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Updated: Aug 7, 2025
In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
Published on: January 2, 2015
Potential Utility of Plasma P-Tau and Neurofilament Light Chain as Surrogate Biomarkers for Preventive Clinical
Pamela C L Ferreira1, João Pedro Ferrari-Souza1, Cécile Tissot1
1From the Departments of Psychiatry (P.C.L.F., J.P.F.-S., C.T., B.B., D.T.L., F.L., G.P., A.D.C., D.L.T., W.E.K., V.V., T.K.K., T.A.P.) and Neurology (O.L.L.), School of Medicine, University of Pittsburgh, PA; Graduate Program in Biological Sciences: Biochemistry (J.P.F.-S., B.B., E.R.Z.), Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Translational Neuroimaging Laboratory (C.T., F.L., J.T., J.-P.S., P.R.-N.), McGill University Research Centre for Studies in Aging, Alzheimer's Disease Research Unit, Douglas Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l'Ouest-de-l'Île-de-Montréal, Pointe-Claire; Department of Neurology and Neurosurgery, Psychiatry and Pharmacology and Therapeutics (C.T., J.T., S.G., P.R.-N.), McGill University, Montreal, Quebec, Canada; Department of Psychiatry and Neurochemistry (A.L.B., N.J.A., H.Z., K.B., T.K.K.), The Sahlgrenska Academy at the University of Gothenburg, Mölndal; Clinical Neurochemistry Laboratory (A.L.B., N.J.A., H.Z., K.B.), Sahlgrenska University Hospital, Gothenburg; Wallenberg Centre for Molecular and Translational Medicine (N.J.A., H.Z.), University of Gothenburg, Sweden; Department of Old Age Psychiatry (N.J.A.), Institute of Psychiatry, Psychology & Neuroscience, King's College London; Department of Neurodegenerative Disease (H.Z.), UCL Queen Square Institute of Neurology; UK Dementia Research Institute at UCL (H.Z.), London, United Kingdom; Hong Kong Center for Neurodegenerative Diseases (H.Z.), China; and Department of Neurology (T.A.P.), School of Medicine, University of Pittsburgh, PA.
Objective:
To test the utility of longitudinal changes in plasma phosphorylated tau 181 (p-tau181) and neurofilament light chain (NfL) as surrogate markers for clinical trials targeting cognitively unimpaired (CU) populations.
Methods:
We estimated the sample size needed to test a 25% drug effect with 80% of power at a 0.05 level on reducing changes in plasma markers in CU participants from Alzheimer's Disease Neuroimaging Initiative database.
Results:
We included 257 CU individuals (45.5% males; mean age = 73 [6] years; 32% β-amyloid [Aβ] positive). Changes in plasma NfL were associated with age, whereas changes in plasma p-tau181 with progression to amnestic mild cognitive impairment. Clinical trials using p-tau181 and NfL would require 85% and 63% smaller sample sizes, respectively, for a 24-month than a 12-month follow-up. A population enrichment strategy using intermediate levels of Aβ PET (Centiloid 20-40) further reduced the sample size of the 24-month clinical trial using p-tau181 (73%) and NfL (59%) as a surrogate.
Discussion:
Plasma p-tau181/NfL can potentially be used to monitor large-scale population interventions in CU individuals. The enrollment of CU with intermediate Aβ levels constitutes the alternative with the largest effect size and most cost-effective for trials testing drug effect on changes in plasma p-tau181 and NfL.
