Hallmark proteins implicated in Alzheimer's disease (AD), amyloid and tau, can now be quantified in plasma samples using single-molecule array (SIMOA). However, these proteins not only circulate in plasma but are also present in neurally-derived extracellular vesicles (NDEVs) secreted by neurons into the plasma. Our objective is to identify the most promising candidate for plasma AD diagnosis and assess the impact of NDEVs on such quantifications.Plasma samples were collected from clinically normal (CN) participants (N=236, female/male sex ratio=1.95, mean age 66.4±7.6, Apoε4 positive n=68, Apoε4 negative n=168) and AD patients (N=55, female/male sex ratio=01.2, mean age 70.09±8.8). Amyloid 42–40 peptides and total-tau protein quantification was accomplished via SIMOA multiplex analysis, and DELFIA ELISA immunoassay was employed for relative quantification of NDBEs circulating in plasma.The Aβ42/40 ratio emerged as the optimal candidate for plasma biomarker. Statistical analysis (Gaussian mixture model) established a threshold of 0.0472 for the general population without dementia screening. NDEVs quantity in plasma correlate with circulating biomarkers in CN individuals (Aβ42: p=0.031, r=-0.51; Aβ40: p=0.009, r=-0.45; t-tau: p=0.0002, r=-0.52), indicating that higher NDEVs counts were associated with lower protein concentrations in plasma. However, this correlation was absent in AD patients.Key findings suggest that the Aβ42/40 ratio is effective for AD screening, reducing the probability of AD diagnosis to 5.2% at age 60 and 12.5% at age 80 if the test yields a negative result. NDEVs quantity in plasma was identified as a significant confounding factor in plasma biomarker measurements.