Streamlined resource-efficient plasma amyloid-beta mass spectrometry assay has improved biomarker performance in preclinical Alzheimer's disease.

Plasma amyloid-β (Aβ) peptides, alone or in ratio with p-tau217, show strong potential as Alzheimer's disease biomarkers. While immunoprecipitation-mass spectrometry (IP-MS) is the preferred method for plasma Aβ quantification, current assays are resource- and time-intensive. Here, we developed a streamlined IP-MS method using a cost-effective instrument that significantly improved the efficiency of an original assay by incorporating a single immunoprecipitation step, an optimized buffer system, and approximately 75% reductions in antibody and sample volume requirements. Technical validation revealed excellent dilution linearity (r²>0.99), high precision (< 10% variation), enhanced sensitivity, improved Aβ recovery, and markedly increased signal-to-noise ratios. In a large cohort of cognitively normal older adults (n = 317), the plasma Aβ1-42/Aβ1-40 ratio achieved stronger concordance with Aβ-PET and superior accuracies to identify abnormal scans (AUC 0.81 vs. 0.65 for the original assay). Notably, accuracies remained high even with plasma volumes as low as 100 μL. The improved IP-MS method enables robust and simplified plasma Aβ assessment in Alzheimer's disease, with implications for prognosis, diagnosis and intervention trials.