Baseline plasma p-tau217/Aβ42 as a sensitive marker for the severity of Alzheimer’s disease continuum

Plasma p-tau217/Aβ42 has shown promising diagnostic accuracy for Alzheimer’s disease (AD), but its prognostic utility for AD risk and clinical phenotype remains unclear. We analyzed 580 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Diagnostic performance of p-tau217/Aβ42 for cognitively normal (CN) vs. AD was evaluated. Cox regression and linear mixed-effects models were used to investigate the relationships of plasma p-tau217/Aβ42 with AD risk, cognitive decline and brain atrophy. We also quantified the incremental predictive value of p-tau217/Aβ42 for AD risk, cognitive decline and brain atrophy beyond demographic data and the Mini-Mental State Examination (MMSE). Mediation analyses were conducted to test whether brain structure accounted for associations between p-tau217/Aβ42 and cognition. Plasma p-tau217/Aβ42 levels were elevated in individuals with amyloid and tau pathology. Combining plasma p-tau217/Aβ42 with MMSE discriminated AD from CN individuals (AUC = 0.988). Higher p-tau217/Aβ42 predicted faster cognitive decline and greater hippocampal atrophy (P < 0.001), increased explained variance for cognitive decline and brain atrophy (ΔmR² = 0.016–0.121). Hippocampal volumes partially mediated the relationships of p-tau217/Aβ42 with cognition (5.3–14.8%). In non-demented participants, the high-risk group of p-tau217/Aβ42 showed higher AD risk (HR = 7.45, 95% CI 4.36–12.74) and faster cognitive decline, remaining significant among those with preserved baseline cognition (MMSE > 28). The addition of p-tau217/Aβ42 improved AD risk prediction beyond MMSE and covariates (ΔC = 0.040), increased time-dependent AUC at 2 years (ΔAUC = 0.030), reduced prediction error (ΔBrier = − 0.017), improved reclassification (NRI/IDI; all P < 0.05). Plasma p-tau217/Aβ42 is a strong prognostic biomarker for AD progression, adding value beyond demographics and brief cognitive screening. It supports a practical blood-first approach for risk stratification and prioritizing confirmatory testing, with additional utility for diagnostic support and trial enrichment.