This study reveals that APOE4 promotes IL-17F release from neutrophils in females, which subsequently suppresses microglial transition into neurodegenerative phenotypes, leading to cognitive decline. It identifies IL-17F as a potential therapeutic target.
Literature Overview
This paper, 'SEX-DEPENDENT APOE4 NEUTROPHIL-MICROGLIA INTERACTIONS DRIVE COGNITIVE IMPAIRMENT IN ALZHEIMER’S DISEASE,' published in Nature Medicine, reviews and summarizes research on the sex-dependent pathogenic mechanisms of the APOE4 genotype in Alzheimer’s disease (AD). By integrating single-cell transcriptomic analysis, multicolor flow cytometry, and validation in independent cohorts, the study identifies a novel IL-17+IL18R1+ neutrophil subset in cognitively impaired female APOE4 carriers. This subset interacts with microglia via the IL-17F–IL-17RA axis, inhibiting their transition to a neurodegenerative disease-associated phenotype (MGnD), thereby exacerbating Aβ plaque deposition and cognitive decline. This mechanism is not significant in males, highlighting an immune pathway jointly regulated by sex and genetic background in AD progression. The study further demonstrates that targeting IL-17F restores microglial function and improves cognitive performance, offering a precision therapeutic strategy for female APOE4 carriers. The research design is rigorous, with extensive multi-level validation, and holds significant translational value.Background Knowledge
The APOE ε4 allele is the strongest genetic risk factor for Alzheimer’s disease, with a particularly pronounced effect in women, although the underlying mechanisms are not fully understood. Traditional research has largely focused on APOE’s roles within the central nervous system, such as influencing Aβ clearance, tau pathology, and neuroinflammation. In recent years, the peripheral immune system’s role in AD has gained increasing attention. Neutrophils, the most abundant granulocytes, have been reported to increase in number in AD patients and may contribute to neuroinflammation. Microglia, the brain’s primary resident immune cells, play a crucial role in limiting Aβ pathology through their transition to disease-associated phenotypes (DAM/MGnD). However, how APOE4 affects crosstalk between peripheral neutrophils and central microglia—especially in the context of sex differences—remains poorly understood. Key unresolved questions include: Why do female APOE4 carriers respond poorly to Aβ-targeted therapies? Are there sex-specific immune regulatory axes? This study systematically investigates the role of neutrophil–microglia interactions in AD sex disparities by examining APOE4-mediated neutrophil phenotype changes using single-cell multi-omics and animal models, filling a critical knowledge gap and providing a theoretical foundation for developing genotype- and sex-stratified precision immunotherapies.
Research Methods and Experiments
The study first used single-nucleus RNA sequencing (snRNA-seq) to analyze brain tissue samples from AD patients carrying APOE ε3/3 and APOE ε3/4 genotypes, focusing on microglial heterogeneity. It found that transitional microglial states (MG6/MG8) were enriched in female APOE4 carriers, with elevated IL17RA expression, which correlated negatively with tau pathology. Trajectory analysis and pathway enrichment revealed significant upregulation of neutrophil degranulation signaling in APOE4-associated microglia, particularly in females.
Next, RNA-seq analysis of peripheral blood neutrophils from patients with mild cognitive impairment (MCI) and AD revealed significant activation of IL-17, IL-1, and TGFβ signaling pathways in female APOE4 carriers, along with enrichment of immune-suppressive genes (e.g., IL-10, PD-1). Multicolor flow cytometry confirmed the expansion of IL-17+CD66b+ neutrophils in female APOE4 MCI patients, identifying a distinct subset, including regulatory neutrophils expressing Foxp3.
Using a conditional APOE knockout mouse model (APOE4NTKO), the study found that neutrophil-specific deletion of APOE4 reversed their immunosuppressive phenotype, reducing IL-17F, TGFβ, and Foxp3 expression, restoring microglial MGnD phenotypes, decreasing Aβ plaque burden, and improving cognitive function in behavioral tests.
Furthermore, using a 5xFAD-hCSF1 humanized mouse model, the study demonstrated that human APOE4 neutrophils suppress LGALS32 expression in human microglia. Intracerebral injection of IL-17F or administration of an anti-IL-17F neutralizing antibody confirmed that IL-17F promotes neutrophil brain infiltration and impairs microglial phagocytic function. Finally, in APP/PS1:Il17raMGKO mice, microglia-specific deletion of IL-17RA enhanced MGnD phenotypes and reduced pathology, while anti-IL-17F treatment in 5xFAD:APOE4 mice significantly improved cognitive performance.Key Conclusions and Perspectives
Research Significance and Prospects
This study is the first to systematically reveal how APOE4 drives AD progression through sex-dependent regulation of neutrophil–microglia interactions, highlighting the critical role of the peripheral immune system in sex disparities in AD. Traditional AD therapies, largely targeting Aβ or tau, have shown limited efficacy, especially in APOE4 carriers. This work proposes IL-17F as a novel intervention target, potentially overcoming the poor response to current therapies in female APOE4 patients and advancing personalized immunotherapy.
Future studies could further explore the dynamic changes in IL-17F signaling across AD stages, develop more specific targeting strategies (e.g., small-molecule inhibitors or gene therapy), and validate their efficacy in non-human primate models. Additionally, whether this neutrophil subset can serve as a biomarker for early screening or treatment monitoring warrants deeper investigation. Integrating single-cell multi-omics with spatial transcriptomics will help refine the spatiotemporal network of neuro-immune crosstalk, opening new avenues for precision medicine in AD.
Conclusion
This study elucidates how APOE4 in females drives neutrophils toward an immunosuppressive phenotype, which subsequently inhibits microglia from acquiring the neurodegenerative disease-associated (MGnD) phenotype via the IL-17F–IL-17RA axis, thereby exacerbating Alzheimer’s pathology and cognitive decline. This mechanism reveals a sex-specific crosstalk between peripheral and central immune systems, offering a novel perspective on the heightened disease susceptibility in female APOE4 carriers. The research not only identifies IL-17+ regulatory neutrophils as potential biomarkers but also proposes that targeting IL-17F can restore microglial function and improve cognition, demonstrating strong clinical translational potential. These findings underscore the importance of considering both sex and genotype in AD treatment strategies, providing a theoretical foundation and new therapeutic targets for developing precision immunotherapies, with the potential to address the current limitations of Aβ-targeted therapies in female APOE4 carriers. Future research should further validate the druggability of this pathway in humans and advance related therapeutics into clinical trials.
