•Profiling both protein and miRNA affords a better prognostic capacity.•Testing both proteins and miRNA expression in EVs can increase benefit.•Differential miRNA and protein expression have no correlation with age and sex. Protein and miRNA enrichment within extracellular vesicles (EVs) isolated from patients with Alzheimer’s disease (AD) has been shown to have putative diagnostic value. However, whether a combination of both will be more advantageous is unknown. EVs were enriched from serum samples obtained from patients with sporadic AD (n = 13), mild cognitive impairment (MCI) (n = 10), vascular dementia (VaD) (n = 10), and healthy controls (HC) (n = 10). Expression of protein levels of beta-amyloid peptide (Aβ1–42), total tau, P-T181-tau, and P-S396-tau and 18 microRNAs (miRNAs) in the EVs was performed by ELISA and qRT-PCR, respectively. Results were validated in an independent cohort of 18 subjects each by qRT-PCR assays. EV protein expression of Aβ1–42, total-tau, P-T181-tau and P-S396-tau, were significantly different among AD, MCI and VaD. Hsa-miR-1306-5p, hsa-miR-342-3p, and hsa-15b-3p were all significantly downregulated in patients with AD compared to HC (P < 0.05), only hsa-miR-1306-5p expression was differentially expressed between AD, MCI, and VaD samples. Similarly, whereas all 14 miRNAs were significantly upregulated in patients with AD compared to HC, only hsa-miR-93-5p, hsa-miR-424-5p, and hsa-miR-3065-5p were differentially expressed when AD samples were compared to MCI and VaD samples. Even though the sample size was small, the results of the current pilot study indicates that hsa-miR-1306-5p, hsa-miR-93-5p, hsa-miR-424-5p, and hsa-miR-3065-5p, and expression of P-S396-tau in EVs might provide a combinatorial protein and miRNA signature to differentiate between HC, patients with MCI or VaD from patient with sporadic AD.