Preclinical Alzheimer's disease shows alterations in circulating neuronal-derived extracellular vesicle microRNAs in a multiethnic cohort.

Introduction: Alzheimer's disease (AD) is the leading cause of dementia, affecting around 50 million individuals worldwide. Brain-derived extracellular vesicles (EVs) can cross the blood-brain barrier carrying neuron-specific molecules, such as microRNAs (miRNAs), which have potential as biomarkers of neurodegeneration.

Methods: We explored the association between neuronal-derived EV miRNAs from serum and AD clinical status by performing a transcriptome-wide association study involving 46 participants with clinical AD, 14 participants with preclinical AD, and 60 neurologically healthy controls.

Results: We identified 14 miRNAs associated with AD risk, with more pronounced transcriptional alterations in preclinical individuals compared to clinical AD individuals. Functional analysis revealed enrichment of miRNA-target genes in neurodegenerative pathways, highlighting synuclein alpha (SNCA), cytochrome c, somatic (CYCS), and microtubule associated protein tau (MAPT) as key targets.

Discussion: Our results highlight the potential role of neuronal-derived EVs in neurodegeneration and suggest avenues for further research into brain-derived biomarkers.

Highlights: Neuronal-derived extracellular vesicles (NDEVs) carry potential brain biomarkers. We tested the association between NDEV microRNAs (miRNAs) and Alzheimer's disease (AD). Fourteen NDEV miRNAs were associated with AD. Preclinical AD displayed more pronounced transcriptional changes than clinical AD. miRNA-target genes were enriched in pathways associated with neurodegeneration.