ORIGINAL RESEARCH article
Front. Immunol.
Sec. Multiple Sclerosis and Neuroimmunology
This article is part of the Research TopicImmune Responses in Neurodegeneration: Opportunities for Targeted InterventionsView all 9 articles
Identification of plasma inflammatory biomarkers for Alzheimer's disease reveals IFN-γ as a regulator of ACSL1-mediated microglia phenotype
Provisionally accepted
Ronghua Huang1Bing-Biao Lin2Zhijie Lu3Yixuan Hao1Chenrui Li1Zixian Lin4Yingjie Zhang1Naili Wei1
Jian Chen1*- 1First Affiliated Hospital of Shantou University Medical College, Shantou, China
- 2Shantou University Medical College Cancer Hospital, Shantou, China
- 3Zhujiang Hospital of Southern Medical University, Guangzhou, China
- 4Rongcheng Women Infant Health Care Hospital, Jieyang, China
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Background The identification of plasma biomarkers for the diagnosis of Alzheimer's disease (AD) has been a longstanding research priority; however, few plasma biomarkers have yet been implemented in routine clinical practice. Methods This study enrolled 141 participants, including 71 patients with AD, 44 individuals with mild cognitive impairment, and 28 cognitively healthy controls (HC). A total of 16 plasma inflammatory proteins were quantified using multiplex liquid-chip assays, and APOE genotyping was performed. The diagnostic utility of plasma proteins was assessed using the least absolute shrinkage and selection operator (LASSO) with nested cross-validation. Results Patients with AD exhibited marked alterations in plasma inflammatory profiles, with elevated levels of IFN-γ, IL-33, and IL-18, and reduced levels of IL-7 and CCL11. Integrating inflammatory markers with clinical variables and APOE genotype substantially improved discrimination between AD and HC, increasing the area under the ROC curve from 0.863 to 0.953. Among all biomarkers, IFN-γ emerged as the most informative predictor and was significantly elevated in AD patients carrying the APOE ε4 allele. Analyses of single-nucleus RNA sequencing data further revealed pronounced enrichment of IFN-γ signaling in APOE4/4 AD-associated lipid droplet-accumulating microglia (LDAM), defined by high ACSL1 expression. Notably, IFN-γ stimulation enhanced ACSL1 expression in ApoE4-overexpressing HMC3 microglial cells. Conclusion These findings provide a new perspective on the involvement of plasma inflammatory markers for AD diagnosis, and suggest a novel link between IFN-γ and APOE ε4-associated AD risk through modulating the ACSL1-driven pathogenic LDAM phenotype.
Keywords: Alzheimer's disease, APOE, biomarker, IFN-gamma, Inflammation
Received: 18 Dec 2025; Accepted: 27 Jan 2026.
Copyright: © 2026 Huang, Lin, Lu, Hao, Li, Lin, Zhang, Wei and Chen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Jian Chen
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