Plasma GDF15 affects long-term dementia risk and alters neuro-immune signaling

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.