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.

Biomarkers measured in neuronal-derived extracellular vesicles (nEVs) more accurately reflected brain pathology than those measured in plasma.

• The study evaluated aging-related biomarkers in both plasma and nEVs from cognitively healthy and AD subjects.
• nEV-derived biomarkers showed stronger associations with cognitive and functional decline compared to plasma measurements.
• Key associations observed in nEVs were confirmed in post-mortem brain tissue from the inferior parietal lobule (IPL).
• The authors characterize nEVs as providing 'superior sensitivity compared to plasma.'

A minimal nEV-derived panel of four biomarkers (lower GDF-11 and higher GDF-15, Jag-1, and Leptin) discriminated AD from controls.

• The panel was identified after correction for age and sex.
• The discriminating panel consisted of lower GDF-11 combined with higher GDF-15, Jag-1, and Leptin.
• This panel was also associated with MRI-determined cortical atrophy in regions vulnerable to AD.
• The study is described as a pilot study, suggesting preliminary sample sizes.

Sex-specific patterns of nEV biomarkers emerged between AD males and females.

• GDF-15 was higher in nEVs from females with AD.
• IL-6, IL-18, and Jag-1 were higher in nEVs from males with AD.
• These sex-specific differences were identified in nEV measurements, underscoring sex-modulated aging signatures.

Post-mortem IPL brain samples from control, pre-clinical AD (PCAD), MCI, and AD cases were used to validate nEV biomarker findings.

• Four groups were represented in post-mortem tissue: control (Ctr), pre-clinical AD (PCAD), mild cognitive impairment (MCI), and AD.
• Key associations observed in nEVs were confirmed in post-mortem brain tissue.
• This convergence with post-mortem findings was described as underscoring 'biological validity and translational potential' of the nEV biomarkers.

The nEV-derived biomarker panel was associated with MRI-determined cortical atrophy in brain regions vulnerable to AD.

• MRI data were included alongside cognitive tests and functional assessments.
• The association was specifically with cortical atrophy in regions known to be vulnerable to AD pathology.
• The nEV panel markers captured 'aging-related molecular trajectories that were disrupted in AD.'

The study identified aging-related biomarkers in nEVs as capturing early, brain-specific aging signatures relevant to AD risk stratification.

• Biomarkers studied included GDF-11, GDF-15, Jag-1, Leptin, IL-6, and IL-18.
• The markers were described as capturing 'early, brain-specific and sex-modulated aging signatures.'
• The authors suggest these results 'highlight the value of nEVs for stratifying individuals at higher risk of AD.'
• The findings are presented as supporting integration of nEV biomarkers into precision medicine approaches for dementia prevention.