ArticleAlzheimer's & dementia : the journal of the Alzheimer's Association2025
Single-microglia transcriptomic transition network-based prediction and real-world patient data validation identifies ketorolac as a repurposable drug for Alzheimer's disease.
Article in Alzheimer's & dementia : the journal of the Alzheimer's Association, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed.
- Ketorolac in the perioperative management of acute type A aortic dissection: a randomized double-blind placebo-controlled trial.BMC medicine · 2025Trial
- Pharmacological modulation of cGAS-STING-NLRP3 signaling by nano-immunomodulators in Alzheimer and Parkinson disease.Inflammopharmacology · 2026Review
- Discovering repurposable drugs for Alzheimer's disease and related dementias: target trial emulation using decentralised real-world data.EBioMedicine · 2026Article
- Alzheimer's Disease as a Multi-Layer Network Disorder: A Systems Biology Framework Integrating Multi-Omics Mechanisms.Biomedicines · 2026Review
- The SHIP1-inflammatory-lipid axis in Alzheimer's disease: from genetic risk to spatiotemporal mechanistic insights.Journal of neuroinflammation · 2026Review
- A perspective: PLA2G4A as drug target for vascular inflammation in Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Review
- A strategy of microglia replacement alleviates microgliopathy in a CSF1R I794T hotspot mutation mouse model of CSF1R-related disorder.Cell reports. Medicine · 2026Article
- Artificial Intelligence to Guide Repurposing of Drugs.Annual review of medicine · 2026Review
- Network-based prediction and real-world patient data observation identify doxycycline as a repurposable drug in Alzheimer's disease.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Article
- The role for artificial intelligence in identifying combination therapies for Alzheimer's disease.The journal of prevention of Alzheimer's disease · 2025Review
- A new ANMerge-based blood transcriptomic resource to support Alzheimer's disease research.medRxiv : the preprint server for health sciences · 2025Article
- Integrative analysis reveals generalizable human neurodegenerative disease-associated glial states.bioRxiv : the preprint server for biology · 2025Article
- VEXAS Syndrome and Alzheimer's Disease-Are There Connections?Brain sciences · 2025Review
- Network Diffusion-Constrained Variational Generative Models for Investigating the Molecular Dynamics of Brain Connectomes Under Neurodegeneration.International journal of molecular sciences · 2025Article
- Single-microglia transcriptomic transition network-based prediction and real-world patient data validation identifies ketorolac as a repurposable drug for Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
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Authors and funding
21 authors.
Funding
Abstract
introductionHigh microglial heterogeneities hinder the development of microglia-targeted treatment for Alzheimer's disease (AD).
methodsWe 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 neuroinflammation-like microglia (NIM). We prioritized drugs by specifically targeting microglia-specific transition networks and validated drugs using two independent real-world patient databases.
resultsWe identified putative AD molecular drivers (e.g., SYK, CTSB, and INPP5D) in transition networks of DAM and NIM. Via specifically targeting NIM, we identified that usage of ketorolac was associated with reduced AD incidence in both MarketScan (hazard ratio [HR] = 0.89) and INSIGHT (HR = 0.83) Clinical Research Network databases, mechanistically supported by ketorolac-treated transcriptomic data from AD patient induced pluripotent stem cell-derived microglia. DISCUSSION: This study offers insights into the pathobiology of AD-relevant microglial subtypes and identifies ketorolac as a potential anti-inflammatory treatment for AD. HIGHLIGHTS: An integrative analysis of ≈ 0.7 million single-nuclei RNA-sequencing transcriptomes from human brains identified Alzheimer's disease (AD)-relevant microglia subtypes. Network-based analysis identified putative molecular drivers (e.g., SYK, CTSB, INPP5D) of transition networks between disease-associated microglia (DAM) and neuroinflammation-like microglia (NIM). Via network-based prediction and population-based validation, we identified that usage of ketorolac (a US Food and Drug Administration-approved anti-inflammatory medicine) was associated with reduced AD incidence in two independent patient databases. Mechanistic observation showed that ketorolac treatment downregulated the Type-I interferon signaling in patient induced pluripotent stem cell-derived microglia, mechanistically supporting its protective effects in real-world patient databases.
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