Cassandra Blew, Michael R. Duggan, Dimitrios Tsitsipatis, Gabriela Gómez, Zulema Hernandez Rodriguez, Luke C. Pilling, Jingsha Chen, E. Jacobsen, Heather E. Dark, Yifei Lü, 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 E. Lyashkov, Yevgeniya Lukyanenko, Mika Kivimäki, Philipp Frank, Lori L. Jennings, Valborg Guðmundsdóttir, Vilmundur Guðnason, Lenore J. Launer, Naoto Kaneko, Shintaro Kato, Makio Furuichi, Masaki Shibayama, Masahisa Katsuno, Keita Hiraga, Yukiko Nishita, Rei Otsuka, James Russell Pike, Mary R. Rooney, Pascal Schlosser, Yuhan Cui, Guray Erus, Christos Davatzikos, Rebecca F. Gottesman, Iwao Waga, Priya Palta, Christie M. Ballantyne, Michael Griswold, Zhonghua Liu, Luigi Ferrucci, Allison B. Herman, Keenan A. Walker
Growth/differentiation factor-15 (GDF15) is a secreted peptide hormone and cytokine that is strongly associated with dementia risk. However, the extent to which plasma 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 dementia compared to Alzheimer's disease (AD). 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, diffuse neurodegeneration, phosphorylated tau, and a cerebrospinal fluid proteomic signature indicative of neuro-immune 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, pyruvate metabolism, and scavenging of heme. 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.