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

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2024年1月6日

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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

摘要

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.