ArticlemedRxiv : the preprint server for health sciences2025
Integrative Genetic, Proteogenomic, and Multi-omics Analyses Reveal Sex-Biased Causal Genes and Drug Targets in Alzheimer's Disease.
Noah Cook, Chenyu Yang, Youjie Zeng, Sathesh K Sivasankaran, Soomin Song, Lia Talozzi, Daniel Western, Chengran Yang, Yue Liu, Yann Le Guen and 13 more
Abstract readPreprint
In one paragraphArticle in medRxiv : the preprint server for health sciences, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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2 · The registryThe trial behind it
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4 · The recordCorrections and comments
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5 · Who and what moneyAuthors and funding
23 authors.
Sathesh K SivasankaranDepartment of Neurology, Washington University in St. Louis, St. Louis, MO, USA.ORCID 0000-0003-3037-6001 Soomin SongNeurogenomics and Informatics Center, Washington University in St. Louis, School of Medicine, St. Louis, MO, USA.ORCID 0000-0002-3648-9632 Lia TalozziDepartment of Neurology and Neurological Sciences, Stanford University, Stanford, CA, 94305, USA.ORCID 0000-0003-1827-0407 Daniel WesternNeurogenomics and Informatics Center, Washington University in St. Louis, School of Medicine, St. Louis, MO, USA.ORCID 0000-0003-3725-9553 Chengran YangNeurogenomics and Informatics Center, Washington University in St. Louis, School of Medicine, St. Louis, MO, USA.ORCID 0000-0003-4577-5590 Yue LiuDepartment of Neurology, University of California, Davis, Sacramento, CA, USA.
Yann Le GuenQuantitative Sciences Unit, Department of Medicine, Stanford University, Stanford, CA, 94304, USA.ORCID 0000-0001-6649-8364 Ilaria StewartDepartment of Neurology and Neurological Sciences, Stanford University, Stanford, CA, 94305, USA.ORCID 0000-0002-8655-9387 Christina YoungDepartment of Neurology and Neurological Sciences, Stanford University, Stanford, CA, 94305, USA.
FinnGen
Elizabeth C MorminoDepartment of Neurology and Neurological Sciences, Stanford University, Stanford, CA, 94305, USA.ORCID 0009-0003-3321-8081 Zihuai HeDepartment of Neurology and Neurological Sciences, Stanford University, Stanford, CA, 94305, USA.ORCID 0000-0002-8220-4183 Valerio NapolioniSchool of Biosciences and Veterinary Medicine, University of Camerino, Camerino, 62032, Italy.ORCID 0000-0002-4378-6838 Aliza P WingoDepartment of Psychiatry, University of California, Davis, Sacramento, CA, USA.
Carlos CruchagaNeurogenomics and Informatics Center, Washington University in St. Louis, School of Medicine, St. Louis, MO, USA.ORCID 0000-0002-0276-2899 Yun Ju SungNeurogenomics and Informatics Center, Washington University in St. Louis, School of Medicine, St. Louis, MO, USA.ORCID 0000-0002-8021-4070 Michael D GreiciusDepartment of Neurology and Neurological Sciences, Stanford University, Stanford, CA, 94305, USA.
Funding
Dissecting the Genomic Etiology of non-Mendelian Early-Onset Alzheimer Disease and Related PhenotypesR01AG064614 · NIA · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · PI BEECHAM, GARY WAYNE, CRUCHAGA, CARLOS · 2019 to 2023
$11.5MIdentification and Characterization of Cell-Specific Transposable Elements Implicated on Alzheimer Disease and Healthy AgingR01AG078964 · NIA · WASHINGTON UNIVERSITY · PI Carlos Cruchaga, Bess Frost · 2022 to 2026
$9.0MThe brain multi-omic approach to identify key molecular drivers of neuropsychiatric symptoms in Alzheimer's dementiaR01AG072120 · NIA · UNIVERSITY OF CALIFORNIA AT DAVIS · PI Aliza Pham Wingo, Thomas Spurgeon Wingo · 2022 to 2026
$4.3MIntegrative genomic, transcriptomic, and proteomic analyses to investigate sex-specific differences in Alzheimer's DiseaseR01AG075827 · NIA · UNIVERSITY OF CALIFORNIA AT DAVIS · PI Aliza Pham Wingo, Thomas Spurgeon Wingo · 2022 to 2026
$3.7MSex-specific Molecular Profiling to Understand Pathology and Identify Causal Genes and Drug Targets forAlzheimer's DiseaseR01AG074007 · NIA · WASHINGTON UNIVERSITY · PI YunJu Sung · 2024 to 2026
$2.4MGenetic Modifiers of TREM2 in Alzheimer's DiseaseR01AG058501 · NIA · WASHINGTON UNIVERSITY · PI Carlos Cruchaga · 2024 to 2026
$2.2MInterpretable machine learning methods for the analysis of Alzheimers disease geneticsR01AG089509 · NIA · STANFORD UNIVERSITY · PI Zihuai He · 2025 to 2026
$1.5MMultimodal Characterization of the Role of Circular RNAs in Alzheimer's DiseaseR01AG071706 · NIA · WASHINGTON UNIVERSITY · PI Carlos Cruchaga · 2025 to 2026
$1.4MElucidating sex-specific risk for Alzheimer's disease through state-of-the-art genetics and multi-omicsR00AG075238 · NIA · WASHINGTON UNIVERSITY · PI BELLOY, MICHAEL · 2024 to 2025
$727kRegional tau deposition and digital assessment of cognition in preclinical AD and MCIR00AG071837 · NIA · UNIVERSITY OF CALIFORNIA AT DAVIS · PI Christina B Young · 2025 to 2026
$606kBLRD VA I01 BX005686BLRD VA IK4 BX005219NIA NIH HHS R00 AG071837NIA NIH HHS R00 AG075238NIA NIH HHS R01 AG058501NIA NIH HHS R01 AG064614NIA NIH HHS R01 AG071706NIA NIH HHS R01 AG072120NIA NIH HHS R01 AG074007NIA NIH HHS R01 AG075827NIA NIH HHS R01 AG078964NIA NIH HHS R01 AG089509
6 · The paper itselfAbstract
Sex differences are pervasive in Alzheimer's disease, but the underlying drivers remain poorly understood. To address this, we performed sex-stratified genome-wide association studies of Alzheimer's disease in ~1,000,000 individuals, which we subsequently integrated with proteogenomics datasets from neurological tissues to identify candidate causal genes. We further prioritized genes through additional multi-omics approaches, including quantitative trait locus summary-based mendelian randomization and colocalization. Altogether, we prioritized 125 female-biased and 21 male-biased risk genes. Female-biased pathways included amyloid, neurite, stress, clearance, and immune processes, with genes enriched for microglia and astrocyte expression. Through computational drug repurposing analyses, a set of sex hormone related drugs, converging on
Identifiers
PMID41282793
PMCPMC12636628
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