Microglial activation plays a pivotal role in the pathogenesis of Alzheimer's disease (AD), influencing both neuroinflammation and synaptic integrity. A study by Jin et al. highlights how type-I interferon signaling can drive microglial dysfunction and senescence in human iPSC models of Down syndrome and AD, suggesting that targeting this pathway may rescue microglial phenotypes during brain development and in response to pathological tau (ref: Jin doi.org/10.1016/j.stem.2022.06.007/). In a sex-specific analysis, Casaletto et al. found that microglial activation mediates a significant portion of the relationship between amyloid-β and tau in females (57%) compared to males (19%), indicating that therapeutic strategies may need to consider sex differences in microglial responses (ref: Casaletto doi.org/10.1093/brain/). Furthermore, Fracassi et al. demonstrated that TREM2-induced microglial activation contributes to synaptic integrity in cognitively intact individuals with AD neuropathology, suggesting that enhancing TREM2 signaling could be a potential therapeutic target (ref: Fracassi doi.org/10.1111/bpa.13108/). Collectively, these studies underscore the complexity of microglial roles in AD, where both protective and detrimental effects are observed depending on the context and underlying mechanisms involved.

Neuroinflammation is a critical component of Alzheimer's disease pathology, with various studies elucidating its mechanisms and implications. Gan et al. provided evidence that monomeric C-reactive protein (mCRP) can induce cellular pathology associated with AD by increasing amyloid beta production and tau phosphorylation in primary neurons, highlighting the inflammatory pathways that contribute to neurodegeneration (ref: Gan doi.org/10.1002/trc2.12319/). Additionally, Španić et al. identified the NLRP1 inflammasome as significantly more active in the hippocampal formation of AD brains, suggesting its potential as a diagnostic marker and therapeutic target (ref: Španić doi.org/10.3390/cells11142223/). The interplay between neuroinflammation and neurovascular dysfunction was further explored by Gerrits et al., who utilized single-nucleus RNA sequencing to reveal alterations in microglia and astrocytes in frontotemporal dementia, a condition closely related to AD (ref: Gerrits doi.org/10.1038/s41593-022-01124-3/). These findings collectively emphasize the multifaceted role of neuroinflammation in AD, where it contributes to both neuronal damage and the progression of cognitive decline.

The genetic landscape of Alzheimer's disease is complex, with several studies identifying key molecular mechanisms that may influence disease progression. Solomon et al. investigated the protective PLCG2 P522R variant, demonstrating that its heterozygous expression enhances amyloid beta clearance while preserving synaptic integrity, suggesting a potential genetic target for therapeutic intervention (ref: Solomon doi.org/10.1007/s00018-022-04473-1/). In contrast, Zhang et al. explored the effects of Demethylenetetrahydroberberine (DMTHB) on neuroinflammation in AD mice, showing that it ameliorates memory impairment by regulating inflammatory responses (ref: Zhang doi.org/10.1016/j.neulet.2022.136770/). Furthermore, Gupta et al. utilized single-cell network biology to characterize gene dysregulation in AD, providing insights into potential drug repurposing strategies based on cell-type specific gene regulation (ref: Gupta doi.org/10.1371/journal.pcbi.1010287/). These studies highlight the importance of understanding genetic variants and molecular pathways in developing targeted therapies for AD.

Therapeutic strategies targeting microglia have emerged as promising avenues for Alzheimer's disease treatment. Piec et al. demonstrated that muramyl dipeptide administration can delay AD physiopathology via NOD2 receptors, suggesting that modulating innate immune responses could improve cognitive outcomes (ref: Piec doi.org/10.3390/cells11142241/). Additionally, La Rosa et al. explored the effects of Stavudine (D4T) on autophagy and inflammation in peripheral blood mononuclear cells from AD patients, finding that D4T reduces NLRP3 inflammasome activation and may stimulate autophagy, presenting a dual mechanism of action (ref: La Rosa doi.org/10.3390/cells11142180/). Moreover, Go et al. reported that Humulus japonicus significantly improved cognitive dysfunction and reduced microglial activation in mouse models, indicating its potential as a natural therapeutic agent (ref: Go doi.org/10.1186/s42826-022-00134-3/). Collectively, these studies illustrate the potential of targeting microglial function and inflammation as a therapeutic strategy in Alzheimer's disease.

Research into sex differences in microglial function has revealed significant disparities in their roles in Alzheimer's disease. Casaletto et al. found that microglial activation mediates a greater proportion of the amyloid-β to tau relationship in females (57%) compared to males (19%), suggesting that sex-specific mechanisms may influence disease progression (ref: Casaletto doi.org/10.1093/brain/). O'Neill et al. further demonstrated that female AD patients exhibit a higher prevalence of dystrophic and rod-shaped microglia, alongside increased iron accumulation, which may reflect underlying mitochondrial changes and contribute to neurodegeneration (ref: O'Neill doi.org/10.3389/fncel.2022.939830/). Espinosa et al. explored how lipophilic bioactive compounds can modulate microglial inflammatory responses, indicating that dietary factors may differentially affect microglial function based on sex (ref: Espinosa doi.org/10.3390/ijms23147706/). These findings underscore the necessity of considering sex differences in the development of therapeutic strategies for Alzheimer's disease.

Comorbidities significantly influence the pathophysiology and progression of Alzheimer's disease. Wang et al. investigated the effects of recurrent transient ischemic attacks (TIA) on neural cytoskeleton modification and gliosis, demonstrating that TIA can trigger neuroinflammation and cytoskeletal changes that may contribute to cognitive impairment and dementia (ref: Wang doi.org/10.1007/s12975-022-01068-7/). Serrano et al. examined the impact of COVID-19 on the brain, finding SARS-CoV-2 viral sequences in various brain regions of decedents, which may exacerbate neuroinflammatory processes and contribute to cognitive decline (ref: Serrano doi.org/10.1093/jnen/). Additionally, Gerrits et al. highlighted neurovascular dysfunction in frontotemporal dementia, which shares pathological features with Alzheimer's disease, emphasizing the interconnectedness of these conditions (ref: Gerrits doi.org/10.1038/s41593-022-01124-3/). These studies illustrate the complex interplay between comorbidities and Alzheimer's disease, suggesting that addressing these factors may be crucial for effective management.

The integrity of the blood-brain barrier (BBB) is crucial in Alzheimer's disease, with its dysfunction contributing to disease progression. Situ et al. reported that cerebral amyloid angiopathy, characterized by amyloid β deposition, leads to BBB remodeling and increased permeability, which exacerbates neuroinflammation and cognitive decline (ref: Situ doi.org/10.3389/fncel.2022.931247/). Espinosa et al. further explored how lipophilic bioactive compounds can modulate microglial inflammatory responses, potentially influencing BBB integrity and function (ref: Espinosa doi.org/10.3390/ijms23147706/). Moreover, Piec et al. demonstrated that muramyl dipeptide administration can delay Alzheimer's disease physiopathology via NOD2 receptors, suggesting that targeting innate immune responses may also impact BBB function (ref: Piec doi.org/10.3390/cells11142241/). Collectively, these studies highlight the critical role of the BBB in Alzheimer's disease and the potential for therapeutic strategies that target BBB integrity and function.