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

Pamela Ferreira; João Pedro Ferrari-Souza; Cécile Tissot; Bruna Bellaver; Douglas Leffa; Firoza Lussier; Guilherme Povala; Joseph Therriault; Andréa L Benedet; Nicholas J Ashton; Ann D Cohen; Oscar L Lopez; Dana 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 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 Mar 6;10.1212/WNL.0000000000207115. doi: 10.1212/WNL.0000000000207115. Online ahead of print.

Authors

Pamela Ferreira¹, João Pedro Ferrari-Souza^{1

2}, Cécile Tissot^{1

3

4}, Bruna Bellaver^{1

2}, Douglas Leffa^{1

5}, Firoza Lussier^{1

3}, Guilherme Povala¹, Joseph Therriault^{3

4}, Andréa L Benedet^{6

7}, Nicholas J Ashton^{6

7

8

9}, Ann D Cohen¹, Oscar L Lopez¹, Dana Tudorascu¹, William E Klunk¹, Jean-Paul Soucy³, Serge Gauthier⁴, Victor Villemagne¹, Henrik Zetterberg, Kaj Blennow^{6

7}, Pedro Rosa-Neto^{3

4}, Eduardo R Zimmer², Thomas K Karikari^{1

6}, Tharick Pascoal^{10

11}; Alzheimer's Disease Neuroimaging Initiative

Affiliations

¹ Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
² Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
³ Translational Neuroimaging Laboratory, 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.
⁴ Department of Neurology and Neurosurgery, Psychiatry and Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
⁵ ADHD Outpatient Program & Development Psychiatry Program, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil.
⁶ Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
⁷ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden.
⁸ Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden.
⁹ Department of Old Age Psychiatry, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
¹⁰ Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA tharick.pascoal@gmail.com.
¹¹ Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.

PMID: 36878697
DOI: 10.1212/WNL.0000000000207115

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 ADNI database.

Results: We included 257 CU individuals [45.5% males; mean age = 73 (6) years; 32% amyloid-beta (Aβ) positive]. Changes in plasma NfL were associated with age, while 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 positron emission tomography (Centiloid 20-40) further reduced the sample size of 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.