Abstract
Alzheimer’s disease (AD) is a common neurodegenerative disorder; however, its molecular complexity remains poorly understood. Single-cell analysis can reveal the molecular changes in AD in different types of brain cells. In this study, we integrated single-cell sequencing and transcriptome data to explore the molecular mechanism of integrated stress response (ISR) in AD. Analysis of the GSE264648 (49 cases) and GSE48350 (253 cases) datasets showed that the integrated stress response (ISR) activity of endothelial cells in patients with AD was significantly increased compared with normal control group. Six key genes (BTG1, EPB41L4A, HERPUD1, SLC3A2, SLC7A11, and SLC7A5) were screened by combining the Least Absolute Shrinkage and Selection Operator (LASSO) regression and the random forest algorithm. Urine test for β-amyloid protein, Clinical Dementia Rating, modified Hachinski Ischemia Scale, Hamilton Depression Scale, Hamilton Anxiety Scale and head magnetic resonance imaging were used to screen cilinical subjects, and then verified the six key genes in their blood samples. These key genes are enriched in inflammatory pathways such as NF-κB and TNF, and are closely related to immune cell infiltration (e.g., M2 macrophages and neutrophils). This research also revealed the association between key and core genes of AD (e.g., APOE) and their clinical predictive value, providing new clues for mechanistic research and targeted therapy of AD.
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Data availability
The datasets generated and/or analyzed during the current study are not publicly available because they protect patient privacy, but are available from the corresponding author upon reasonable request.
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Acknowledgements
This work was supported by the [Natural Science Foundation of China] under Grant [Number 82205064] and [Hunan Provincial Science and Technology Innovation Program] under Grant [2023RC3215], the [Hunan Provincial Natural Science Foundation] under Grant [2024JJ5236], and the [Furong Laboratory Science and Technology Research Project] under Grant [2023SK2113-2].
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This work was supported by the [Natural Science Foundation of China] under Grant [Number 82205064] and [Natural Science Foundation of Shandong Province] under Grant [Number ZR2021QH110].
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NS: Original draft. HYW: Project administration, Visualization. KS: Project administration, Formal analysis. YZ: Visualization. ZYZ: Formal analysis. JWG: Methodology. DHW: Methodology, Supervision. YHW: Writing—review & editing, Funding acquisition.
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Sheng, N., Wang, HY., Song, K. et al. Uncovering the role of integrated stress in Alzheimer’s disease through single-cell and transcriptomic analysis. Sci Rep (2026). https://doi.org/10.1038/s41598-026-34997-6
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DOI: https://doi.org/10.1038/s41598-026-34997-6
