaired phagocytic activity and altered lipid metabolism. Specifically, Prakash et al. found that LD-laden microglia exhibited a decrease in free fatty acids and an increase in triacylglycerols, indicating a significant metabolic shift that compromises their ability to clear Aβ (ref: Prakash doi.org/10.1016/j.immuni.2025.04.029/). Furthermore, Lee et al. provided evidence that microglia-driven inflammation can induce tauopathies and synucleinopathies, suggesting that inflammatory processes may facilitate the spread of neurodegenerative pathology beyond localized regions (ref: Lee doi.org/10.1038/s12276-025-01450-z/). This highlights the dual role of microglia in both neuroprotection and neurodegeneration, depending on their activation state and the surrounding microenvironment. In addition to lipid metabolism, insulin signaling in microglia has been shown to influence Aβ uptake and neuroinflammatory responses. Chen et al. reported that loss of insulin signaling impairs microglial uptake of Aβ and exacerbates neuroinflammatory responses, leading to worsened AD-like neuropathology (ref: Chen doi.org/10.1073/pnas.2501527122/). The role of genetic factors, particularly the APOE isoforms, is also critical in shaping microglial responses to Aβ. Murphy et al. highlighted that different APOE isoforms modulate the transcriptomic and epigenomic landscapes of microglia, with APOE4 being associated with increased risk for AD (ref: Murphy doi.org/10.1038/s41467-025-60099-4/). Collectively, these findings underscore the complex interplay between microglial dysfunction, metabolic changes, and genetic predispositions in the context of Alzheimer's disease.

The relationship between amyloid-beta (Aβ) accumulation and neuroinflammation is a central theme in Alzheimer's disease research. Recent studies have elucidated various mechanisms through which Aβ influences microglial activation and neuroinflammatory responses. Liu et al. demonstrated that the mechanical properties of Aβ plaques activate microglia via the PIEZO1 mechanotransduction pathway, leading to impaired phagocytosis and an oxidative-stressed microenvironment (ref: Liu doi.org/10.1002/advs.202503389/). This finding suggests that the physical characteristics of Aβ plaques can significantly impact microglial function and contribute to the neuroinflammatory milieu observed in AD. Moreover, Zhang et al. explored the potential of GLP-1 receptor agonists to mitigate Aβ-related phenotypes by activating AMPK signaling, which may offer a neuroprotective strategy against AD (ref: Zhang doi.org/10.1038/s43587-025-00869-3/). In contrast, the study by Raïch et al. highlighted the therapeutic potential of cannabidiol (CBD) in reducing Aβ aggregation and promoting cognitive function, indicating that targeting neuroinflammation may provide a multifaceted approach to AD treatment (ref: Raïch doi.org/10.1186/s13195-025-01756-0/). Additionally, the role of gut microbiota-derived extracellular vesicles in modulating neuroinflammation was emphasized by Xie et al., suggesting that the gut-brain axis may play a significant role in AD pathogenesis (ref: Xie doi.org/10.1080/19490976.2025.2501193/). Overall, these studies highlight the intricate relationship between Aβ, neuroinflammation, and potential therapeutic interventions in Alzheimer's disease.

Genetic and molecular mechanisms play a pivotal role in the development and progression of Alzheimer's disease (AD). Recent research has focused on the impact of specific genes and molecular pathways on neuroinflammatory processes and neuronal health. For instance, Lish et al. demonstrated that clusterin (CLU) modulates astrocyte reactivity and microglia-dependent synaptic density, suggesting that CLU may have protective effects against AD-related processes (ref: Lish doi.org/10.1016/j.neuron.2025.03.034/). This highlights the importance of astrocytic and microglial interactions in maintaining synaptic integrity in the context of neurodegeneration. Furthermore, Shen et al. identified GADD45G as a key regulator of reactive gliosis and neurodegeneration, proposing it as a potential therapeutic target for AD (ref: Shen doi.org/10.1016/j.neuron.2025.04.033/). The role of the STING pathway in AD was also investigated by Thanos et al., who found that STING deletion in a mouse model led to reduced Aβ deposition and improved neuronal health, indicating that modulating this pathway could be beneficial in AD (ref: Thanos doi.org/10.1002/alz.70305/). Additionally, the differential effects of APOE isoforms on microglial responses were highlighted by Murphy et al., reinforcing the notion that genetic predispositions significantly influence the pathophysiological landscape of AD (ref: Murphy doi.org/10.1038/s41467-025-60099-4/). Collectively, these findings underscore the complexity of genetic and molecular interactions in Alzheimer's disease and their implications for therapeutic strategies.

Therapeutic interventions for Alzheimer's disease (AD) are increasingly focusing on targeting the underlying pathophysiological mechanisms rather than just symptomatic relief. Recent studies have explored various pharmacological agents and their potential to modify disease progression. Zhang et al. investigated GLP-1 receptor agonists, demonstrating their ability to activate AMPK signaling and alleviate AD-related phenotypes in transgenic mice, suggesting a promising avenue for neuroprotective therapies (ref: Zhang doi.org/10.1038/s43587-025-00869-3/). In contrast, the clinical trials of semorinemab, a monoclonal antibody targeting tau, revealed challenges in demonstrating clinical efficacy despite its safety profile, highlighting the complexities of targeting tau pathology (ref: Abdel-Haleem doi.org/10.1093/brain/). Moreover, the potential of cannabidiol (CBD) as a multifaceted therapeutic agent was explored by Raïch et al., who found that CBD could decrease Aβ aggregation and improve cognitive function, indicating its neuroprotective properties (ref: Raïch doi.org/10.1186/s13195-025-01756-0/). Additionally, Yu et al. highlighted the neurotoxic effects of nanoplastics on Aβ plaque deposition, suggesting that environmental factors may also play a role in AD pathology and could be targeted for therapeutic intervention (ref: Yu doi.org/10.1016/j.ecoenv.2025.118379/). These studies collectively emphasize the need for a multi-targeted approach in AD therapy, addressing both genetic and environmental factors to improve treatment outcomes.

Environmental and lifestyle factors are increasingly recognized as significant contributors to the risk and progression of Alzheimer's disease (AD). Recent research has focused on the impact of chronic inflammation and environmental toxins on neurodegenerative processes. Eid et al. demonstrated that chronic exposure to lipopolysaccharides (LPS) from pathogens can induce AD-like pathology in mice, suggesting that inflammatory conditions may exacerbate neurodegeneration (ref: Eid doi.org/10.1096/fj.202403117RR/). This highlights the potential role of systemic inflammation in the development of AD, particularly in the context of chronic diseases such as periodontitis and inflammatory bowel disease. In addition, Marongiu et al. explored the effects of perimenopause on neuroinflammation in a mouse model of AD, revealing that hormonal changes may influence disease susceptibility and progression in women (ref: Marongiu doi.org/10.3389/fmolb.2025.1597130/). Furthermore, Du et al. proposed the use of engineered hybrid exosomes as Aβ nanoscavengers and inflammatory modulators, emphasizing the need for innovative therapeutic strategies that address the multifaceted nature of AD pathology (ref: Du doi.org/10.1016/j.biomaterials.2025.123403/). Collectively, these findings underscore the importance of considering environmental and lifestyle factors in the prevention and treatment of Alzheimer's disease.

Neuroinflammation and the immune response are central to the pathophysiology of Alzheimer's disease (AD), with recent studies elucidating the mechanisms by which these processes contribute to neurodegeneration. Lee et al. provided compelling evidence that microglia-driven inflammation can induce tauopathies and synucleinopathies, suggesting that neuroinflammatory responses play a critical role in the progression of neurodegenerative diseases (ref: Lee doi.org/10.1038/s12276-025-01450-z/). This highlights the need for targeted therapies that modulate microglial activation to mitigate neuroinflammation. Additionally, Liu et al. investigated the mechanotransduction pathways activated by Aβ plaques, revealing that the stiffness of these plaques impairs microglial phagocytosis and promotes an inflammatory environment (ref: Liu doi.org/10.1002/advs.202503389/). The NLRP3 inflammasome has also been implicated in AD pathology, with Kurmi et al. discussing its activation by Aβ and the subsequent inflammatory cascade that ensues (ref: Kurmi doi.org/10.2174/0118715273377780250505115039/). Furthermore, the role of cannabidiol (CBD) in modulating neuroinflammation and enhancing cognitive function was highlighted by Raïch et al., indicating its potential as a therapeutic agent in AD (ref: Raïch doi.org/10.1186/s13195-025-01756-0/). These findings collectively emphasize the critical role of neuroinflammation in Alzheimer's disease and the potential for therapeutic interventions targeting immune responses to alter disease outcomes.

Sex differences in Alzheimer's disease (AD) are becoming increasingly recognized, with research highlighting distinct molecular and pathological variations between males and females. Ali et al. examined temporal transcriptomic changes in a tauopathy mouse model, revealing sex-specific differences that may contribute to the varying prevalence and progression of AD (ref: Ali doi.org/10.1186/s40478-025-02013-z/). This underscores the importance of considering sex as a biological variable in AD research and therapeutic development. Marongiu et al. further explored the impact of perimenopause on neuroinflammation in a mouse model of AD, suggesting that hormonal changes during this transition may heighten the risk of developing AD in women (ref: Marongiu doi.org/10.3389/fmolb.2025.1597130/). In contrast, Eid et al. investigated the effects of chronic inflammatory conditions on male mice, demonstrating that LPS exposure can induce AD-like pathology, indicating that both sexes may be affected by environmental factors but potentially through different mechanisms (ref: Eid doi.org/10.1096/fj.202403117RR/). These findings highlight the necessity for tailored approaches in AD research and treatment that account for sex differences in disease susceptibility and progression.