In addition to the characterization of microglial profiles, studies have explored the genetic and environmental factors influencing microglial behavior in AD. Yang et al. showed that genetic variation significantly alters microglial dynamics in response to amyloidosis in various mouse models, indicating that genetic background can affect neuroimmune functions (ref: Yang doi.org/10.1016/j.celrep.2021.108739/). Kenkhuis et al. found that iron accumulation in activated microglia is a prominent feature in AD patients, suggesting a link between iron dysregulation and microglial activation states (ref: Kenkhuis doi.org/10.1186/s40478-021-01126-5/). Moreover, Xue et al. reported that deregulation of Mef2C in microglia correlates with early AD pathology, highlighting the interplay between microglial activation and neuroinflammation (ref: Xue doi.org/10.1016/j.nbd.2021.105272/). Overall, these studies illustrate the multifaceted role of microglia in AD, emphasizing their potential as biomarkers and therapeutic targets.

In addition to identifying risk genes, studies have focused on the functional implications of these genetic variations. Wißfeld et al. demonstrated that deletion of CD33, a gene associated with late-onset AD, leads to an inflammatory phenotype in human microglia, suggesting that CD33 plays a critical role in modulating microglial responses (ref: Wißfeld doi.org/10.1002/glia.23968/). Tsai et al. found that INPP5D expression is upregulated in AD and correlates with amyloid plaque density, indicating its potential as a biomarker for microglial activation in the disease (ref: Tsai doi.org/10.1016/j.nbd.2021.105303/). These studies collectively highlight the intricate relationship between genetic factors and microglial function in AD, paving the way for targeted therapeutic strategies.

Moreover, Rivers-Auty et al. investigated the impact of zinc status on AD progression, revealing that zinc deficiency may exacerbate inflammation through NLRP3-dependent pathways, thereby linking nutritional factors to neuroinflammatory processes in AD (ref: Rivers-Auty doi.org/10.1523/JNEUROSCI.1980-20.2020/). Lanfranco et al. examined the secretion of apoE isoforms by microglia during inflammation, finding that APOE4 microglia exhibited heightened inflammatory responses, which may contribute to the increased risk of AD associated with this allele (ref: Lanfranco doi.org/10.1002/glia.23974/). Collectively, these studies underscore the complex interplay between neuroinflammation and immune responses in AD, highlighting potential targets for therapeutic intervention.

Furthermore, Go et al. investigated the effects of the gut microbiota-derived compound SR79 in APP/PS1 mice, finding that it improved cognitive function and reduced neuroinflammation, thereby presenting a promising avenue for AD treatment through microbiome modulation (ref: Go doi.org/10.1016/j.nutres.2020.12.010/). Zuo et al. demonstrated that Bacille Calmette-Guérin (BCG) treatment, combined with amyloid-β immunotherapy, effectively reduces vascular amyloid pathology and enhances synaptic preservation, indicating that immunotherapeutic strategies may be beneficial in AD management (ref: Zuo doi.org/10.1016/j.neurobiolaging.2021.01.001/). These findings collectively emphasize the potential of diverse therapeutic approaches in addressing the multifactorial nature of AD.

Additionally, Xue et al. reported that deregulation of Mef2C in microglia is associated with early AD pathology, linking microglial changes to brain aging and neuroinflammation (ref: Xue doi.org/10.1016/j.nbd.2021.105272/). Molina-Martínez et al. observed that microglial hyperreactivity evolves into an immunosuppressive state in aging and AD models, suggesting that aging may alter microglial functionality and contribute to disease progression (ref: Molina-Martínez doi.org/10.3389/fnagi.2020.622360/). These studies collectively underscore the importance of understanding microglial heterogeneity and aging in the context of AD, as they may reveal novel therapeutic targets and strategies.

Moreover, Kenkhuis et al. found that iron accumulation in activated microglia is a prominent feature in AD patients, which may exacerbate neuroinflammation and accelerate disease progression (ref: Kenkhuis doi.org/10.1186/s40478-021-01126-5/). Wenzel et al. reported that extracellular cardiolipin modulates microglial phagocytosis and cytokine secretion, further illustrating the complex interactions between microglial activity and amyloid pathology (ref: Wenzel doi.org/10.1016/j.jneuroim.2021.577496/). These findings highlight the critical role of microglia in mediating the effects of amyloid and tau pathology in AD, emphasizing the need for integrated therapeutic approaches.

Additionally, Yu et al. isolated novel oligosaccharides from Kunlun Chrysanthemum flower tea, which have been traditionally used in folk medicine for their potential health benefits, including in AD (ref: Yu doi.org/10.1016/j.fct.2021.112032/). Alghamdi et al. synthesized analogs of the selective CB2 inverse agonist SMM-189, demonstrating enhanced potency and efficacy in regulating neuroinflammation, which could have implications for AD treatment (ref: Alghamdi doi.org/10.1016/j.bmc.2021.116035/). These studies collectively highlight the potential of identifying neuroprotective mechanisms and biomarkers that could inform therapeutic strategies for AD.