INTRODUCTION: Blood-based biomarkers (BBBMs), including plasma amyloid beta (Aβ) or phosphorylated tau (p-tau), combined with apolipoprotein E ( METHODS: We conducted a simulation study utilizing data from our ongoing Japanese Trial-Ready Cohort (J-TRC) onsite study ( RESULTS: Applying BBBM prescreening significantly decreased sensitivity and increased specificity and PPV compared to the no-prescreening scenario. Although no single model was superior in all performance metrics, a trade-off between sensitivity and specificity was observed. Generalized linear models (GLMs) simultaneously incorporating plasma Aβ42/Aβ40 ratio and p-tau217 showed a balanced efficacy (the best level of improvement in number needed to screen (NNS) but modest worsening in sensitivity) and the best level of cost-effectiveness compared to other models, although there were substantial overlaps in their 95% confidence intervals (CIs). The minimum-required PET/BBBM cost ratio to achieve improved cost-effectiveness by employing the prescreening process was negatively associated with the background prevalence of amyloid positivity. DISCUSSION: The choice of prescreening strategy in AD prevention studies/trials should be tailored to specific trial requirements, considering the relative importance of sensitivity versus cost-effectiveness, local testing cost environments, and background population characteristics. HIGHLIGHTS: We investigated different models of blood-based biomarker (BBBM) prescreening.Data from Japanese Trial-Ready Cohort Study were used for simulation.BBBM reduced the number needed to screen with positron emission tomography (PET) but decreased the sensitivity.The cost-effectiveness improved with a higher PET/BBBM cost ratio.No single model was optimal for all scenarios.