Changes in five cerebrospinal fluid and three plasma Alzheimer's disease biomarkers across increasing brain amyloid-beta and tau pathology burden.

CSF Aβ42/Aβ40 declines earliest, dropping at the second quartile of Aβ burden (p<0.001) and detecting low/intermediate Aβ with AUC 0.984, while CSF p-tau markers rise only at the third quartile and perform best at advanced Aβ (AUCs 0.889 to 0.980) and intermediate tau stages (AUCs 0.949 to 0.995). In 250 participants with ante-mortem fluid sampled a median of 1.5 months (CSF) or 1 month (plasma) before death, p-tau217-based markers outperformed p-tau181 counterparts, and plasma p-tau217 measures identified only advanced Aβ and tau burden (AUCs 0.893 to 0.928). The findings support a sequential biomarker model and show current fluid biomarkers miss the earliest Aβ deposition.