Midlife GDF15 elevation predicts vascular dementia more strongly than Alzheimer's across six cohorts

Researchers combined proteomic data with longitudinal clinical, neuroimaging, and CSF measures. GDF15, a stress-induced cytokine linked to inflammation and mitochondrial dysfunction, emerged as the strongest midlife signal for all-cause dementia. Associations were substantially stronger for vascular dementia than for Alzheimer's disease or related dementias, with elevated levels also correlating to accelerated brain atrophy even in cognitively normal participants. This pattern suggests GDF15 captures vascular and metabolic injury pathways that precede typical amyloid-tau accumulation.

Existing blood-biomarker work has centered on phosphorylated tau and neurofilament light for Alzheimer's staging. The current findings shift attention to earlier, upstream stressors detectable decades prior. Because GDF15 also tracks cardiovascular and renal aging, it may integrate multiple modifiable risk factors rather than serving as a disease-specific marker. In vitro experiments showed GDF15 impairs antiviral responses in immune cells, hinting at mechanistic overlap with chronic low-grade inflammation.

Validation across more diverse ancestries and integration with vascular risk scores remain essential before any screening use. Randomized trials testing whether GDF15-stratified lifestyle or pharmacologic interventions alter trajectories will determine clinical utility.