Microglial activation plays a crucial role in the pathogenesis of Alzheimer's disease (AD), particularly through its relationship with neuroinflammation and cognitive decline. A study found that tau pathology and neuroinflammation, assessed via PET imaging, predicted cognitive decline in patients with symptomatic AD, highlighting the importance of temporo-parietal tau pathology and anterior temporal neuroinflammation (ref: Malpetti doi.org/10.1093/brain/). Another longitudinal PET study demonstrated a biphasic trajectory of inflammation in prodromal AD, where microglial activation correlated with rising beta-amyloid loads, suggesting that inflammation may initially increase before declining as tau tangles form (ref: Ismail doi.org/10.1186/s12974-020-01820-6/). Furthermore, research indicated that N-AS-triggered specialized pro-resolving mediators (SPMs) can enhance microglial phagocytosis and improve memory in AD models, emphasizing the potential for therapeutic strategies targeting microglial function (ref: Lee doi.org/10.1038/s41467-020-16080-4/). Contradictory findings regarding the role of microglial activation in early-onset AD suggest that while neuroinflammation is a common theme, the specific mechanisms may differ based on the age of onset (ref: Tondo doi.org/10.1186/s13195-020-00619-0/). Overall, these studies underscore the complex interplay between microglial activation, neuroinflammation, and cognitive outcomes in AD, suggesting that targeting these pathways could offer new therapeutic avenues.

Recent advancements in proteomics and genetic studies have shed light on the role of microglia in Alzheimer's disease. A study utilizing flow-cytometric sorting and quantitative proteomics identified moesin as a highly abundant microglial protein relevant to AD, providing insights into the molecular underpinnings of microglial function (ref: Rayaprolu doi.org/10.1186/s13024-020-00377-5/). Additionally, research on human induced pluripotent stem cell-derived microglia has revealed their potential as a model for studying neuroimmune interactions in AD and related disorders, highlighting the genetic relevance of these cells in understanding disease mechanisms (ref: Butler Iii doi.org/10.1159/000501935/). Gene ontology curation of microglial proteins implicated in AD has improved the interpretation of gene expression data, facilitating a deeper understanding of the inflammatory processes involved (ref: Kramarz doi.org/10.3233/JAD-200207/). Furthermore, studies have explored the role of tumor necrosis factor-alpha (TNF-α) in modulating AD-like phenotypes in mouse models, suggesting that peripheral TNF-α influences brain inflammation and pathology (ref: Kalovyrna doi.org/10.1038/s41598-020-65378-2/). Collectively, these findings emphasize the importance of proteomic and genetic approaches in elucidating the complex roles of microglia in AD pathology.

Therapeutic strategies targeting microglia and neuroinflammation are gaining traction in the quest to mitigate Alzheimer's disease progression. Recent studies have explored various compounds, such as co-ultramicronized palmitoylethanolamide and luteolin, which have shown promise in addressing early-stage AD by inducing cellular and molecular modifications (ref: Facchinetti doi.org/10.3390/ijms21113802/). Additionally, the neuroprotective effects of tormentic acid have been demonstrated in mouse models, where it reduced neuroinflammation and cognitive impairments associated with AD (ref: Cui doi.org/10.3892/mmr.2020.11154/). Graphene oxide has also been investigated for its ability to enhance beta-amyloid clearance through autophagy induction in microglia and neurons, presenting a novel approach to address amyloid deposition in the brain (ref: Li doi.org/10.1016/j.cbi.2020.109126/). Moreover, natural compounds like gelsemine have shown potential in alleviating cognitive deficits and neuroinflammatory responses in AD models, indicating a shift towards utilizing traditional medicinal resources in therapeutic development (ref: Chen doi.org/10.1007/s00213-020-05522-y/). These findings collectively highlight the diverse range of therapeutic approaches being explored to target microglial activation and neuroinflammation in Alzheimer's disease.

Neurodegeneration and cognitive decline are central features of Alzheimer's disease, with various studies elucidating their underlying mechanisms. Research has shown that neuroaxonal degeneration correlates with both gray matter demyelination and white matter tract pathology, contributing to clinical deterioration in neurodegenerative conditions (ref: Kiljan doi.org/10.1177/1352458520918978/). In a transgenic mouse model, the deletion of Nrf2 exacerbated AD-like pathology, indicating that oxidative stress and neuroinflammation play critical roles in cognitive impairment (ref: Ren doi.org/10.1155/2020/). Additionally, the overexpression of TREM2 in the hippocampus has been linked to ameliorating cognitive deficits and modulating microglial polarization, suggesting a protective role against neurodegeneration (ref: Wu doi.org/10.1016/j.gendis.2020.05.005/). These findings underscore the multifactorial nature of neurodegeneration in Alzheimer's disease, highlighting the interplay between neuroinflammation, oxidative stress, and cognitive decline, and suggesting potential targets for therapeutic intervention.

The interplay between Aβ and tau pathology is a critical area of research in understanding Alzheimer's disease progression. Longitudinal studies have demonstrated that rising tau loads in mild cognitive impairment (MCI) patients correlate with increased neuroinflammation, suggesting that tau pathology may exacerbate inflammatory responses in the brain (ref: Ismail doi.org/10.1186/s12974-020-01820-6/). Moreover, compounds like engeletin and tenuifolin have been shown to attenuate Aβ-induced oxidative stress and neuroinflammation through specific signaling pathways, indicating potential therapeutic avenues for mitigating Aβ-related pathology (ref: Huang doi.org/10.1007/s10753-020-01250-9/; Chen doi.org/10.3233/JAD-200077/). The genetic relevance of microglia derived from human induced pluripotent stem cells has also been highlighted, providing a model for studying the interactions between Aβ, tau, and neuroinflammation in AD (ref: Butler Iii doi.org/10.1159/000501935/). These studies collectively emphasize the need for a comprehensive understanding of Aβ and tau interactions, as well as their contributions to neuroinflammation and cognitive decline in Alzheimer's disease.

Environmental and lifestyle factors are increasingly recognized as significant contributors to Alzheimer's disease risk and progression. Research has indicated that early-onset Alzheimer's disease is characterized by severe neurodegeneration and rapid progression, with microglial activation playing a pivotal role in its pathogenesis (ref: Tondo doi.org/10.1186/s13195-020-00619-0/). Additionally, studies have shown that graphene oxide can enhance beta-amyloid clearance by inducing autophagy in microglia and neurons, suggesting that lifestyle interventions aimed at promoting autophagy may have therapeutic potential (ref: Li doi.org/10.1016/j.cbi.2020.109126/). Furthermore, the use of humanized tau antibodies has been explored as a therapeutic strategy, promoting tau uptake by microglia without increasing inflammation, which may offer a novel approach to managing tau pathology in AD (ref: Zilkova doi.org/10.1186/s40478-020-00948-z/). These findings highlight the importance of considering environmental and lifestyle factors in the context of Alzheimer's disease, as they may influence disease onset and progression.