Multiscale proteomic modeling reveals protein networks driving Alzheimer's disease pathogenesis

Erming Wang¹, Kaiwen Yu², Jiqing Cao³, Minghui Wang¹, Pavel Katsel⁴, Won-Min Song¹, Zhen Wang⁵, Yuxin Li², Xusheng Wang⁶, Qian Wang¹, Peng Xu¹, Gefei Yu¹, Li Zhu³, Jia Geng⁷, Parnian Habibi⁸, Lu Qian⁹, Tony Tuck⁹, Aiqun Li¹, Julia Tcw¹⁰, Panos Roussos¹¹, Kristen J Brennand¹², Vahram Haroutunian⁴, Erik C B Johnson¹³, Nicholas T Seyfried¹⁴, Allan I Levey¹³, David A Bennett¹⁵, Junmin Peng¹⁶, Dongming Cai¹⁷, Bin Zhang¹⁸

Affiliations

¹ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
² Departments of Structural Biology and Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
³ Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Neurology, University of Minnesota, Minneapolis, MN 55455, USA; N. Bud Grossman Center for Memory Research and Care, University of Minnesota, Minneapolis, MN 55455, USA; Geriatric Research Education & Clinical Center (GRECC), Minneapolis VA Health Care System, Minneapolis, MN 55417, USA.
⁴ Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA; MIRECC, Peters VA Medical Center, 130 West Kingsbridge Road, Bronx, New York, NY 10468, USA.
⁵ Departments of Structural Biology and Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
⁶ Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Neurology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
⁷ Department of Neurology, University of Minnesota, Minneapolis, MN 55455, USA; N. Bud Grossman Center for Memory Research and Care, University of Minnesota, Minneapolis, MN 55455, USA; Geriatric Research Education & Clinical Center (GRECC), Minneapolis VA Health Care System, Minneapolis, MN 55417, USA.
⁸ Department of Neurology, University of Minnesota, Minneapolis, MN 55455, USA; N. Bud Grossman Center for Memory Research and Care, University of Minnesota, Minneapolis, MN 55455, USA.
⁹ Department of Pharmacology, Physiology & Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA.
¹⁰ Department of Pharmacology, Physiology & Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA; Bioinformatics Program, Boston University Faculty of Computing & Data Sciences, Boston, MA 02215, USA.
¹¹ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.
¹² Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511, USA.
¹³ Goizueta Alzheimer's Disease Research Center, Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
¹⁴ Goizueta Alzheimer's Disease Research Center, Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA; Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA.
¹⁵ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
¹⁶ Departments of Structural Biology and Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: junmin.peng@stjude.org.
¹⁷ Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; MIRECC, Peters VA Medical Center, 130 West Kingsbridge Road, Bronx, New York, NY 10468, USA; Department of Neurology, University of Minnesota, Minneapolis, MN 55455, USA; N. Bud Grossman Center for Memory Research and Care, University of Minnesota, Minneapolis, MN 55455, USA; Geriatric Research Education & Clinical Center (GRECC), Minneapolis VA Health Care System, Minneapolis, MN 55417, USA. Electronic address: cai00268@umn.edu.
¹⁸ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA. Electronic address: bin.zhang@mssm.edu.

PMID: 41005309
DOI: 10.1016/j.cell.2025.08.038

Free article

Multiscale proteomic modeling reveals protein networks driving Alzheimer's disease pathogenesis

Erming Wang et al. Cell. 2025.

Free article

. 2025 Sep 25:S0092-8674(25)01031-1.

doi: 10.1016/j.cell.2025.08.038. Online ahead of print.

Authors

Affiliations

¹ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
² Departments of Structural Biology and Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
³ Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Neurology, University of Minnesota, Minneapolis, MN 55455, USA; N. Bud Grossman Center for Memory Research and Care, University of Minnesota, Minneapolis, MN 55455, USA; Geriatric Research Education & Clinical Center (GRECC), Minneapolis VA Health Care System, Minneapolis, MN 55417, USA.
⁴ Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA; MIRECC, Peters VA Medical Center, 130 West Kingsbridge Road, Bronx, New York, NY 10468, USA.
⁵ Departments of Structural Biology and Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
⁶ Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Neurology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
⁷ Department of Neurology, University of Minnesota, Minneapolis, MN 55455, USA; N. Bud Grossman Center for Memory Research and Care, University of Minnesota, Minneapolis, MN 55455, USA; Geriatric Research Education & Clinical Center (GRECC), Minneapolis VA Health Care System, Minneapolis, MN 55417, USA.
⁸ Department of Neurology, University of Minnesota, Minneapolis, MN 55455, USA; N. Bud Grossman Center for Memory Research and Care, University of Minnesota, Minneapolis, MN 55455, USA.
⁹ Department of Pharmacology, Physiology & Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA.
¹⁰ Department of Pharmacology, Physiology & Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA; Bioinformatics Program, Boston University Faculty of Computing & Data Sciences, Boston, MA 02215, USA.
¹¹ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.
¹² Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511, USA.
¹³ Goizueta Alzheimer's Disease Research Center, Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
¹⁴ Goizueta Alzheimer's Disease Research Center, Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA; Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA.
¹⁵ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
¹⁶ Departments of Structural Biology and Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: junmin.peng@stjude.org.
¹⁷ Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; MIRECC, Peters VA Medical Center, 130 West Kingsbridge Road, Bronx, New York, NY 10468, USA; Department of Neurology, University of Minnesota, Minneapolis, MN 55455, USA; N. Bud Grossman Center for Memory Research and Care, University of Minnesota, Minneapolis, MN 55455, USA; Geriatric Research Education & Clinical Center (GRECC), Minneapolis VA Health Care System, Minneapolis, MN 55417, USA. Electronic address: cai00268@umn.edu.
¹⁸ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA. Electronic address: bin.zhang@mssm.edu.

PMID: 41005309
DOI: 10.1016/j.cell.2025.08.038

Abstract

The molecular mechanisms underlying the pathogenesis of Alzheimer's disease (AD), the most common form of dementia, remain poorly understood. Proteomics offers a crucial approach to elucidating AD pathogenesis, as alterations in protein expression are more directly linked to phenotypic outcomes than changes at the genetic or transcriptomic level. In this study, we develop multiscale proteomic network models for AD by integrating large-scale matched proteomic and genetic data from brain regions vulnerable to the disease. These models reveal detailed protein interaction structures and identify putative key driver proteins (KDPs) involved in AD progression. Notably, the network analysis uncovers an AD-associated subnetwork that captures glia-neuron interactions. AHNAK, a top KDP in this glia-neuron network, is experimentally validated in human induced pluripotent stem cell (iPSC)-based models of AD. This systematic identification of dysregulated protein regulatory networks and KDPs lays down a foundation for developing innovative therapeutic strategies for AD.

Keywords: AHNAK; Alzheimer’s disease; Bayesian causal inference network; co-expression network; key driver analysis; proteomics; transcriptomics.

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Declaration of interests The authors declare no competing interests.

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Multiscale proteomic modeling reveals protein networks driving Alzheimer's disease pathogenesis

Affiliations

Multiscale proteomic modeling reveals protein networks driving Alzheimer's disease pathogenesis

Authors

Affiliations

Abstract

Conflict of interest statement

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