Serum neuron-derived extracellular vesicle mitochondrial DNA as a potential biomarker for mild cognitive impairment due to AD

Mild cognitive impairment (MCI) represents the initial clinical manifestation, eventually evolving into the distinctive features of Alzheimer's disease (AD), making its early identification crucial. Notably, mitochondrial dysfunction is an early characteristic of AD. Neuron-derived extracellular vesicles (NDEVs) can cross the blood-brain barrier, and their mitochondrial DNA (mtDNA) can reflect intracerebral lesions, showing considerable potential. In this study, we investigated the alterations in mtDNA within serum NDEVs and evaluated their potential as early diagnostic biomarkers for MCI due to AD.

A total of 42 MCI patients, 49 AD patients, and 57 age-matched cognitively unimpaired (CU) controls were enrolled. Serum NDEVs were enriched and characterized, and their mtDNA levels were quantified by qPCR. ROC curve was used to analyze diagnostic performance, and the integration of multimodal biomarkers was explored.

Serum NDEVs mtDNA levels were decreased in patients with AD-MCI, and a significant positive correlation was observed between serum NDEVs mtDNA levels and MMSE scores in MCI patients (r = 0.4864, P = 0.0407), and a similar association was observed in the AD group (r = 0.3857, P = 0.0469). In terms of diagnostic performance, serum NDEV mtDNA demonstrated outstanding discrimination between CU controls and AD subjects, achieving an area under the curve (AUC) of 0.965 (95% CI: 0.933-0.997), with 97.92% sensitivity and 89.09% specificity. Moreover, it also demonstrated moderate efficacy in differentiating early MCI from AD (AUC = 0.736, 95% CI: 0.629-0.842; sensitivity = 72.92%, specificity = 66.67%). In exploratory analyses of clinical and metabolic factors, serum NDEV mtDNA levels were positively correlated with HCY in MCI patients, while in AD patients, NDEV mtDNA levels were elevated in those with diabetes and positively correlated with TG. Notably, integrating NDEV mtDNA with established biomarkers, including p-Tau 217, GFAP, and APOE ε4 carrier status, significantly improved the accuracy of MCI detection, highlighting its value in multimodal biomarker strategies.

Serum NDEVs mtDNA levels were significantly reduced in patients with MCI and AD, suggesting strong potential as an early diagnostic biomarker for MCI due to AD.