Plasma pTau217 as a Prognostic, Risk-Stratification, and Monitoring Biomarker of Clinical Progression in Lewy Body Disease

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Abstract Background and Objectives While plasma phosphorylated tau-217 (pTau217) detects co-occurring Alzheimer’s disease (AD) neuropathologic change in Lewy body disease (LBD), relationships with long-term clinical outcomes remain unclear. Our aim was to evaluate plasma pTau217 as a prognostic, risk-stratification, and monitoring biomarker of cognitive and functional decline in LBD. Methods This prospective longitudinal study included Stanford Alzheimer’s Disease Research Center participants enrolled from 2015-2023 with plasma pTau217 data and clinical diagnoses of LBD spectrum, AD spectrum, or healthy control (HC). To evaluate prognostic and monitoring utility, respectively, linear mixed-effect models tested whether baseline level and longitudinal change (2-5 years) in plasma pTau217 were associated with longitudinal changes (2-8-years) in daily functioning (Clinical Dementia Rating-Sum of Boxes [CDR-SB]), global cognition (Montreal Cognitive Assessment [MoCA]), and 5 domain-specific cognitive indices. For risk-stratification, baseline plasma pTau217 status was defined using an amyloid PET-derived, LBD-specific cut-point to examine whether participants with abnormal levels demonstrated faster clinical progression in separate linear-mixed effects and survival models. Results A total of 501 participants (mean[SD] age = 71.1[8.5]; 51.5% female) were included across LBD ( n = 131), AD ( n = 133), and HC ( n = 237) groups. In LBD, higher baseline plasma pTau217 was associated with faster CDR-SB increase ( β = 0.30; 95% CI: [0.14, 0.45]; p < 0.001), MoCA decline ( β = −0.35; 95% CI: [−0.57, −0.13]; p = 0.002), and cognitive index decline (all p ≤ 0.028). Participants with abnormal baseline pTau217 had a 0.85 points/year faster CDR-SB increase (95% CI: [0.56, 1.15]; p < 0.001), 0.87 points/year faster MoCA decline (95% CI: −1.38, −0.37; p = 0.001), faster decline on cognitive indices (all p ≤ 0.018), and a three-fold higher risk of diagnostically progressing to MCI or dementia (HR = 3.41; 95% CI: [1.60, 7.28]; p = 0.002) compared to participants with normal pTau217. Faster longitudinal pTau217 increase was associated with faster CDR-SB increase ( β = 0.24; 95% CI: [0.10, 0.38]; p = 0.003). Discussion Plasma pTau217 is a promising prognostic, risk-stratification, and monitoring biomarker of clinical progression in LBD, underscoring its utility for clinical practice and trials in mixed pathology groups.

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