Plasma P-Tau217 as a Prognostic, Monitoring, and Risk-Stratification Biomarker of Clinical Progression in Lewy Body Disease.

Abstract (English)

BACKGROUND AND OBJECTIVES: Although plasma phosphorylated tau-217 (pTau217) detects co-occurring Alzheimer 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 AD Research Center participants enrolled from 2015 to 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 (<i>n</i> = 131), AD (<i>n</i> = 133), and HC (<i>n</i> = 237) groups. In LBD, higher baseline plasma pTau217 was associated with faster CDR-SB increase (<i>&#x3b2;</i> = 0.30; 95% CI [0.14, 0.45]; <i>p</i> < 0.001), MoCA decline (<i>&#x3b2;</i> = -0.35; 95% CI [-0.57, -0.13]; <i>p</i> = 0.002), and cognitive index decline (all <i>p</i> ≤ 0.028). Participants with abnormal baseline pTau217 had a 0.85 points/year faster CDR-SB increase (95% CI [0.56, 1.15]; <i>p</i> < 0.001), 0.87 points/year faster MoCA decline (95% CI [-1.38, -0.37]; <i>p</i> = 0.001), faster decline on cognitive indices (all <i>p</i> ≤ 0.018), and a three-fold higher risk of diagnostically progressing to mild cognitive impairment or dementia (HR = 3.41; 95% CI [1.60, 7.28]; <i>p</i> = 0.002) compared to participants with normal pTau217. Faster longitudinal pTau217 increase was associated with faster CDR-SB increase (<i>&#x3b2;</i> = 0.24; 95% CI [0.10, 0.38]; <i>p</i> = 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.