Microglia play a crucial role in the pathogenesis of Alzheimer's disease (AD), particularly through their interaction with amyloid plaques. Choi et al. demonstrated that autophagy activation in microglia is essential for their engagement with amyloid plaques, and inhibiting this process leads to microglial disengagement and worsened neuropathology in AD mouse models (ref: Choi doi.org/10.1038/s41556-023-01158-0/). Prater et al. provided insights into the transcriptional changes in human microglia associated with AD, revealing diverse functional phenotypes that complicate therapeutic targeting (ref: Prater doi.org/10.1038/s43587-023-00424-y/). Furthermore, Lantz et al. found that N-terminal amyloid-beta fragments can reverse gliosis and gliotoxicity in AD models, highlighting the potential for targeting microglial responses to amyloid pathology (ref: Lantz doi.org/10.1186/s12974-023-02807-9/). The role of microglial receptors, such as P2X4, was further elucidated by Hua et al., who showed that these receptors contribute to ApoE degradation and memory deficits in AD (ref: Hua doi.org/10.1007/s00018-023-04784-x/). Additionally, Meng et al. linked microglial activation to cognitive impairment induced by circadian rhythm disruption, suggesting that microglial responses are influenced by environmental factors (ref: Meng doi.org/10.1016/j.jneuroim.2023.578102/). Overall, these studies underscore the multifaceted roles of microglia in AD pathology, from their engagement with amyloid plaques to their response to systemic and environmental changes.

Neuroinflammation is a critical component of Alzheimer's disease pathology, with the NLRP3 inflammasome emerging as a key player. Li et al. demonstrated that inhibiting the NLRP3 inflammasome alleviates cognitive decline and AD-like changes in a chronic unpredictable mild stress model, suggesting a protective role against neuroinflammation (ref: Li doi.org/10.1186/s12974-023-02791-0/). Canepa et al. explored the therapeutic potential of FDA-approved carbonic anhydrase inhibitors, showing that these compounds reduce amyloid beta pathology and improve cognitive function by enhancing cerebrovascular health (ref: Canepa doi.org/10.1002/alz.13063/). Ibrahim et al. investigated the effects of scoparone on microglial polarization, revealing that it shifts M1 to M2 polarization and inhibits the TLR4 axis, which is crucial for mitigating neuroinflammation in AD models (ref: Ibrahim doi.org/10.1016/j.intimp.2023.110239/). Peng et al. highlighted the neuroprotective effects of thymopentin against lipopolysaccharide-induced neuroinflammation, linking its mechanism to the NF-kB/NLRP3 signaling pathway (ref: Peng doi.org/10.1016/j.intimp.2023.110109/). Wu et al. further elucidated the role of the cGAS-STING pathway in Aβ-induced neuroinflammation, indicating that microglial activation is a significant contributor to AD pathogenesis (ref: Wu doi.org/10.1007/s11064-023-03945-5/). Collectively, these studies emphasize the importance of targeting neuroinflammatory pathways as a therapeutic strategy in AD.

Innovative therapeutic strategies are crucial for addressing the challenges posed by Alzheimer's disease. Wang et al. reported that extracellular vesicles secreted by microglia, particularly macrosomes, significantly reduce amyloid-beta burden and ameliorate AD pathology, indicating a novel approach to therapy (ref: Wang doi.org/10.1126/sciadv.ade0293/). Canepa et al. also highlighted the efficacy of carbonic anhydrase inhibitors in reducing amyloid pathology and improving cognition, reinforcing the potential of repurposing existing drugs for AD treatment (ref: Canepa doi.org/10.1002/alz.13063/). Ju et al. investigated the neuroprotective effects of Andrographolide, demonstrating its ability to regulate the LRP1-mediated PPARγ/NF-kB pathway, which is crucial for mitigating neuroinflammation and promoting neuronal health (ref: Ju doi.org/10.1016/j.ejphar.2023.175756/). Liu et al. examined the interaction between environmental cadmium exposure and genetic factors in AD progression, suggesting that environmental modifications could be a target for therapeutic intervention (ref: Liu doi.org/10.3233/JAD-221205/). Nakanishi et al. explored the effects of physical exercise on neuroinflammation and neuronal loss, providing evidence for lifestyle interventions as a complementary therapeutic strategy (ref: Nakanishi doi.org/10.1016/j.neulet.2023.137297/). These findings collectively highlight the diverse avenues for therapeutic intervention in AD, ranging from pharmacological approaches to lifestyle modifications.

Genetic factors play a significant role in the susceptibility and progression of Alzheimer's disease. Chernyaeva et al. elucidated how the APOE4 variant affects amyloid-beta oligomerization and neuroinflammation, revealing that reduced binding of apoE4 to complement factor H promotes neurotoxic effects (ref: Chernyaeva doi.org/10.15252/embr.202256467/). Meuret et al. investigated the glycosylation profiles of apoE in cerebrospinal fluid, finding that the E4 isoform exhibits lower glycosylation, which may influence its role in AD pathology (ref: Meuret doi.org/10.1186/s13195-023-01239-0/). Cosma et al. focused on TREM2, a receptor implicated in AD, demonstrating that macrophage differentiation modulates TREM2 expression, which may have therapeutic implications (ref: Cosma doi.org/10.1007/s10571-023-01351-7/). Ibrahim et al. also highlighted the role of NLRP3 inflammasome inhibition in shifting microglial polarization, further linking genetic and molecular mechanisms to neuroinflammatory processes in AD (ref: Ibrahim doi.org/10.1016/j.intimp.2023.110239/). Walgrave et al. examined the role of microRNA-132 in microglial homeostasis, showing that its supplementation can ameliorate amyloid and tau pathologies, suggesting a potential therapeutic target (ref: Walgrave doi.org/10.1016/j.isci.2023.106829/). Together, these studies underscore the complex interplay between genetic factors and molecular pathways in the context of Alzheimer's disease.

Cognitive impairment in Alzheimer's disease is closely linked to neurodegenerative processes and neuroinflammation. Kuchroo et al. utilized single-cell analysis to identify inflammatory interactions that drive neurodegeneration, revealing common pathways between age-related macular degeneration and Alzheimer's disease, which may inform therapeutic strategies (ref: Kuchroo doi.org/10.1038/s41467-023-37025-7/). Meng et al. connected microglial activation to cognitive impairment resulting from circadian rhythm disruption, suggesting that lifestyle factors may exacerbate cognitive decline in AD (ref: Meng doi.org/10.1016/j.jneuroim.2023.578102/). Gama Sosa et al. investigated the effects of repetitive low-level blast overpressures on cognitive decline and neuroinflammation, indicating that environmental stressors can contribute to neuropsychiatric disorders (ref: Gama Sosa doi.org/10.1186/s40478-023-01553-6/). Li et al. explored the relationship between menopause and AD, identifying radiomic features that correlate with cognitive decline and neuroinflammation in both human and animal models (ref: Li doi.org/10.1093/cercor/). Wei et al. examined the effects of N,N-dimethylacetamide on neuroinflammation, demonstrating its potential to target inflammatory pathways associated with cognitive impairment (ref: Wei doi.org/10.1038/s41598-023-34355-w/). These findings highlight the multifactorial nature of cognitive impairment in AD, emphasizing the need for comprehensive approaches to address both neurodegenerative and environmental factors.

Cellular interactions, particularly between microglia and astrocytes, are pivotal in the neurodegenerative processes of Alzheimer's disease. Kerrebijn et al. employed virtual histology to elucidate the cell types associated with cortical thickness differences in AD, revealing that altered cellular composition may contribute to disease pathology (ref: Kerrebijn doi.org/10.1016/j.neuroimage.2023.120177/). Li et al. investigated the role of Contactin 1 (CNTN1) in neuroinflammation, demonstrating that it exacerbates cognitive deficits by enhancing crosstalk between microglia and astrocytes (ref: Li doi.org/10.14336/AD.2023.0228/). Chinnathambi et al. focused on the mechanisms by which microglia degrade tau oligomers, highlighting the importance of purinergic signaling in mediating microglial migration and tau clearance (ref: Chinnathambi doi.org/10.1186/s13578-023-01028-0/). Wei et al. also contributed to this theme by showing that N,N-dimethylacetamide targets neuroinflammation through the NF-kB signaling pathway, further linking cellular interactions to neuroinflammatory responses in AD (ref: Wei doi.org/10.1038/s41598-023-34355-w/). Nakanishi et al. examined the effects of exercise on neuroinflammation and neuronal loss, suggesting that physical activity may modulate cellular interactions to promote neuroprotection (ref: Nakanishi doi.org/10.1016/j.neulet.2023.137297/). Collectively, these studies underscore the significance of cellular interactions in the pathogenesis of Alzheimer's disease and their potential as therapeutic targets.

Environmental and lifestyle factors significantly influence the progression of Alzheimer's disease. Liu et al. investigated the interaction between genetic predisposition and environmental cadmium exposure, finding that low-dose cadmium exacerbates AD progression in mice, highlighting the importance of environmental toxins in disease etiology (ref: Liu doi.org/10.3233/JAD-221205/). Ibrahim et al. explored the effects of scoparone on microglial polarization, suggesting that lifestyle interventions may modulate neuroinflammatory responses in AD (ref: Ibrahim doi.org/10.1016/j.intimp.2023.110239/). Elzinga et al. examined the cGAS/STING pathway's role in obesity and prediabetes, linking metabolic dysfunction to neurodegenerative diseases, including AD (ref: Elzinga doi.org/10.3389/fncel.2023.1167688/). Ju et al. highlighted the neuroprotective effects of Andrographolide, which may be influenced by lifestyle factors affecting inflammation (ref: Ju doi.org/10.1016/j.ejphar.2023.175756/). Nakanishi et al. provided evidence for the benefits of physical exercise in preventing cognitive decline and neuroinflammation, reinforcing the role of lifestyle modifications in AD prevention (ref: Nakanishi doi.org/10.1016/j.neulet.2023.137297/). These findings collectively emphasize the need for a holistic approach to Alzheimer's disease that considers both genetic and environmental factors.