This study shows plasma pTau217 predicts accelerated cognitive and functional decline and a three-fold higher risk of progression to MCI/dementia in Lewy body disease, supporting its use as a prognostic and monitoring biomarker.

A blood-based tau measure that identifies Alzheimer co-pathology in LBD enables better patient stratification and longitudinal monitoring for clinical trials and practice, improving chances to test and target therapies in biologically defined subgroups even though it does not itself propose a…

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.