Microglial cells play a crucial role in the pathogenesis of Alzheimer's disease (AD), particularly through their response to amyloid-beta (Aβ) and tau pathology. Variants of the triggering receptor expressed on myeloid cells 2 (TREM2) have been shown to increase AD risk, with studies indicating that TREM2 is essential for the activation of disease-associated microglia (DAM) in mouse models. Zhou et al. utilized single-nucleus RNA sequencing to reveal TREM2-dependent and TREM2-independent cellular responses in both human and mouse models of AD, highlighting the complexity of microglial responses to AD pathology (ref: Zhou doi.org/10.1038/s41591-019-0695-9/). Nugent et al. further elucidated the role of TREM2 in regulating microglial cholesterol metabolism during chronic phagocytic challenges, demonstrating that TREM2-deficient microglia fail to adopt a disease-associated transcriptional state, leading to neuronal damage (ref: Nugent doi.org/10.1016/j.neuron.2019.12.007/). Additionally, El Gaamouch et al. explored the modulation of microglial function through VGF-derived peptides, showing that TLQP-21 can influence microglial activity via C3aR1 signaling pathways, which may reduce neuropathology in AD models (ref: El Gaamouch doi.org/10.1186/s13024-020-0357-x/). These findings collectively underscore the pivotal role of microglial activation and the influence of genetic factors like TREM2 in AD pathology, while also suggesting potential therapeutic avenues targeting microglial dysfunction.

The genetic landscape of Alzheimer's disease (AD) is complex, with numerous studies identifying risk genes that influence disease progression and pathology. Sierksma et al. investigated the impact of novel Alzheimer risk genes on microglial responses to amyloid-beta and tau pathology, revealing that certain genetic variants can modulate the transcriptional responses of microglia in mouse models (ref: Sierksma doi.org/10.15252/emmm.201910606/). This highlights the importance of genetic predisposition in shaping the neuroinflammatory environment in AD. Furthermore, Imamura et al. demonstrated that insulin deficiency promotes the formation of toxic amyloid-beta conformers, exacerbating neuroinflammation and cognitive decline in AD models (ref: Imamura doi.org/10.1016/j.nbd.2020.104739/). The role of mitochondrial dysfunction was also emphasized by Ren et al., who developed mitochondria-targeted nanozymes to address oxidative stress and Aβ accumulation, suggesting that targeting mitochondrial health could be a viable therapeutic strategy (ref: Ren doi.org/10.1016/j.biomaterials.2019.119752/). Collectively, these studies underscore the interplay between genetic factors, metabolic dysregulation, and mitochondrial health in the pathophysiology of AD, paving the way for targeted interventions.

Neuroinflammation is increasingly recognized as a key contributor to cognitive impairment in Alzheimer's disease (AD). Giridharan et al. demonstrated that neuroinflammation trajectories following experimental meningitis precede cognitive deficits, suggesting that early inflammatory responses can have long-lasting effects on cognitive function (ref: Giridharan doi.org/10.1186/s12974-019-1692-0/). Similarly, Sankar et al. found that diabetic conditions exacerbate neuroinflammatory responses and Aβ pathology in AD mouse models, indicating a synergistic effect of metabolic dysregulation and neuroinflammation on cognitive decline (ref: Sankar doi.org/10.1186/s12974-020-1707-x/). Ivanova et al. further supported these findings by showing that metabolic syndrome exacerbates white matter inflammation and cognitive deficits in a rat model of prodromal AD (ref: Ivanova doi.org/10.1186/s12974-020-1698-7/). These studies collectively highlight the critical role of neuroinflammation in the progression of cognitive impairment in AD, suggesting that targeting inflammatory pathways may offer therapeutic benefits.

Recent research has focused on developing therapeutic interventions aimed at modulating microglial function to combat Alzheimer's disease (AD). Liu et al. introduced a zwitterionic nanoparticle designed to normalize dysfunctional microglia and facilitate Aβ clearance, demonstrating significant potential for treating AD by addressing the vicious cycle of microglial dysfunction and amyloid accumulation (ref: Liu doi.org/10.1002/advs.201901555/). Gunesch et al. explored the neuroprotective effects of taxifolin esters, which exhibited pronounced anti-neuroinflammatory properties and improved cognitive outcomes in AD models, suggesting that natural compounds may provide a low-toxicity alternative for AD treatment (ref: Gunesch doi.org/10.1016/j.redox.2019.101378/). Additionally, Ano et al. reported that β-lactolin, a whey-derived peptide, can prevent AD pathologies and cognitive decline, further emphasizing the potential of dietary interventions in AD management (ref: Ano doi.org/10.3233/JAD-190997/). These findings collectively underscore the promise of targeting microglial activity and exploring natural compounds as therapeutic strategies for AD.

Amyloid-beta (Aβ) continues to be a focal point in Alzheimer's disease (AD) research, with numerous studies investigating its role in disease progression and neuroinflammation. Liu et al. developed an 'Aβ cleaner' nanoparticle aimed at normalizing microglial dysfunction and enhancing Aβ clearance, highlighting the potential for targeted therapies that address the pathological cycle of Aβ accumulation and microglial activation (ref: Liu doi.org/10.1002/advs.201901555/). Sankar et al. further elucidated the interaction between diabetes and Aβ pathology, demonstrating that diabetic conditions can amplify neuroinflammatory responses and Aβ deposition in AD models, thereby linking metabolic health to AD progression (ref: Sankar doi.org/10.1186/s12974-020-1707-x/). Das et al. examined the phagocytic activity of microglia in response to tau oligomers, revealing that Aβ and tau pathology can synergistically drive neuroinflammation and cognitive decline (ref: Das doi.org/10.1186/s12974-019-1694-y/). These studies collectively reinforce the central role of Aβ in AD pathology and the need for therapeutic strategies that target both Aβ accumulation and the associated neuroinflammatory responses.

Environmental and lifestyle factors have been increasingly recognized as significant contributors to the risk and progression of Alzheimer's disease (AD). Hashiguchi et al. demonstrated that resistance exercise can decrease amyloid load and modulate inflammatory responses in the APP/PS1 mouse model, suggesting that physical activity may have protective effects against AD pathology (ref: Hashiguchi doi.org/10.3233/JAD-190729/). Conversely, Svensson et al. reported that voluntary running did not yield beneficial effects on neuroinflammation or cognitive behavior in the 5xFAD mouse model, raising questions about the efficacy of certain types of exercise in AD prevention (ref: Svensson doi.org/10.1038/s41598-020-58309-8/). Ano et al. highlighted the potential of β-lactolin, a whey-derived peptide, in preventing AD pathologies and cognitive decline, indicating that dietary interventions could play a role in mitigating AD risk (ref: Ano doi.org/10.3233/JAD-190997/). These findings underscore the complex interplay between lifestyle factors and AD, suggesting that both physical activity and dietary choices may influence disease outcomes.