Evidence map›Paper›PMID 40695276›Full record

ArticleCell2025

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

Yaqiao Li, Carlota Pereda Serras, Jessica Blumenfeld, Min Xie, Yanxia Hao, Elise Deng, You Young Chun, Julia Holtzman, Alice An, Seo Yeon Yoon and 11 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.

0numbers the graph read from it
0cells of the map it votes in
30citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

30 citing papers in PubMed.

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  12. Lecanemab treatment improves B cell subpopulation immune homeostasis in patients with Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026
    Article
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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

21 authors.

Yaqiao LiBakar 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.
Carlota Pereda SerrasBakar 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.
Jessica BlumenfeldGladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA; Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA.
Min XieGladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA.
Yanxia HaoGladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA; Gladstone Center for Translational Advancement, Gladstone Institutes, San Francisco, CA 94158, USA.
Elise DengGladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA.
You Young ChunGladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA.
Julia HoltzmanGladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA.
Alice AnGladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA; Gladstone Center for Translational Advancement, Gladstone Institutes, San Francisco, CA 94158, USA.
Seo Yeon YoonGladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA.
Xinyu TangBakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
Antara RaoGladstone 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.
Sarah WoldemariamBakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
Alice TangBakar 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.
Alex ZhangGladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA.
Jeffrey SimmsGladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA.
Iris LoGladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA.
Tomiko OskotskyBakar 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.
Michael J KeiserBakar 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.
Yadong HuangGladstone 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.
Marina SirotaBakar 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.

Funding

Project 4: Cross-species Dissection of Cellular Response to APOE Genotype and AD Pathology Using Single-cell Multi-omicsP01AG073082 · NIA · J. DAVID GLADSTONE INSTITUTES · PI HUANG, YADONG, MUCKE, LENNART · 2021 to 2025
$23.4M
Develop AD Connectivity Maps with Human iPSC-Derived Brain Cells and their UseR01AG078164 · NIA · J. DAVID GLADSTONE INSTITUTES · PI YADONG HUANG · 2022 to 2026
$4.7M
ApoE Genotype-Directed Drug Repositioning and Combination Therapy for Alzheimer's DiseaseR01AG057683 · NIA · J. DAVID GLADSTONE INSTITUTES · PI HUANG, YADONG, SIROTA, MARINA · 2017 to 2021
$4.3M
An Integrative Multi-Omics Approach to Elucidate Sex-Specific Differences in Alzheimers DiseaseR01AG060393 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI SIROTA, MARINA · 2018 to 2022
$4.1M
Study Susceptibility and Resistance to ApoE4 in Alzheimer's DiseaseRF1AG076647 · NIA · J. DAVID GLADSTONE INSTITUTES · PI HUANG, YADONG · 2022 to 2022
$2.6M
Pharmaceutical Sciences and PharmacogenomicsT32GM142516 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Su Guo · 2022 to 2026
$2.4M
Study Susceptibility and Resistance to ApoE4 in Alzheimer's DiseaseR01AG076647 · NIA · J. DAVID GLADSTONE INSTITUTES · PI YADONG HUANG · 2025 to 2026
$1.7M
NIA NIH HHS P01 AG073082NIA NIH HHS R01 AG057683NIA NIH HHS R01 AG060393NIA NIH HHS R01 AG076647NIA NIH HHS R01 AG078164NIA NIH HHS RF1 AG076647NIGMS NIH HHS T32 GM142516
6 · The paper itself

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.

Indexed as

Alzheimer DiseaseAmyloid beta-PeptidesAnimalsDisease Models, AnimalDrug Therapy, CombinationGene Regulatory NetworksHumansIrinotecanMaleMiceMice, TransgenicNeurogliaNeuronsNitrilesSingle-Cell Analysistau ProteinsAmyloid beta-PeptidesIrinotecanNitrilestau ProteinsTriazolesAlzheimer’s diseaseamyloid pathologyconnectivity mapdrug repurposingelectronic medical recordirinotecanletrozolemouse modelsingle-cell transcriptometau pathology

Identifiers

PMID40695276
PMCPMC12313259

What Socratic holds

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Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.