Plasma pTau181 reveals a pathological signature that predicts cognitive outcomes in Lewy body disease

ABSTRACT Lewy body disease (LBD) often co-exists with Alzheimer’s disease (AD), influencing disease progression, cognitive decline, and neurodegeneration. This study aims to determine whether plasma phosphorylated-Tau181 (pTau181) could be used as 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 LBD. Our sample comprised 565 Stanford research participants: 94 LBD with normal cognition, 83 LBD with abnormal cognition, 114 AD, and 274 who were cognitively normal. We measured plasma pTau181 levels 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. We used linear mixed effects models to examine the associations between baseline and longitudinal plasma pTau181 levels and clinical outcomes. Plasma pTau181 predicted concurrent ADNC and amyloidosis in LBD with abnormal cognition with 87% and 72% accuracy, respectively. In the LBD 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 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. These 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.