Abstract Background Plasma amyloid-β (Aβ) peptide levels have been examined as a low-cost accessible marker for risk of incident Alzheimer's disease (AD) and dementia, but results have varied between studies. We reassessed these associations in one of the largest, prospective, community-based studies to date. Methods A total of 2189 dementia-free, Framingham Study participants aged >60 years (mean age, 72 ± 8 years; 56% women) had plasma Aβ1-42 and Aβ1-40 measured and were followed prospectively (mean, 7.6 ± 3.0 years) for dementia/AD. Results Increased plasma Aβ1-42 levels were associated with lower risk of dementia (Aβ1-42 : hazard ratio HR = 0.80 0.71‒0.90, P  < .001; Aβ1-42 -to-Aβ1-40 ratio: HR = 0.86 0.76‒0.98, P  = .027) and AD (Aβ1-42 : HR = 0.79 0.69‒0.90, P  < .001; Aβ1-42 -to-Aβ1-40 ratio: HR = 0.83 0.72‒0.96, P  = .012). Conclusion Our results suggest that lower plasma Aβ levels are associated with risk of incident AD and dementia. They encourage further evaluation of plasma Aβ levels as a biomarker for risk of developing clinical AD and dementia.