Exosomal microRNAs (miRNAs) have been demonstrated to be biomarkers of Alzheimer's disease (AD). However, whether exosomal miRNAs can predict AD at the asymptomatic stage remains unclear.This study is a multicenter study with four independent datasets to verify the capacity of exosomal miRNAs to identify preclinical AD. Subjects were recruited from a Beijing center in the pilot study (dataset 1: subjects with AD, n = 20; control subjects, n = 20), from other centers across China (dataset 2: subjects with AD, n = 95; control subjects, n = 93), a longitudinal cohort (dataset 3: subjects with preclinical AD, n = 101; control subjects, n = 102), and a confirmation study on familial AD (dataset 4: mutation carriers, n = 56; nonmutation carriers, n = 57).A panel of miRNAs was changed in subjects with AD and can detect preclinical AD 5 to 7 years before the onset of cognitive impairment (areas under the curve = 0.85-0.88).Exosomal miRNAs can be effective biomarkers for predicting AD 5 to 7 years prior to cognitive impairment onset.Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.