miR-132–3p is down-regulated in plasma and CD171+ extracellular vesicles isolated from patients with mild Alzheimer’s disease

Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder in aging populations, demands minimally invasive biomarkers for early diagnosis and monitoring. Circulating microRNAs (miRNAs) show promise as such biomarkers. In this study, we examined the levels of five selected miRNAs, implicated in neurodegenerative processes, in plasma and neuron-derived extracellular vesicles (EVs) from cognitively healthy controls (n = 5), and patients with mild (n = 10) and moderate AD (n = 10), stratified by Mini-Mental State Examination (MMSE). miR-23a-3p, miR-223a-3p, and miR-132–3p were significantly downregulated in both plasma and EVs of AD patients, with miR-132–3p emerging as the strongest biomarker candidate for mild AD. Plasma miRNA levels strongly correlated with EV cargo, supporting plasma-based assessments. To validate these findings, miR-132–3p levels were analyzed in expanded cohorts, including cognitively healthy subjects (n = 36), mild AD (n = 37), and moderate AD (n = 40), as well as a cohort of subjects with mild cognitive impairment (MCI, n = 31) and an additional external cohort of cognitively healthy subjects (CTR external, n = 37). Results confirmed miR-132–3p downregulation in AD patients and revealed a significant elevation in MCI individuals, suggesting a potential neuroprotective role in AD early stages. These findings highlight miR-132–3p as a promising, minimally invasive biomarker for early AD diagnosis and disease progression monitoring. • CD171 + EVs and miR-23a-3p, miR-223a-3p, and miR-132–3p are significantly reduced in patients with Alzheimer’s disease. • miR-132–3p in EVs and plasma distinguishes mild AD from controls with high diagnostic accuracy. • miR-132–3p shows a U-shaped trend, elevated in MCI and reduced in AD, highlighting potential as an early neurodegeneration marker. • Plasma miRNAs mirror neuronal EV cargo, supporting their role as non-invasive AD biomarkers.