Abstract
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.