There is a significant need for a minimally invasive, cost-effective and reliable method to diagnose early-stage Alzheimer disease. Building on previous work, Nakamura et al. demonstrate the use of immunoprecipitation coupled with mass spectrometry to measure plasma amyloid-β (Aβ) biomarkers. Using two independent data sets, which included cognitively normal individuals and individuals with mild cognitive impairment or Alzheimer disease, they demonstrate that plasma amyloid-β precursor protein (APP)669–711/Aβ1–42 and Aβ1–40/Aβ1–42 ratios, and their composites, can accurately predict brain Aβ burden.