Cell-type-directed network-correcting combination therapy for Alzheimer's disease

Yaqiao Li¹, Carlota Pereda Serras², Jessica Blumenfeld³, Min Xie⁴, Yanxia Hao⁵, Elise Deng⁴, You Young Chun⁴, Julia Holtzman⁴, Alice An⁵, Seo Yeon Yoon⁴, Xinyu Tang⁶, Antara Rao⁷, Sarah Woldemariam⁶, Alice Tang⁸, Alex Zhang⁴, Jeffrey Simms⁴, Iris Lo⁴, Tomiko Oskotsky⁹, Michael J Keiser², Yadong Huang¹⁰, Marina Sirota¹¹

Affiliations

¹ Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA 94143, USA; Pharmaceutical Science and Pharmacogenomics Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA. Electronic address: yaqiao.li@ucsf.edu.
² Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA 94143, USA; Pharmaceutical Science and Pharmacogenomics Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA.
³ Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA; Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA.
⁴ Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA.
⁵ Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA; Gladstone Center for Translational Advancement, Gladstone Institutes, San Francisco, CA 94158, USA.
⁶ Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
⁷ Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA; Developmental and Stem Cell Biology Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA.
⁸ Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA 94143, USA; Bioengineering Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Bioengineering Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA.
⁹ Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA 94143, USA; Division of Clinical Informatics and Digital Transformation, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
¹⁰ Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA; Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Gladstone Center for Translational Advancement, Gladstone Institutes, San Francisco, CA 94158, USA; Developmental and Stem Cell Biology Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Departments of Neurology and Pathology, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: yadong.huang@gladstone.ucsf.edu.
¹¹ Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA 94143, USA; Pharmaceutical Science and Pharmacogenomics Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: marina.sirota@ucsf.edu.

PMID: 40695276
PMCID: PMC12313259 (available on 2026-07-21)
DOI: 10.1016/j.cell.2025.06.035

Cell-type-directed network-correcting combination therapy for Alzheimer's disease

Yaqiao Li et al. Cell. 2025.

. 2025 Oct 2;188(20):5516-5534.e18.

doi: 10.1016/j.cell.2025.06.035. Epub 2025 Jul 21.

Authors

Affiliations

¹ Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA 94143, USA; Pharmaceutical Science and Pharmacogenomics Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA. Electronic address: yaqiao.li@ucsf.edu.
² Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA 94143, USA; Pharmaceutical Science and Pharmacogenomics Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA.
³ Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA; Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA.
⁴ Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA.
⁵ Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA; Gladstone Center for Translational Advancement, Gladstone Institutes, San Francisco, CA 94158, USA.
⁶ Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
⁷ Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA; Developmental and Stem Cell Biology Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA.
⁸ Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA 94143, USA; Bioengineering Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Bioengineering Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA.
⁹ Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA 94143, USA; Division of Clinical Informatics and Digital Transformation, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
¹⁰ Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA; Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Gladstone Center for Translational Advancement, Gladstone Institutes, San Francisco, CA 94158, USA; Developmental and Stem Cell Biology Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Departments of Neurology and Pathology, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: yadong.huang@gladstone.ucsf.edu.
¹¹ Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA 94143, USA; Pharmaceutical Science and Pharmacogenomics Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: marina.sirota@ucsf.edu.

PMID: 40695276
PMCID: PMC12313259 (available on 2026-07-21)
DOI: 10.1016/j.cell.2025.06.035

Abstract

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by heterogeneous molecular changes across diverse cell types, posing significant challenges for treatment development. To address this, we introduced a cell-type-specific, multi-target drug discovery strategy grounded in human data and real-world evidence. This approach integrates single-cell transcriptomics, drug perturbation databases, and clinical records. Using this framework, letrozole and irinotecan were identified as a potential combination therapy, each targeting AD-related gene expression changes in neurons and glial cells, respectively. In an AD mouse model with both Aβ and tau deposits, this combination therapy significantly improved memory performance and reduced AD-related pathologies compared with vehicle and single-drug treatments. Single-nucleus transcriptomic analysis confirmed that the therapy reversed disease-associated gene networks in a cell-type-specific manner. These results highlight the promise of cell-type-directed combination therapies in addressing multifactorial diseases like AD and lay the groundwork for precision medicine tailored to patient-specific transcriptomic and clinical profiles.

Keywords: Alzheimer’s disease; amyloid pathology; connectivity map; drug repurposing; electronic medical record; irinotecan; letrozole; mouse model; single-cell transcriptome; tau pathology.

Published by Elsevier Inc.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests Y. Huang is a co-founder and scientific advisory board member of GABAeron Inc. Y.L., Y. Huang, and M.S. are co-inventors on a patent application based on this study.

Update of

Data-driven discovery of cell-type-directed network-correcting combination therapy for Alzheimer's disease.
Li Y, Serras CP, Blumenfeld J, Xie M, Hao Y, Deng E, Chun YY, Holtzman J, An A, Yoon SY, Tang X, Rao A, Woldemariam S, Tang A, Zhang A, Simms J, Lo I, Oskotsky T, Keiser MJ, Huang Y, Sirota M. Li Y, et al. bioRxiv [Preprint]. 2024 Dec 13:2024.12.09.627436. doi: 10.1101/2024.12.09.627436. bioRxiv. 2024. Update in: Cell. 2025 Oct 2;188(20):5516-5534.e18. doi: 10.1016/j.cell.2025.06.035. PMID: 39713353 Free PMC article. Updated. Preprint.

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Cell-type-directed network-correcting combination therapy for Alzheimer's disease

Affiliations

Cell-type-directed network-correcting combination therapy for Alzheimer's disease

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases