OMG! A proteomic determinant of neurodegenerative resiliency

Molecular neurodegeneration |

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, David A Bennett, Carlos Cruchaga, Tony Wyss-Coray, Mika Kivimäki, Josef Coresh, Keenan A Walker

Mol Neurodegener. 2026 Jan 5;21(1):9. doi: 10.1186/s13024-025-00921-1.

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.

PMID:41491993 | PMC:PMC12870269 | DOI:10.1186/s13024-025-00921-1