Quantifying proteins at ultra-low levels in high ionic-strength solutions by silicon nanowire field-effect transistor (SiNWFET) immunosensors is critically hindered due to the limited Debye length, charge distributions and uncontrollable orientations of protein molecules on the NW surfaces. In this study, we propose a novel strategy to overcome this issue by employing aptamer as bio-amplifier for different types of SiNWFET immunosensors to quantify Amyloid Beta (Aβ) 1-42, a biomarker for early-stage diagnosis of Alzheimer disease (AD) with ultra-low level in human serum (HS), as a representative target. Our method, presented for the first time, exhibits an outstanding performance in combination with mSAM-SiNWFET immunosensors (designed by integrating SiNWFET as transducer, mouse antibody as bio-receptor, and mixed self-assembled monolayers (mSAMs) for biofouling resistance) to sense Aβ 1-42 down to 100 fg/mL in HS, the lowest level achieved in comparison with the most advanced sensing technologies for Aβ 1-42. The empirical data also reveal that varied concentrations of Aβ 1-42 in diverse high ionic-strength environments (150 mM BTP and HS) express good linear relationship with signal amplified by aptamer. This novel approach is therefore potentially applied for early-stage diagnosis of AD and other clinical trials of biomarkers with ultra-low content in blood.