Journal Article Ahead of print
PubMed: 41491993 DOI: 10.1186/s13024-025-00921-1
OMG! A proteomic determinant of neurodegenerative resiliency.
Mol Neurodegener
Authors: Michael R Duggan, Hamilton Se-Hwee Oh, Philipp Frank, Gabriela T Gomez, David Zweibaum, Yuhan Cui, Jingsha Chen, Aditya Surapaneni, Cassandra O Blew, Heather E Dark, Cassandra M Joynes, Sridhar Kandala, Murat Bilgel, Amelia Farinas, Guray Erus, Qu Tian, Julián Candia, Krishna A Pucha, Bennett A Landman, Logan Dumitrescu, Timothy J Hohman, Alexandria Lewis, Abhay Moghekar, Fatemeh Siavoshi, Muhammad Ali, Menghan Liu, Ying Xu, Daniel Western, Naoto Kaneko, Shintaro Kato, Makio Furuichi, Masaki Shibayama, Masahisa Katsuno, Yukiko Nishita, Rei Otsuka, Rebecca F Gottesman, Eric B Dammer, Nicholas T Seyfried, Allan I Levey, Erik C B Johnson, Elizabeth Mormino, Anthony D Wagner, Kathleen L Poston, Dimitrios Kapogiannis, Morgan E Grams, Pavan Bhargava, Iwao Waga, Christos Davatzikos, Susan M Resnick, Luigi Ferrucci … and 6 other authors
Affiliations
- Laboratory of Behavioral Neuroscience, National Institute on Aging, NIH BRC BG RM 04B311, 251 Bayview Blvd, Baltimore, MD, 21224, USA.
- Graduate Program in Stem Cell and Regenerative Medicine, Stanford University, Stanford, CA, USA.
- The Phil and Penny Knight Initiative for Brain Resilience, Stanford University, Stanford, CA, USA.
- Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
- Department of Epidemiology and Public Health, University College London, London, UK.
- Brain Sciences, University College London, London, UK.
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
- Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA.
- Artificial Intelligence in Biomedical Imaging Laboratory, Perelman School of Medicine, Philadelphia, PA, USA.
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
- Department of Medicine, NYU Grossman School of Medicine, New York, NY, USA.
- Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
- Department of Radiology & Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.
- Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN, USA.
- Department of Electrical and Computer Engineering, Vanderbilt University, Nashville, TN, USA.
- Department of Computer Science, Vanderbilt University, Nashville, TN, USA.
- Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA.
- Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Psychiatry, Washington University, St. Louis, MO, USA.
- NeuroGenomics and Informatics Center, Washington University, St. Louis, MO, USA.
- NEC Solution Innovators Limited, Koto-ku, Tokyo, Japan.
- Foneslife Corporation, Chuo-ku, Tokyo, Japan.
- Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
- Department of Clinical Research Education, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
- Department of Epidemiology of Aging, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan.
- Stroke Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
- Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia, USA.
- Goizueta Brain Health Institute and Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, Georgia, USA.
- Center for Neurodegenerative Disease Center, Emory University School of Medicine, Atlanta, Georgia, USA.
- Department of Neurology, School of Medicine, Emory University, Atlanta, Georgia, USA.
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
- Department of Psychology, Stanford University, Stanford, CA, USA.
- Tohoku University, Aoba-ku, Sendai, Japan.
Abstract
BACKGROUND
Biofluid proteomics can enhance our understanding of the neurodegenerative mechanisms underlying Alzheimer's disease and related dementias (ADRDs). Oligodendrocyte myelin glycoprotein (OMG) is a brain-specific protein implicated in myelination, but its potential mechanistic, biomarker, and therapeutic roles in ADRDs requires further elucidation.
METHODS
After detecting an inverse association between its abundance in peripheral circulation and cortical amyloid deposition in two community-based cohorts, the current study characterized OMG's role in ADRDs with high-throughput proteomics from sixteen independent cohorts. Data included a variety of cross-sectional and longitudinal community-based and clinical cohorts from North America, Europe, and Asia, and incorporated complementary biofluids, biospecimens, and proteomic platforms. Statistical analyses were conducted separately in each cohort.
RESULTS
We detected lower plasma OMG in individuals with cortical amyloid deposition, compromised brain structure, dementia, and multiple sclerosis, as well as in individuals who developed dementia over 7- to 20-year follow-up periods. OMG's CSF and brain proteomic signatures reflected broader neuroprotective mechanisms, especially axonal structural integrity, and two-sample Mendelian randomization causally implicated OMG as protective against multiple neurodegenerative diseases.
CONCLUSIONS
Our findings implicate OMG as a mechanistic determinant of neurodegenerative resiliency among older adults, which is reliably captured by its abundance in peripheral circulation.
MeSH
Dementia, Brain, Proteomics, Amyloid