Peer-Reviewed Publication
Alzheimers Dement2025;21(1):e14373.January 1, 2025Journal Article
Single-microglia transcriptomic transition network-based prediction and real-world patient data validation identifies ketorolac as a repurposable drug for Alzheimer's disease.
Jielin Xu1,2, Wenqiang Song1, Zhenxing Xu3,4, Michael M Danziger5, Ehud Karavani5, Chengxi Zang3,4, Xin Chen1,2, Yichen Li1,2, Isabela M Rivera Paz2, Dhruv Gohel1,2, Chang Su3,4, Yadi Zhou1,2, Yuan Hou1,2, Yishai Shimoni5, Andrew A Pieper6,7,8,9,10, Jianying Hu11, Fei Wang3,4, Michal Rosen-Zvi5, James B Leverenz12, Jeffrey Cummings13, Feixiong Cheng1,2,14
1Cleveland Clinic Genome Center, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
2Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
3Department of Population Health Sciences, Weill Cornell Medicine, Cornell University, New York, New York, USA.
4Institute of Artificial Intelligence for Digital Health, Weill Cornell Medicine, Cornell University, New York, New York, USA.
5AI for Accelerated Healthcare and Life Sciences Discovery, IBM Research-Israel, Haifa, Israel.
6Brain Health Medicines Center, Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA.
7Department of Psychiatry, Case Western Reserve University, Cleveland, Ohio, USA.
8Geriatric Psychiatry, GRECC, Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, USA.
9Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
10Department of Neurosciences, Case Western Reserve University, School of Medicine, Cleveland, Ohio, USA.
11IBM T.J. Watson Research Center, Yorktown Heights, New York, USA.
12Lou Ruvo Center for Brain Health, Neurological Institute, Cleveland Clinic, Cleveland, Ohio, USA.
13Chambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, School of Integrated Health Sciences, University of Nevada Las Vegas, Las Vegas, Nevada, USA.
14Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
Abstract
INTRODUCTION: High microglial heterogeneities hinder the development of microglia-targeted treatment for Alzheimer's disease (AD).
METHODS: We integrated 0.7 million single-nuclei RNA-sequencing transcriptomes from human brains using a variational autoencoder. We predicted AD-relevant microglial subtype-specific transition networks for disease-associated microglia (DAM), tau microglia, and neuroi…
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