Early stages of many neurodegenerative diseases, such as Alzheimer's disease, vascular and frontotemporal dementia, and Parkinson's disease, are frequently associated with Mild Cognitive Impairment (MCI). A minimally invasive screening test for early detection of MCI may be used to select optimal patient groups in clinical trials, to monitor disease progression and response to treatment, and to better plan patient clinical care. Here, we examined the feasibility of using pairs of brain-enriched plasma microRNA (miRNA), at least one of which is enriched in synapses and neurites, as biomarkers that could differentiate patients with MCI from age-matched controls. The identified biomarker pairs fall into two sets: the “miR-132 family” (miR-128/miR-491-5p, miR-132/miR-491-5p and mir-874/miR-491-5p) and the “miR-134 family” (miR-134/miR-370, miR-323-3p/miR-370 and miR-382/miR-370). The area under the Receiver-Operating Characteristic curve for the differentiation of MCI from controls using these biomarker pairs is 0.91-0.95, with sensitivity and specificity at 79%-100% (miR-132 family) and 79%-95% (miR-134 family), and p < 0.001. In a separate longitudinal study, the identified miRNA biomarker pairs successfully detected MCI in majority of patients at asymptomatic stage 1-5 years prior to clinical diagnosis. The reported biomarker pairs also appear useful for detecting age-related brain changes. Further testing in a larger study is necessary for validation of these results.