The present study aimed to determine whether peripheral blood neural cell adhesion molecule (NCAM)/amphiphysin 1 dual-labeled exosomal proteins and microRNAs (miRs) might serve as a marker for the early diagnosis of Alzheimer's disease (AD).This observational, retrospective, multicenter study used a two-stage design conducted in Beijing and Shanghai, China. The subjects included 76 patients with subjective cognitive decline (SCD), 80 with amnestic mild cognitive impairment (aMCI), 76 with dementia of Alzheimer's type (AD), 40 with vascular dementia (VaD), and 40 controls in the discovery stage. These results were confirmed in the verification stage. The levels of Aβ42, Aβ42/40, T-Tau, P-T181-tau, neurofilament light chain (NfL), and miR-29c-3p in peripheral blood amphiphysin 1 single-labeled and NCAM/amphiphysin 1 dual-labeled exosomes were captured and detected by immunoassay.In the discovery stage, the levels of Aβ42 and miR-29c-3p in peripheral blood NCAM/amphiphysin 1 dual-labeled exosome of the SCD group were significantly higher than those in control and VaD groups (all P < 0.05). The verification stage further confirmed the results of the discovery stage. Plasma NCAM/amphiphysin 1 dual-labeled exosomal miR-29c-3p showed a good diagnostic performance. The NCAM/amphiphysin 1 dual-labeled exosomal miR-29c-3p had the highest AUC for diagnosis of SCD. The levels of Aβ42, Aβ42/40, Tau, P-T181-tau, and miR-29c-3p in peripheral blood exosomes were correlated to those in CSF (all P < 0.05). The combination of exosomal biomarkers had slightly higher diagnostic efficiency than the individual biomarkers and that the exosomal biomarkers had the same diagnostic power as the CSF biomarkers.The plasma NCAM/amphiphysin 1 dual-labeled exosomal miR-29c-3p had potential advantages in the diagnosis of SCD.Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.