AbstractBackgroundin the clinical course of Alzheimer’s disease (AD) development, the dementia phase is commonly preceded by a prodromal AD phase, which is mainly characterized by reaching the highest levels of Aβ and p‐tau‐mediated neuronal injury and a mild cognitive impairment (MCI) clinical status. Because of that, most AD cases are diagnosed when neuronal damage is already established and irreversible. Therefore, a differential diagnosis of MCI causes in these prodromal stages is one of the greatest challenges for clinicians. Blood biomarkers are emerging as desirable tools for pre‐screening purposes, but the current results are still being analyzed and much more data is needed to be implemented in clinical practice. Because of that, plasma exosomes (pEXOs) are gaining popularity as a new source of biomarkers for the early stages of AD developmentMethodto identify an exosome proteomics signature linked to prodromal AD, we performed a cross‐sectional study on two groups of patients with early‐onset MCI (EOMCI) (Aβ +/‐) in which 184 biomarkers were measured in pEXOs, cerebrospinal fluid (CSF), and plasma samples using multiplex PEA technology of Olink^© proteomics.Resultthe obtained results showed that proteins measured in pEXOs from EOMCI patients with established amyloidosis correlated with CSF p‐tau¹⁸¹ levels, brain ventricle volume changes, white matter hyperintensities, and MMSE scores. In addition, the correlations of pEXOs proteins with different parameters were able to discriminate between EOMCI Aβ(+) and Aβ(‐) patients, whereas the CSF or plasma proteome did not.Conclusionour findings suggest that pEXOs could be able to provide information regarding the initial amyloidotic changes of AD. At this early stage, our results may indicate that pEXOs biomarker profile is associated with the AD‐specific neurodegeneration process governed by p‐tau and Aβ. Circulating exosomes may acquire a pathological protein signature of AD before raw plasma, becoming potential biomarkers for identifying subjects at the earliest stages of AD development. However, additional research is required to comprehend the molecular pathways underlying these findings and validate the obtained results in an independent cohort.