GDF-11, GDF-15, Jag-1, and Leptin in Neuronal-Derived Extracellular Vesicles As Aging-Related Biomarkers to Identify Individuals at Risk of Alzheimer's Dementia: A Pilot Study.

Aging is the strongest risk factor for Alzheimer's disease (AD). Identifying reliable biomarkers of brain aging helps to predict functional decline and dementia onset. Evaluations of aging-related biomarkers in plasma and neuronal-derived extracellular vesicles (nEVs) from cognitively healthy and AD subjects, alongside post-mortem IPL brain samples from control (Ctr), pre-clinical AD (PCAD), mild cognitive impairment (MCI) and AD cases were performed. Cognitive tests, functional assessments, and MRI data were also included. Biomarkers in nEVs more accurately reflected brain pathology than those measured in plasma and showed stronger associations with cognitive and functional decline. Sex-specific patterns also emerged: GDF-15 was higher in nEVs from females with AD, whereas IL-6, IL-18 and Jag-1 were higher in nEVs from males with AD. A minimal nEV-derived panel including lower GDF-11 and higher GDF-15, Jag-1 and Leptin (after correction for age and sex) discriminated AD from Ctr and was associated with MRI-determined cortical atrophy in regions vulnerable to AD. These markers captured aging-related molecular trajectories that were disrupted in AD, and key associations observed in nEVs were confirmed in post-mortem brain tissue. Our results suggests that nEV-derived biomarkers capture early, brain-specific and sex-modulated aging signatures, providing superior sensitivity compared to plasma. Their convergence with post-mortem findings underscores their biological validity and translational potential. These results highlight the value of nEVs for stratifying individuals at higher risk of AD and support their integration into precision medicine approaches for dementia prevention.