Plasma Phosphorylated Tau181 as a Biomarker for Alzheimer's Disease Co-Pathology in Lewy Body Disease

Abstract

Background: Plasma phosphorylated tau181 (pTau181) is proving to be a useful predictor of Alzheimer's disease (AD). AD co-pathology is frequently observed across the Lewy body disease (LBD) spectrum.

Objective: To determine whether pTau181 in LBD is associated with postmortem Alzheimer's disease neuropathologic changes (ADNC) and with antemortem positron emission spectrometry measurements of β-amyloid and tau deposition.

Methods: We studied 53 participants with LBD who underwent plasma pTau181 assessment, contrasting them with 129 healthy control participants and 67 participants with AD. Postmortem assessments were conducted on 24 LBD cases. Spearman correlation analyses were used to assess the association between plasma pTau181 and the severity of amyloid deposits, tau accumulation, and neurodegeneration (A/T/N) measured at autopsy or via neuroimaging.

Results: Plasma pTau181 in LBD participants was higher than in healthy participants and lower than in AD participants. Plasma pTau181 in LBD was moderately correlated with Thal stage, Braak neurofibrillary tangle (NFT) stage, and CERAD (Consortium to Establish a Registry for Alzheimer's Disease) scores but not Lewy body Braak stage. Plasma pTau181 was associated with cortical PiB (Pittsburgh Compound-B) retention. Elevated plasma pTau181 levels were associated with greater cortical thinning, particularly in later Braak NFT regions. The addition of plasma pTau181 improved models that included age, sex, and APOE ε4 to detect amyloid and tau positivity.

Conclusions: Plasma pTau181 reflects amyloid and tau pathology but not α-synuclein pathology in LBD. Plasma pTau181 is a useful indicator for neurodegeneration in cortical regions vulnerable to NFT pathology and adds value in identifying AD co-pathology. These findings support plasma pTau181 as a cost-effective screening tool for AD co-pathology in LBD. © 2025 International Parkinson and Movement Disorder Society.

Keywords: Alzheimer's disease co‐pathology; Lewy body disease; neuroimaging; neuropathology; plasma pTau181.