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.