Plasma pTau181 Reveals a Pathological Signature that Predicts Cognitive Outcomes in Lewy Body Disease

Abstract

Objective: To determine whether plasma phosphorylated-Tau181 (pTau181) could be used as a diagnostic biomarker of concurrent Alzheimer's disease neuropathologic change (ADNC) or amyloidosis alone, as well as a prognostic, monitoring, and susceptibility/risk biomarker for clinical outcomes in Lewy body disease (LBD).

Methods: We studied 565 participants: 94 LBD with normal cognition, 83 LBD with abnormal cognition, 114 with Alzheimer's disease, and 274 cognitively normal. Plasma pTau181 levels were measured with the Lumipulse G platform. Diagnostic accuracy for concurrent ADNC and amyloidosis was assessed with Receiver Operating Characteristic curves in a subset of participants with CSF pTau181/Aβ42, and CSF Aβ42/Aβ40 or amyloid-β PET, respectively. Linear mixed effects models were used to examine the associations between baseline and longitudinal plasma pTau181 levels and clinical outcomes.

Results: Plasma pTau181 predicted concurrent ADNC and amyloidosis in LBD with abnormal cognition with 87% and 72% accuracy, respectively. In LBD patients with abnormal cognition, higher baseline plasma pTau181 was associated with worse baseline MoCA and CDR-SB, as well as accelerated decline in CDR-SB. Additionally, in this group, rapid increases in plasma pTau181 over 3 years predicted a faster decline in CDR-SB and memory. In LBD patients with normal cognition, there was no association between baseline or longitudinal plasma pTau181 levels and clinical outcomes; however, elevated pTau181 at baseline increased the risk of conversion to cognitive impairment.

Interpretation: Our findings suggest that plasma pTau181 is a promising biomarker for concurrent ADNC and amyloidosis in LBD. Furthermore, plasma pTau181 holds potential as a prognostic, monitoring, and susceptibility/risk biomarker, predicting disease progression in LBD. ANN NEUROL 2024;96:526-538.

Figure 1:. Plasma pTau181 as a diagnostic biomarker in Lewy body disease.

A) Comparison of plasma pTau181 levels among diagnostic groups: CN (purple), LBD-nlCog (blue), LBD-abnlCog (green), and AD (orange). Differences were analyzed using log-transformed plasma values with ANOVA and corrected for multiple comparisons with the Bonferroni method. B) ROC curve analysis of plasma pTau181 levels in distinguishing: LBD-abnlCog ADNC+ (19.1%) vs ADNC- (80.9%) (continuous green line), LBD-abnlCog Aβ+ (51.1%) vs Aβ- (48.9%) (dashed green line), and LBD-nlCog Aβ+ (12.8%) vs Aβ- (87.2%) (dotted blue line). Abbreviations: Aβ: amyloid-β, AD: Alzheimer’s disease, ANOVA: analysis of variance, CN: cognitively normal, FPR: false positive rate, LBD-abnlCog: Lewy body disease with abnormal cognition, LBD-nlCog: Lewy body disease with normal cognition, pTau181: phosphorylated-Tau181, TPR: true positive rate.

Figure 2:. Survival curves of conversion to cognitive impairment (MCI or dementia) in CN and LBD-nlCog participants with normal and abnormal plasma pTau181 levels.

LBD-nlCog with normal plasma pTau181 levels (N= 44, dark blue line), LBD-nlCog with abnormal plasma pTau181 levels (N= 17, light blue line), CN with normal plasma pTau181 levels (N= 95, purple line), CN with abnormal plasma pTau181 levels (N= 78, light purple line). Normal plasma pTau181 levels were defined as < 1.71 pg/mL, while abnormal levels were ≥ 1.71 pg/mL, using a cut point determined by the Youden J Index method to distinguish LBD-nlCog Aβ+ from Aβ- individuals. Abbreviations: Aβ: amyloid-β, CN: cognitively normal, LBD-nlCog: Lewy body disease with normal cognition, pTau181: phosphorylated-Tau181.