Plasma GDF15 affects long-term dementia risk and alters neuroimmune signaling
Cassandra O. Blew, Michael R. Duggan, Dimitrios Tsitsipatis, Gabriela T. Gomez, Zulema Rodriguez-Hernandez, Luke C. Pilling, Jingsha Chen, Eva Jacobsen, Heather E. Dark, Yifei Lu, Shannon M. Drouin, Cassandra M. Joynes, Minhao Yao, Murat Bilgel, Abhay Moghekar, Qu Tian, Julián Candia, Mary Kaileh, Aditi Gupta, Krystyna Mazan-Mamczarz, Myriam Gorospe, Alexey Lyashkov, Yevgeniya Lukyanenko, Mika Kivimaki, Philipp Frank, Lori L. Jennings, Valborg Gudmundsdottir, Vilmundur Gudnason, Lenore J. Launer, Naoto Kaneko, Shintaro Kato, Makio Furuichi, Masaki Shibayama, Masahisa Katsuno, Keita Hiraga, Yukiko Nishita, Rei Otsuka, James R. Pike, Mary R. Rooney, Pascal Schlosser, Yuhan Cui, Guray Erus, Christos Davatzikos, Rebecca F. Gottesman, Iwao Waga, Priya Palta, Christie Ballantyne, Michael Griswold, Zhonghua Liu, Luigi Ferrucci, Allison B. Herman, Keenan A. WalkerGrowth/differentiation factor–15 (GDF15) is a secreted cytokine strongly associated with dementia risk. However, the extent to which GDF15 represents a biomarker and driver of dementia risk remains unclear. Across multiple cohorts, we demonstrated that plasma GDF15 is associated with greater dementia risk over 15- to 25-year follow-up periods when measured in midlife, with stronger associations observed for vascular, compared to Alzheimer’s disease (AD), dementia. Two-sample Mendelian randomization supported plasma GDF15’s mechanistic role in AD and related dementias, while cohort studies linked it to cerebral small vessel disease, neurodegeneration, phosphorylated tau, and a cerebrospinal fluid proteomic signature indicative of neuroimmune activation. Exposure of cultured myeloid cells to recombinant GDF15 altered biological pathways that we subsequently demonstrated are predictive of dementia risk, including interferon/antiviral responses. These findings support circulating GDF15’s role as an early biomarker—particularly for vascular dementia and neuroinflammation—and identify the mechanisms by which it may drive dementia risk.