Most of the existing electrochemical systems failed to achieve satisfactory results in early diagnosis of Alzheimer's disease (AD) owing to a deficiency of effective signal transduction. A new method for the electrochemical detection of AD biomarkers (amyloid-beta oligomers, Aβ1-42 oligomers) was developed based on a double amplification strategy. Titanium carbide (TiC) MXene decorated by gold nanoparticles (Au-MXene) as the electrode substrate not only gave rise to the electrochemical response due to its paradoxical surface area and conspicuous charge mobility, but also provided vast numbers of binding sites for aptamers (Apt) of Aβ1-42 oligomers. Meanwhile, AuNPs were incorporated into covalent organic frameworks (COFs), which were further modified by Apt and electron mediator (toluidine blue, TB). The Apt/TB-Au@COFs composite was utilized as a label because of their improvement of the electron-hole separation efficiency and optimization of the charge-carrier utilization. The proposed electrochemical assay established highly efficient platform for the detection of Aβ1-42 oligomers with a linear range from 0.01 pg mL to 180 pg mL and an ultralow detection limit of 4.27 fg mL (S/N = 3). This biosensing platform had potential applications in molecular diagnostics of AD serum samples.