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

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 (rSp205 = 0.67, rSp202 = 0.45) than Aβ-PET (rSp205 = 0.40, rSp202 = 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 (rSp205 = − 0.36, rSp202 = − 0.33) and regionally, and correlated with cognition (rSp205 = − 0.38/− 0.40, rSp202 = − 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.

Virus-like particle (VLP)-based vaccine targeting tau phosphorylated at Ser396/Ser404 (PHF1) site outperforms phosphorylated S199/S202 (AT8) site in reducing tau pathology and restoring cognitive deficits in the rTg4510 mouse model of tauopathy

“…Recent findings, however, suggest that pS199 and pS202 are not elevated in AD brains relative to healthy controls until much later stages of disease, such as Braak stage V/VI. 45 , 46 These pathologically modified epitopes may appear too late in the disease process for successful therapeutic targeting which could explain the failure of our Qβ-AT8 vaccine to reduce tau pathology and rescue cognition. Alternatively, the rapid disease progression and short timeline of our study in the rTg4510 model may have limited our ability to assess the efficacy of the Qβ-AT8 vaccine, because the pS199/pS202 epitopes may not have been abundantly present for therapeutic targeting.…”

“… 33 – 39 The phosphorylation sites recognized by AT8 (S199, S202, T205, and S208) 40 – 42 and the phosphorylation sites recognized by PHF1 (S396 and S404) 43 increase with disease progression in the brain. 36 , 37 , 44 – 46 The S199 site in particular has shown dramatic increases in phosphorylation at later stages of AD compared to other tau residues. 36 , 44 , 45 These sites may also reflect important steps in tau misfolding, assembly, or seed-competency contributing to the pathological process.…”

The Relationship between p-tau217, p-tau231, and p-tau205 in the Human Brain Is Affected by the Cellular Environment and Alzheimer’s Disease Pathology

“…This p-tau variant has lately gained interest, as its levels in the cerebrospinal fluid increase in the later stages of AD [17] and is (unlike most other p-tau variants) related to reduced white matter integrity [18]. P-tau205 is further strongly associated with tau pathology detected with both positron emission tomography (PET) [19] and immunoassays [20], but less with Aβ-PET status [19]. Thus, given its relationship with specific pathological changes, p-tau205 may have the capability to distinguish between different tauopathies.…”