Potential Utility of Plasma P-Tau and Neurofilament Light Chain as Surrogate Biomarkers for Preventive Clinical Trials

Pamela C L Ferreira; João Pedro Ferrari-Souza; Cécile Tissot; Bruna Bellaver; Douglas T Leffa; Firoza Lussier; Guilherme Povala; Joseph Therriault; Andréa L Benedet; Nicholas J Ashton; Ann D Cohen; Oscar L Lopez; Dana L Tudorascu; William E Klunk; Jean-Paul Soucy; Serge Gauthier; Victor Villemagne; Henrik Zetterberg; Kaj Blennow; Pedro Rosa-Neto; Eduardo R Zimmer; Thomas K Karikari; Tharick A Pascoal; Alzheimer's Disease Neuroimaging Initiative

doi:10.1212/WNL.0000000000207115

Potential Utility of Plasma P-Tau and Neurofilament Light Chain as Surrogate Biomarkers for Preventive Clinical Trials

Neurology. 2023 Jul 4;101(1):38-45. doi: 10.1212/WNL.0000000000207115. Epub 2023 Mar 6.

Authors

Pamela C L Ferreira¹, João Pedro Ferrari-Souza¹, Cécile Tissot¹, Bruna Bellaver¹, Douglas T Leffa¹, Firoza Lussier¹, Guilherme Povala¹, Joseph Therriault¹, Andréa L Benedet¹, Nicholas J Ashton¹, Ann D Cohen¹, Oscar L Lopez¹, Dana L Tudorascu¹, William E Klunk¹, Jean-Paul Soucy¹, Serge Gauthier¹, Victor Villemagne¹, Henrik Zetterberg¹, Kaj Blennow¹, Pedro Rosa-Neto¹, Eduardo R Zimmer¹, Thomas K Karikari¹, Tharick A Pascoal²; Alzheimer's Disease Neuroimaging Initiative

Affiliations

¹ From 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.
² From 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. pascoalt@upmc.edu.

Abstract

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.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Alzheimer Disease* / diagnostic imaging
Amyloid beta-Peptides
Biomarkers
Cognitive Dysfunction* / diagnostic imaging
Female
Humans
Intermediate Filaments
Male
Research Design
tau Proteins

Substances

Biomarkers
Amyloid beta-Peptides
tau Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding