A blood protein long associated with dementia in older adults may also identify people at increased risk decades before symptoms develop, according to a large international study published in Science Advances.
Analyzing data from six large longitudinal cohorts, researchers from the National Institute on Aging found that elevated levels of growth differentiation factor-15 (GDF15)—a circulating cytokine involved in inflammation and cellular stress responses—in adults younger than 55 years were associated with a significantly greater risk of developing dementia later in life, particularly vascular dementia. The findings suggest that molecular changes associated with neurodegeneration may be detectable years before cognitive symptoms emerge.
“Our findings extend existing evidence by demonstrating that elevated GDF15 levels are detectable in midlife—before age 55—in individuals who later develop dementia,’” the authors write.
The study included approximately 500,000 participants from the UK Biobank, more than 15,000 from the Atherosclerosis Risk in Communities (ARIC) study, nearly 5,700 from the AGES-Reykjavik Study, and three additional cohorts. Participants were followed for 15 to 25 years, enabling investigators to determine whether plasma GDF15 levels measured in midlife predicted future dementia.
Across nearly all cohorts, elevated plasma GDF15 was associated with increased risk for all-cause dementia. However, the relationship was strongest for vascular dementia, with effect sizes approximately two to five times greater than those observed for Alzheimer’s disease.
The distinction suggests GDF15 may be particularly useful for identifying individuals at risk for vascular cognitive impairment rather than the amyloid-driven pathology typically associated with Alzheimer’s disease. As the authors note, “the association was particularly pronounced for vascular dementia,” supporting the protein’s potential as an early marker of vascular brain injury.
To investigate whether GDF15 might play a biological role in disease rather than simply reflect ongoing pathology, the researchers performed Mendelian randomization analyses using genetic data. The analyses supported a potential causal relationship between elevated circulating GDF15 and Alzheimer’s disease and related dementias.
Additional analyses linked higher plasma GDF15 concentrations with several established indicators of neurodegeneration, including cerebral small vessel disease, elevated phosphorylated tau (pTau-181) in both plasma and cerebrospinal fluid, and increased neurofilament light, a marker of neuronal injury. In contrast, GDF15 was not associated with amyloid pathology, suggesting that it may reflect alternative disease mechanisms.
Instead, multiple lines of evidence pointed toward inflammation and immune dysregulation. Individuals with elevated GDF15 exhibited cerebrospinal fluid protein signatures consistent with neuroimmune activation, including complement activation, inflammatory signaling pathways, and disease-associated microglial responses.
To better understand these mechanisms, the investigators exposed cultured human macrophages to recombinant GDF15. The protein altered cellular pathways involved in interferon signaling, energy metabolism, and heme scavenging—processes that have all been implicated in dementia risk. Together, the experimental and clinical findings suggest that GDF15 may actively influence neurodegeneration through immune and vascular pathways rather than acting solely as a marker of biological aging.
The authors conclude that “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.”
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