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
2026-06-26
Growth/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.