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

Abstract Background and Objectives In Lewy body disease (LBD), co-occurring Alzheimer’s disease (AD) neuropathologic change (ADNC) is associated with worse clinical outcomes. While plasma pTau217 detects ADNC in LBD, its prognostic, monitoring, and risk-stratification utility remains unclear. We evaluated whether plasma pTau217 predicted cognitive and functional decline and risk for progression to MCI or dementia in LBD. Methods We included 501 participants enrolled in the Stanford Alzheimer’s Disease Research Center with plasma pTau217 data who were clinically diagnosed as LBD spectrum ( n = 131), AD spectrum ( n = 133), or healthy controls (HC; n = 237). To assess prognostic and monitoring utility in LBD, linear mixed-effect models tested continuous baseline and longitudinal (2-5 years) plasma pTau217 as predictors of change in 2-8-year clinical outcome trajectories including: daily functioning (CDR-SB), global cognition (MoCA), and five domain-specific cognitive indices. For risk-stratification in LBD, baseline plasma pTau217 was dichotomized using an amyloid PET-derived, LBD-specific cut-point to examine effects of abnormal versus normal levels on clinical outcomes in separate mixed-effects and survival models. Results In LBD, higher continuous baseline plasma pTau217 predicted accelerated CDR-SB increase (β = 0.29, p < 0.001), MoCA decline (β =-0.37, p = 0.014), and cognitive index decline (memory, executive function, visuospatial function, processing speed; βs =-2.24 to-0.06, ps ≤ 0.01). Faster longitudinal pTau217 increase predicted accelerated CDR-SB increase (β = 0.24, p = 0.001). In AD, higher continuous baseline pTau217 predicted accelerated CDR-SB increase and MoCA decline, whereas faster longitudinal increase predicted accelerated cognitive index decline ( ps ≤ 0.04). In HC, higher continuous baseline pTau217 predicted accelerated memory index decline ( p = 0.008). In LBD, abnormal baseline pTau217 predicted a 0.87 points/year (95% CI:-1.62,-0.58) faster MoCA decline, 0.85 points/year (95% CI: 0.56, 1.14) faster CDR-SB increase, accelerated decline on cognitive indices, and a three-fold higher risk of progressing to MCI or dementia (HR = 3.41, 95% CI 1.60, 7.28, p = 0.002) compared to normal pTau217. Discussion Plasma pTau217 is a promising prognostic, monitoring, and risk stratification biomarker of clinical progression in LBD, underscoring its utility in mixed pathology groups for clinical practice and trials.