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Background Cerebrospinal fluid (CSF) p-tau235 is a novel biomarker highly specific of Alzheimer’s disease (AD). However, CSF p-tau235 has only been studied in well-characterized research cohorts, which do not fully reflect the patient landscape found in clinical settings. Therefore, in this multicentre study, we investigated the performance of CSF p-tau235 to detect symptomatic AD in clinical settings and compared it with CSF p-tau181, p-tau217 and p-tau231. Methods CSF p-tau235 was measured using an in-house single molecule array (Simoa) assay in two independent memory clinic cohorts: Paris cohort (Lariboisière Fernand-Widal University Hospital Paris, France; n=212) and BIODEGMAR cohort (Hospital del Mar, Barcelona, Spain; n=175). Patients were classified by the syndromic diagnosis (cognitively unimpaired [CU], mild cognitive impairment [MCI] or dementia) and their biological diagnosis (amyloid-beta [Aβ]+ or Aβ $$-$$ - ). Both cohorts included detailed cognitive assessments and CSF biomarker measurements (clinically validated core AD biomarkers [Lumipulse CSF Aβ1–42/40 ratio, p-tau181 and t-tau] and in-house developed Simoa CSF p-tau181, p-tau217 and p-tau231). Results High CSF p-tau235 levels were strongly associated with CSF amyloidosis regardless of the clinical diagnosis, being significantly increased in MCI Aβ+ and dementia Aβ+ when compared with all other Aβ− groups (Paris cohort: P ˂0.0001 for all; BIODEGMAR cohort: P ˂0.05 for all). CSF p-tau235 was pronouncedly increased in the A+T+ profile group compared with A−T− and A+T− groups (P ˂0.0001 for all). Moreover, CSF p-tau235 demonstrated high diagnostic accuracies identifying CSF amyloidosis in symptomatic cases (AUCs=0.86 to 0.96) and discriminating AT groups (AUCs=0.79 to 0.98). Overall, CSF p-tau235 showed similar performances to CSF p-tau181 and CSF p-tau231 when discriminating CSF amyloidosis in various scenarios, but lower than CSF p-tau217. Finally, CSF p-tau235 associated with global cognition and memory domain in both cohorts. Conclusions CSF p-tau235 was increased with the presence of CSF amyloidosis in two independent memory clinic cohorts. CSF p-tau235 accurately identified AD in both MCI and dementia patients. Overall, the diagnostic performance of CSF p-tau235 was comparable to that of other CSF p-tau measurements, indicating its suitability to support a biomarker-based AD diagnosis in clinical settings.

Additional file 1: Supplementary Figure 1. CSF levels of p-tau235 across clinical diagnosis. Supplementary Figure 2. CSF levels of p-tau235 in Aβ+ and Aβ- cases. Supplementary Figure 3. CSF p-tau235 diagnostic performance discriminating Aβ+ from Aβ- cases. Supplementary Table 1. Clinical diagnosis included in each syndrome group in Paris cohort. Supplementary Table 2. Clinical diagnosis included in each syndrome group in BIODEGMAR cohort. Supplementary Table 3. CSF AD biomarkers cut-offs for BIODEGMAR and Paris Cohort. Supplementary Table 4. Accuracies of CSF p-tau181, p-tau217, p-tau231 and p-tau235 when identifying CSF amyloidosis in dementia and MCI cases in Paris and BIODEGMAR cohort. Supplementary Table 5. Clinical diagnosis included in each AT group in Paris cohort. Supplementary Table 6. Clinical diagnosis included in each AT group in BIODEGMAR cohort. Supplementary Table 7. Accuracies of CSF p-tau181, p-tau217, p-tau231 and p-tau235 when discriminating AT groups in Paris and BIODEGMAR cohort. Supplementary Table 8. Accuracies of CSF p-tau181, p-tau217, p-tau231 and p-tau235 when discriminating Aβ- from Aβ+ in Paris and BIODEGMAR cohort.