BACKGROUND: Identifying individuals at risk for dementia and Alzheimer's disease (AD) in the general population (GP) is increasingly essential due to new diagnostic criteria and opportunities for effective interventions. Plasma-based biomarkers (pBB) offer a promising approach for detecting positive amyloid profile. However, their effectiveness in predicting clinical dementia and AD risk at the GP level remains largely unexplored. OBJECTIVES: To assess the risk of clinical dementia and AD using pBB amyloid biomarkers in GP using the most up-to-date proteomic techniques. DESIGN: Case-cohort study randomly selected from a prospective cohort. SETTING: The three-city community-living study. PARTICIPANTS: Over 65 years recruited from the electoral rolls of three French cities. MEASUREMENTS: pBB amyloid levels (Aβ42, Aβ40 and APP669-711) were measured in the plasma using the mass spectrometry-based (IPMS)-Shimadzu modified technology. Patients were monitored for up to 6 years for incident dementia and AD according to DSM-IV and NINCDS/ADRDA criteria. Cox proportional hazard models adjusted for multiple covariables, including age and renal function, were used to estimate hazard ratios. RESULTS: Plasma samples from 327 participants were analyzed with a mean age 83 years (80-87), 64.8 % females and a median follow-up time of 2.7 years (0.8-4.8) and including 121 incident dementia cases. Our findings indicate that the Aβ42/Aβ40 ratio, along with a composite score that encompasses APP669-711 and Aβ40/Aβ42 ratios, serves as significant predictors of clinical dementia [HR(95 %CI) = 3.52 (1.69-7.32), p-value<0.001 and 4.34 (2.06-9.17), p-value<0.001, respectively] and AD risk over a six-year period, while also accounting for age and sex interactions. Furthermore, elevated Aβ40 levels correlate with an increased risk of developing dementia (HR=2.56, 95 % CI 1.22-5.35, p = 0.01) and AD (HR=2.60, 95 %CI 1.06-6.36, p = 0.04), and our study confirms that Aβ42 concentrations are significantly influenced by renal function. CONCLUSIONS: This research advances the potential application of plasma amyloid biomarkers for assessing the risk of clinical dementia and AD in the general population within short period of time, positioning it as a valuable tool alongside existing plasma PT217 biomarkers or using ratio of both of them.< Réduire