Genetic and clinical correlates of two neuroanatomical AI dimensions in the Alzheimer's disease continuum.

Humans Alzheimer Disease / genetics Male Female Cognitive Dysfunction / genetics Aged Genome-Wide Association Study Atrophy Brain / pathology Magnetic Resonance Imaging Temporal Lobe / pathology Aged, 80 and over Apolipoprotein E4 / genetics Middle Aged

Journal

Translational psychiatry
ISSN: 2158-3188
Titre abrégé: Transl Psychiatry
Pays: United States
ID NLM: 101562664

Informations de publication

Date de publication:
05 Oct 2024
Historique:
received: 04 06 2024
accepted: 23 09 2024
revised: 18 09 2024
medline: 6 10 2024
pubmed: 6 10 2024
entrez: 5 10 2024
Statut: epublish

Résumé

Alzheimer's disease (AD) is associated with heterogeneous atrophy patterns. We employed a semi-supervised representation learning technique known as Surreal-GAN, through which we identified two latent dimensional representations of brain atrophy in symptomatic mild cognitive impairment (MCI) and AD patients: the "diffuse-AD" (R1) dimension shows widespread brain atrophy, and the "MTL-AD" (R2) dimension displays focal medial temporal lobe (MTL) atrophy. Critically, only R2 was associated with widely known sporadic AD genetic risk factors (e.g., APOE ε4) in MCI and AD patients at baseline. We then independently detected the presence of the two dimensions in the early stages by deploying the trained model in the general population and two cognitively unimpaired cohorts of asymptomatic participants. In the general population, genome-wide association studies found 77 genes unrelated to APOE differentially associated with R1 and R2. Functional analyses revealed that these genes were overrepresented in differentially expressed gene sets in organs beyond the brain (R1 and R2), including the heart (R1) and the pituitary gland, muscle, and kidney (R2). These genes were enriched in biological pathways implicated in dendritic cells (R2), macrophage functions (R1), and cancer (R1 and R2). Several of them were "druggable genes" for cancer (R1), inflammation (R1), cardiovascular diseases (R1), and diseases of the nervous system (R2). The longitudinal progression showed that APOE ε4, amyloid, and tau were associated with R2 at early asymptomatic stages, but this longitudinal association occurs only at late symptomatic stages in R1. Our findings deepen our understanding of the multifaceted pathogenesis of AD beyond the brain. In early asymptomatic stages, the two dimensions are associated with diverse pathological mechanisms, including cardiovascular diseases, inflammation, and hormonal dysfunction-driven by genes different from APOE-which may collectively contribute to the early pathogenesis of AD. All results are publicly available at https://labs-laboratory.com/medicine/ .

Identifiants

DOI: 10.1038/s41398-024-03121-5 PMID: 39368996
pubmed: 39368996
doi: 10.1038/s41398-024-03121-5
pii: 10.1038/s41398-024-03121-5
doi:

Substances chimiques

Apolipoprotein E4 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

420

Informations de copyright

© 2024. The Author(s).

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Auteurs

Junhao Wen (J)

Laboratory of AI and Biomedical Science (LABS), University of Southern California, Los Angeles, CA, USA. Junhao.wen89@gmail.com.
ORCID: 0000-0003-2077-3070

Zhijian Yang (Z)

Artificial Intelligence in Biomedical Imaging Laboratory (AIBIL), Center for AI and Data Science for Integrated Diagnostics (AI2D), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Ilya M Nasrallah (IM)

Artificial Intelligence in Biomedical Imaging Laboratory (AIBIL), Center for AI and Data Science for Integrated Diagnostics (AI2D), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
ORCID: 0000-0003-2346-7562

Yuhan Cui (Y)

Artificial Intelligence in Biomedical Imaging Laboratory (AIBIL), Center for AI and Data Science for Integrated Diagnostics (AI2D), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Guray Erus (G)

Artificial Intelligence in Biomedical Imaging Laboratory (AIBIL), Center for AI and Data Science for Integrated Diagnostics (AI2D), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
ORCID: 0000-0001-6633-4861

Dhivya Srinivasan (D)

Artificial Intelligence in Biomedical Imaging Laboratory (AIBIL), Center for AI and Data Science for Integrated Diagnostics (AI2D), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Ahmed Abdulkadir (A)

Artificial Intelligence in Biomedical Imaging Laboratory (AIBIL), Center for AI and Data Science for Integrated Diagnostics (AI2D), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Research Lab in Neuroimaging of the Department of Clinical Neurosciences at Lausanne University Hospital, Lausanne, Switzerland.

Elizabeth Mamourian (E)

Artificial Intelligence in Biomedical Imaging Laboratory (AIBIL), Center for AI and Data Science for Integrated Diagnostics (AI2D), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Gyujoon Hwang (G)

Artificial Intelligence in Biomedical Imaging Laboratory (AIBIL), Center for AI and Data Science for Integrated Diagnostics (AI2D), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Ashish Singh (A)

Artificial Intelligence in Biomedical Imaging Laboratory (AIBIL), Center for AI and Data Science for Integrated Diagnostics (AI2D), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Mark Bergman (M)

Artificial Intelligence in Biomedical Imaging Laboratory (AIBIL), Center for AI and Data Science for Integrated Diagnostics (AI2D), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Jingxuan Bao (J)

Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
ORCID: 0000-0001-7127-3258

Erdem Varol (E)

Department of Statistics, Center for Theoretical Neuroscience, Zuckerman Institute, Columbia University, New York, NY, USA.

Zhen Zhou (Z)

Artificial Intelligence in Biomedical Imaging Laboratory (AIBIL), Center for AI and Data Science for Integrated Diagnostics (AI2D), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Aleix Boquet-Pujadas (A)

Laboratory of AI and Biomedical Science (LABS), University of Southern California, Los Angeles, CA, USA.

Jiong Chen (J)

Artificial Intelligence in Biomedical Imaging Laboratory (AIBIL), Center for AI and Data Science for Integrated Diagnostics (AI2D), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Arthur W Toga (AW)

Laboratory of NeuroImaging, Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA, USA.

Andrew J Saykin (AJ)

Radiology and Imaging Sciences, Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana Alzheimer's Disease Research Center and the Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA.
ORCID: 0000-0002-1376-8532

Timothy J Hohman (TJ)

Vanderbilt Memory and Alzheimer's Center, Vanderbilt Genetics Institute, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA.
ORCID: 0000-0002-3377-7014

Paul M Thompson (PM)

Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, University of Southern California, Marina del Rey, CA, USA.

Sylvia Villeneuve (S)

Douglas Mental Health University Institute, McGill University, Montréal, QC, Canada.

Randy Gollub (R)

Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
ORCID: 0000-0002-9434-4044

Aristeidis Sotiras (A)

Department of Radiology and Institute for Informatics, Washington University School of Medicine, St. Louis, MO, USA.
ORCID: 0000-0003-0795-8820

Katharina Wittfeld (K)

Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
ORCID: 0000-0003-4383-5043

Hans J Grabe (HJ)

Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.

Duygu Tosun (D)

Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA.
ORCID: 0000-0001-8644-7724

Murat Bilgel (M)

Laboratory of Behavioral Neuroscience, National Institute on Aging, NIH, Baltimore, MD, USA.
ORCID: 0000-0001-5042-7422

Yang An (Y)

Laboratory of Behavioral Neuroscience, National Institute on Aging, NIH, Baltimore, MD, USA.

Daniel S Marcus (DS)

Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA.

Pamela LaMontagne (P)

Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA.

Tammie L Benzinger (TL)

Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA.

Susan R Heckbert (SR)

Cardiovascular Health Research Unit and Department of Epidemiology, University of Washington, Seattle, WA, USA.

Thomas R Austin (TR)

Cardiovascular Health Research Unit and Department of Epidemiology, University of Washington, Seattle, WA, USA.

Lenore J Launer (LJ)

Neuroepidemiology Section, Intramural Research Program, National Institute on Aging, Bethesda, MD, USA.
ORCID: 0000-0002-3238-7612

Mark Espeland (M)

Sticht Center for Healthy Aging and Alzheimer's Prevention, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Colin L Masters (CL)

Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia.

Paul Maruff (P)

Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia.

Jurgen Fripp (J)

CSIRO Health and Biosecurity, Australian e-Health Research Centre CSIRO, Brisbane, QLD, Australia.

Sterling C Johnson (SC)

Wisconsin Alzheimer's Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
ORCID: 0000-0002-8501-545X

John C Morris (JC)

Knight Alzheimer Disease Research Center, Washington University in St. Louis, St. Louis, MO, USA.

Marilyn S Albert (MS)

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

R Nick Bryan (RN)

Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA.

Susan M Resnick (SM)

Laboratory of Behavioral Neuroscience, National Institute on Aging, NIH, Baltimore, MD, USA.
ORCID: 0000-0003-1115-7145

Luigi Ferrucci (L)

Translational Gerontology Branch, Longitudinal Studies Section, National Institute on Aging, National Institutes of Health, MedStar Harbor Hospital, 3001 S. Hanover Street, Baltimore, MD, 21225, USA.
ORCID: 0000-0002-6273-1613

Yong Fan (Y)

Artificial Intelligence in Biomedical Imaging Laboratory (AIBIL), Center for AI and Data Science for Integrated Diagnostics (AI2D), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Mohamad Habes (M)

Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
ORCID: 0000-0001-9447-5805

David Wolk (D)

Artificial Intelligence in Biomedical Imaging Laboratory (AIBIL), Center for AI and Data Science for Integrated Diagnostics (AI2D), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Neurology and Penn Memory Center, University of Pennsylvania, Philadelphia, PA, USA.

Li Shen (L)

Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
ORCID: 0000-0002-5443-0503

Haochang Shou (H)

Artificial Intelligence in Biomedical Imaging Laboratory (AIBIL), Center for AI and Data Science for Integrated Diagnostics (AI2D), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Penn Statistics in Imaging and Visualization Center, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Christos Davatzikos (C)

Artificial Intelligence in Biomedical Imaging Laboratory (AIBIL), Center for AI and Data Science for Integrated Diagnostics (AI2D), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Christos.Davatzikos@pennmedicine.upenn.edu.
ORCID: 0000-0002-1025-8561

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Genetic and clinical correlates of two...
questionsmedicales.fr › Troubles mentaux › Troubles neurocognitifs › Démence › Maladie d'Alzheimer › Genetic and clinical correlates of two...
questionsmedicales.fr › Troubles mentaux › Troubles neurocognitifs › Troubles de la cognition › Dysfonctionnement cognitif › Genetic and clinical correlates of two...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › Genetic and clinical correlates of two...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Épidémiologie moléculaire › Étude d'association pangénomique › Genetic and clinical correlates of two...
questionsmedicales.fr › États, signes et symptômes pathologiques › États anatomopathologiques › Atrophie › Genetic and clinical correlates of two...
questionsmedicales.fr › Système nerveux › Système nerveux central › Encéphale › Genetic and clinical correlates of two...
questionsmedicales.fr › Diagnostic › Techniques et procédures diagnostiques › Imagerie diagnostique › Tomographie › Imagerie par résonance magnétique › Genetic and clinical correlates of two...
questionsmedicales.fr › Système nerveux › Système nerveux central › Encéphale › Prosencéphale › Télencéphale › Cerveau › Cortex cérébral › Lobe temporal › Genetic and clinical correlates of two...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › Sujet âgé de 80 ans ou plus › Genetic and clinical correlates of two...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Lipoprotéines › Apolipoprotéines › Apolipoprotéines E › Apolipoprotéine E4 › Genetic and clinical correlates of two...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Adulte d'âge moyen › Genetic and clinical correlates of two...