This study investigates the clinical performance of plasma pTau181 in combination with plasma ApoE4 as a potential IVD to detect amyloid pathology from a broad population as seen in routine clinical practice.

In this prospective multicenter study, we enrolled 604 patients aged 55-80 with SCD, MCI, or mild dementia being evaluated for Alzheimer's disease or other causes of cognitive decline. Plasma samples from eligible patients were analyzed using Elecsys® pTau181 and ApoE4 plasma assays (Roche Diagnostics International Ltd, Rotkreuz, Switzerland). The discriminative ability of pTau181 alone, or in combination with ApoE4 with respect to amyloid PET visual read status and to CSF ratio of the Elecsys Phospho-Tau (181P) and Elecsys Amyloid (1-42) II CSF was evaluated. 

The study population was heterogeneous regarding sex, race, and comorbidities. The area under the curve (AUC) of a combination of pTau181 and ApoE4 was 0.896, while pTau181 alone achieved an AUC of 0.873 (AUCs with respect to amyloid PET positive versus negative). Based on an amyloid positivity prevalence of 23.0% (based on amyloid PET), the negative predictive value (NPV) was 96.5%, paired with a positive predictive value of 49.8% (sensitivity: 91.3%, specificity: 72.5%). The performance was only minimally impacted by age, sex, body mass index or impaired kidney function. The rule-out performance of pTau181 alone was similar (NPV: 97.3%, PPV: 43.5%). The study also showed 100% concordance of plasma ApoE4 results with genetic APOE4 carrier status.

The observed clinical performance in this study highlights the potential of plasma pTau181 with the combination of ApoE4 as robust and accurate tools for ruling out individuals with a low likelihood of amyloid pathology in the early stages of the AD continuum.