CSF p-tau205: a biomarker of tau pathology in Alzheimer's disease

Juan Lantero-Rodriguez; Laia Montoliu-Gaya; Andrea L Benedet; Agathe Vrillon; Julien Dumurgier; Emmanuel Cognat; Wagner S Brum; Nesrine Rahmouni; Jenna Stevenson; Stijn Servaes; Joseph Therriault; Bruno Becker; Gunnar Brinkmalm; Anniina Snellman; Hanna Huber; Hlin Kvartsberg; Nicholas J Ashton; Henrik Zetterberg; Claire Paquet; Pedro Rosa-Neto; Kaj Blennow

doi:10.1007/s00401-023-02659-w

CSF p-tau205: a biomarker of tau pathology in Alzheimer's disease

Acta Neuropathol. 2024 Jan 6;147(1):12. doi: 10.1007/s00401-023-02659-w.

Authors

Juan Lantero-Rodriguez^#¹, Laia Montoliu-Gaya^#², Andrea L Benedet², Agathe Vrillon³, Julien Dumurgier³, Emmanuel Cognat³, Wagner S Brum^{2

4}, Nesrine Rahmouni^{5

6}, Jenna Stevenson^{5

6}, Stijn Servaes^{5

6}, Joseph Therriault^{5

6}, Bruno Becker², Gunnar Brinkmalm², Anniina Snellman^{2

7}, Hanna Huber², Hlin Kvartsberg^{2

8}, Nicholas J Ashton^{2

9

10

11}, Henrik Zetterberg^{2

8

12

13

14

15}, Claire Paquet³, Pedro Rosa-Neto^{5

6}, Kaj Blennow^{2

8}

Affiliations

¹ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden. juan.rodriguez.2@gu.se.
² Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
³ Cognitive Neurology Center, Université de Paris Cité, GHU Nord APHP Hospital Lariboisière Fernand Widal, Paris, France.
⁴ Graduate Program in Biological Sciences: Biochemistry, Universidade Federal Do Rio Grande Do Sul (UFRGS), Porto Alegre, Brazil.
⁵ Montreal Neurological Institute, Montreal, QC, Canada.
⁶ Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
⁷ Turku PET Centre, University of Turku, Turku University Hospital, Turku, Finland.
⁸ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
⁹ Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden.
¹⁰ Department of Old Age Psychiatry, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK.
¹¹ NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, UK.
¹² Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, London, UK.
¹³ UK Dementia Research Institute, University College London, London, UK.
¹⁴ Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.
¹⁵ Wisconsin Alzheimer's Disease Research Center, School of Medicine and Public Health, University of Wisconsin, University of Wisconsin-Madison, Madison, WI, USA.

^# Contributed equally.

Abstract

Post-mortem staging of Alzheimer's disease (AD) neurofibrillary pathology is commonly performed by immunohistochemistry using AT8 antibody for phosphorylated tau (p-tau) at positions 202/205. Thus, quantification of p-tau205 and p-tau202 in cerebrospinal fluid (CSF) should be more reflective of neurofibrillary tangles in AD than other p-tau epitopes. We developed two novel Simoa immunoassays for CSF p-tau205 and p-tau202 and measured these phosphorylations in three independent cohorts encompassing the AD continuum, non-AD cases and cognitively unimpaired participants: a discovery cohort (n = 47), an unselected clinical cohort (n = 212) and a research cohort well-characterized by fluid and imaging biomarkers (n = 262). CSF p-tau205 increased progressively across the AD continuum, while CSF p-tau202 was increased only in AD and amyloid (Aβ) and tau pathology positive (A+T+) cases (P < 0.01). In A+ cases, CSF p-tau205 and p-tau202 showed stronger associations with tau-PET (r_Sp205 = 0.67, r_Sp202 = 0.45) than Aβ-PET (r_Sp205 = 0.40, r_Sp202 = 0.09). CSF p-tau205 increased gradually across tau-PET Braak stages (P < 0.01), whereas p-tau202 only increased in Braak V-VI (P < 0.0001). Both showed stronger regional associations with tau-PET than with Aβ-PET, and CSF p-tau205 was significantly associated with Braak V-VI tau-PET regions. When assessing the contribution of Aβ and tau pathologies (indexed by PET) to CSF p-tau205 and p-tau202 variance, tau pathology was found to be the most prominent contributor in both cases (CSF p-tau205: R² = 69.7%; CSF p-tau202: R² = 85.6%) Both biomarkers associated with brain atrophy measurements globally (r_Sp205 = - 0.36, r_Sp202 = - 0.33) and regionally, and correlated with cognition (r_Sp205 = - 0.38/- 0.40, r_Sp202 = - 0.20/- 0.29). In conclusion, we report the first high-throughput CSF p-tau205 immunoassay for the in vivo quantification of tau pathology in AD, and a potentially cost-effective alternative to tau-PET in clinical settings and clinical trials.

Keywords: Alzheimer’s disease; Biomarker; CSF; Tau; p-tau205.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease*
Amyloidogenic Proteins
Antibodies
Biomarkers
Humans
Neurofibrillary Tangles

Substances

Amyloidogenic Proteins
Antibodies
Biomarkers

Abstract

Publication types

MeSH terms

Substances

Grants and funding