Microglia play a critical role in the pathophysiology of Alzheimer's disease (AD), with recent studies highlighting the influence of apolipoprotein E (APOE) isoforms on microglial activity. Liu et al. demonstrated that the presence of APOE4 restricts microglial activation and function, which is crucial for maintaining brain homeostasis and responding to AD pathology (ref: Liu doi.org/10.1038/s41590-023-01640-9/). This finding is corroborated by Kiani et al., who identified a VCAM1-APOE pathway that facilitates microglial migration towards amyloid-β plaques, suggesting that APOE isoforms may differentially affect microglial responses to amyloid pathology (ref: Kiani doi.org/10.1038/s41582-023-00885-0/). Furthermore, Taddei et al. explored the relationship between tau oligomers and synapse elimination, revealing that microglia and astrocytes significantly internalize synaptic elements in dementia-affected brains, with microglial involvement being markedly higher in dementia compared to resilient individuals (ref: Taddei doi.org/10.1001/jamaneurol.2023.3530/). These studies collectively underscore the complex interplay between microglial function, APOE isoforms, and synaptic integrity in the context of AD, highlighting potential therapeutic targets for modulating neuroinflammation and synaptic health in this disease.

The role of APOE in neuroinflammation and its implications for Alzheimer's disease have garnered significant attention. Wogram et al. investigated how different APOE isoforms affect brain energy metabolism, finding that APOE2 promotes better glucose uptake compared to APOE4, which is associated with impaired metabolic profiles (ref: Wogram doi.org/10.1038/s41590-023-01651-6/). This metabolic dysfunction may contribute to the neuroinflammatory processes observed in AD. Koutsodendris et al. further elucidated the mechanisms by which APOE4 exacerbates tau pathology and gliosis, linking the release of HMGB1 from neurons to increased microgliosis and neurodegeneration (ref: Koutsodendris doi.org/10.1016/j.celrep.2023.113252/). Additionally, Zhang et al. highlighted the protective role of soluble TREM2 in modulating tau phosphorylation and cognitive deficits, suggesting that TREM2 may interact with APOE pathways to influence neuroinflammatory responses (ref: Zhang doi.org/10.1038/s41467-023-42505-x/). Together, these studies illustrate the multifaceted role of APOE in neuroinflammation, emphasizing its potential as a therapeutic target in AD.

Tau pathology is a hallmark of Alzheimer's disease, and its relationship with synaptic dysfunction has been extensively studied. Taddei et al. provided compelling evidence that tau oligomers are associated with excessive synapse elimination by microglia and astrocytes, particularly in dementia-affected brains, where significant losses of presynaptic and postsynaptic elements were observed (ref: Taddei doi.org/10.1001/jamaneurol.2023.3530/). This study revealed that microglia internalized a higher percentage of mature synapses in dementia compared to resilient individuals, suggesting that tau oligomers may drive synaptic loss through microglial activation. In a related context, Wu et al. explored the immune response to Candida albicans in the brain, highlighting the role of microglia in clearing fungal infections, which may also intersect with tau pathology and neuroinflammation (ref: Wu doi.org/10.1016/j.celrep.2023.113240/). These findings underscore the importance of understanding the interplay between tau pathology, synaptic integrity, and immune responses in the progression of Alzheimer's disease.

Neuroinflammation is a critical factor in the pathogenesis of Alzheimer's disease, with various studies elucidating the immune mechanisms involved. Kiraly et al. emphasized that neuroinflammation often precedes clinical symptoms of AD, highlighting the need for understanding the interactions between the central nervous system and the immune system to develop preventive strategies (ref: Kiraly doi.org/10.14283/jpad.2023.109/). Balu et al. investigated the effects of a small-molecule TLR4 antagonist on neuroinflammation in E4FAD mice, demonstrating that targeting TLR4 can mitigate neuroinflammatory responses associated with APOE4 (ref: Balu doi.org/10.1186/s13195-023-01330-6/). Furthermore, Son et al. reported that side-chain immune oxysterols activate microglia and induce IL-1β expression, linking lipid metabolism to neuroinflammatory processes (ref: Son doi.org/10.3390/ijms242015288/). Collectively, these studies highlight the intricate relationship between neuroinflammation and immune responses in Alzheimer's disease, suggesting that modulating these pathways could offer therapeutic avenues.

Therapeutic strategies targeting microglial function and neuroinflammation are emerging as promising approaches in Alzheimer's disease management. Kantor et al. proposed a fibrin-targeting immunotherapy, demonstrating that disrupting the blood-brain barrier and targeting fibrin can activate innate immune responses beneficial for neurodegenerative diseases (ref: Kantor doi.org/10.14283/jpad.2023.105/). Balu et al. also explored the potential of a TLR4 antagonist to reduce neuroinflammation in E4FAD mice, suggesting that modulating TLR4 signaling could be a viable strategy to address APOE-related neuroinflammation (ref: Balu doi.org/10.1186/s13195-023-01330-6/). Additionally, Li et al. investigated hydrocortisone's effects on cognitive decline in AD, revealing its potential to mitigate oxidative stress and neuroinflammation (ref: Li doi.org/10.3390/cells12192348/). These studies collectively indicate that targeting microglial activity and neuroinflammatory pathways may provide effective therapeutic strategies for Alzheimer's disease.

Recent research has focused on identifying genetic markers and shared biomarkers between Alzheimer's disease and other conditions, such as myocardial infarction. Xue et al. utilized single-cell sequencing to uncover significant differences in RGS1 expression in macrophages and microglia between disease groups, suggesting its potential as a biomarker for both Alzheimer's disease and myocardial infarction (ref: Xue doi.org/10.3233/JAD-230559/). Bian et al. explored the effects of rivaroxaban on white matter integrity in a mouse model of Alzheimer's disease combined with cerebral hypoperfusion, indicating that anticoagulants may influence neurodegenerative processes (ref: Bian doi.org/10.3233/JAD-230413/). Furthermore, Son et al. examined the role of side-chain oxysterols in inducing neuroinflammation, linking lipid metabolism to microglial activation and potential biomarkers for Alzheimer's disease (ref: Son doi.org/10.3390/ijms242015288/). These findings highlight the importance of genetic and biomarker research in understanding Alzheimer's disease and developing targeted interventions.

Aging is a significant risk factor for neurodegenerative diseases, including Alzheimer's disease, and chronic neuroinflammation plays a pivotal role in this process. Gamage et al. demonstrated that chronic neuroinflammation leads to cholinergic neurodegeneration in the medial septum of aging mice, providing insights into the mechanisms underlying cognitive decline associated with aging (ref: Gamage doi.org/10.1186/s12974-023-02897-5/). Boboc et al. investigated the impact of chronic administration of ion channel blockers on microglial morphology and function in a murine model of Alzheimer's disease, revealing that systemic medications could influence microglial responses in the context of neuroinflammation (ref: Boboc doi.org/10.3390/ijms241914474/). Additionally, Kiraly et al. emphasized the need to understand the interactions between the central nervous system and the immune system in aging-related neurodegeneration (ref: Kiraly doi.org/10.14283/jpad.2023.109/). These studies collectively underscore the importance of addressing aging-related neuroinflammation in the prevention and treatment of Alzheimer's disease.

Metabolic factors significantly influence microglial activity and their role in neuroinflammation. Jin et al. explored the effects of the ketone body β-hydroxybutyrate on microglial metabolism, demonstrating that it can suppress amyloid-β oligomer-induced inflammation in human microglia (ref: Jin doi.org/10.1096/fj.202301254R/). This finding suggests that metabolic interventions may modulate microglial responses and potentially mitigate neuroinflammation in Alzheimer's disease. Du et al. identified moesin and CD44 as hub proteins linked to Alzheimer's disease traits, indicating that metabolic pathways may intersect with microglial function and disease progression (ref: Du doi.org/10.1016/j.jbc.2023.105382/). Furthermore, Kiraly et al. emphasized the need to understand the interactions between metabolism and immune responses in the context of neurodegeneration (ref: Kiraly doi.org/10.14283/jpad.2023.109/). Together, these studies highlight the critical role of metabolic influences on microglial activity and their implications for Alzheimer's disease.