An integrative single-cell genetic analysis prioritizes immune cell-specific genes and drug repurposing hypotheses in Alzheimer’s disease

Immune dysregulation is increasingly recognized as a critical contributor to Alzheimer’s disease (AD), but the specific immune cell contexts and regulatory genes underlying genetic susceptibility remain incompletely understood. Here, we integrated immune cell-specific cis-expression quantitative trait loci (cis-eQTL) from the OneK1K resource with AD genome-wide association study data using two-sample Mendelian randomization (MR), Bayesian colocalization, and independent DICE replication. Exploratory peripheral blood single-cell RNA sequencing (scRNA-seq) was further applied to characterize cell-type expression patterns of prioritized genes.

We identified naïve/central memory T-cell subsets and monocyte-related populations as major immune contexts enriched for AD-associated genetic regulatory signals and prioritized several immune cell-specific candidate genes, including KANSL1-AS1, CTSH, FCER1G, EPHA1-AS1, CRHR1, and JAZF1. Independent datasets supported the reproducibility of multiple prioritized signals. Integration with drug-signature resources, blood–brain barrier (BBB) permeability prediction, molecular docking, and phenome-wide association analyses generated exploratory compound–gene repurposing hypotheses while assessing potential genetic safety concerns.

Collectively, this study provides an immune cell-resolved genetic framework for interpreting AD susceptibility and identifies candidate targets and therapeutic hypotheses that require further experimental validation. This research was supported by the Science and Technology Innovation 2030 Major Projects (2022ZD0211600), the National Science Foundation of China (82271574, 82202137, and 81871069), and the Key Projects of Commission of Health Jiangsu Province (ZDB2020008). We express our sincere appreciation to all the researchers who generously provided the GWAS summary statistics and scRNA-seq datasets that were essential to this study.

These authors contributed equally: Yifu Sun, Zhe Zhong. Department of Neurology, Affiliated ZhongDa Hospital, School of Medicine, Jiangsu Key Laboratory of Brain Science and Medicine, Southeast University, Nanjing, China Yifu Sun, Zhe Zhong, Wu Zhou & Chunming Xie Department of Neurology, Xuzhou Medical University Affiliated Hospital of Huai’an, Huai’an, China Institute of Neuropsychiatry, Affiliated Zhongda Hospital, Southeast University, Nanjing, China The Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, China Correspondence to Liandong Zhao or Chunming Xie. The authors declare no competing interests.

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