OMG! A proteomic determinant of neurodegenerative resiliency.
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Duggan Michael R, Oh Hamilton Se-Hwee, Frank Philipp, Gomez Gabriela T, Zweibaum David, Cui Yuhan, Chen Jingsha, Surapaneni Aditya, Blew Cassandra O, Dark Heather E, Joynes Cassandra M, Kandala Sridhar, Bilgel Murat, Farinas Amelia, Erus Guray, Tian Qu, Candia Julián, Pucha Krishna A, Landman Bennett A, Dumitrescu Logan, Hohman Timothy J, Lewis Alexandria, Moghekar Abhay, Siavoshi Fatemeh, Ali Muhammad, Liu Menghan, Xu Ying, Western Daniel, Kaneko Naoto, Kato Shintaro, Furuichi Makio, Shibayama Masaki, Katsuno Masahisa, Nishita Yukiko, Otsuka Rei, Gottesman Rebecca F, Dammer Eric B, Seyfried Nicholas T, Levey Allan I, B Johnson Erik C, Mormino Elizabeth, Wagner Anthony D, Poston Kathleen L, Kapogiannis Dimitrios, Grams Morgan E, Bhargava Pavan, Waga Iwao, Davatzikos Christos, Resnick Susan M, Ferrucci Luigi, Bennett David A, Cruchaga Carlos, Wyss-Coray Tony, Kivimäki Mika, Coresh Josef, Walker Keenan A
Аннотация
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.