This study investigates the biomarker potential of cerebrospinal fluid (CSF) p-tau205 and p-tau202 in Alzheimer's disease (AD). The authors developed two novel Simoa immunoassays to measure these phosphorylations and evaluated their performance in three independent cohorts: a discovery cohort (n = 47), a clinical cohort (Paris cohort, n = 212), and a research cohort (TRIAD cohort, n = 262). Key findings include: 1. **CSF p-tau205 and p-tau202 Levels Across Diagnostic Groups**: - CSF p-tau205 levels increased progressively across the AD continuum, while CSF p-tau202 was only increased in AD and amyloid (Aβ) and tau pathology positive (A+T+) cases. - CSF p-tau205 showed high diagnostic accuracy in distinguishing AD, non-AD+ and MCI+ from CU-, MCI– and non-AD–, with an AUC of 99.5% and 85.9%, respectively. - CSF p-tau202 showed modest accuracies in all scenarios, with an AUC of 72.7–81.6% for AD, 50.7–61.5% for non-AD+, and 62.8–72.8% for MCI+. 2. **CSF p-tau205 and p-tau202 Across AT Groups**: - CSF p-tau205 increased progressively across AT groups, while CSF p-tau202 was only increased in A+T+ cases. - CSF p-tau205 showed higher accuracies in discriminating AT groups, with a stepwise increase across tau-PET Braak stages. - CSF p-tau202 displayed a stepwise increase but only in Braak stages V-VI. 3. **Associations with Aβ and Tau Pathology**: - CSF p-tau205 showed strong correlations with Aβ-PET SUVRs and tau-PET SUVRs, with a stronger association with tau-PET. - CSF p-tau202 also correlated with tau-PET SUVRs but to a lesser extent. - Both biomarkers were significantly increased in tau-PET positive individuals and showed higher accuracies in discriminating tau-PET positivity. 4. **Associations with Neurodegeneration and Cognition**: - CSF p-tau205 and p-tau202 showed significant negative correlations with global grey matter volume and cognitive performance (MMSE score). 5. **Conclusion**: - CSF p-tau205 has superior performance in discriminatingThis study investigates the biomarker potential of cerebrospinal fluid (CSF) p-tau205 and p-tau202 in Alzheimer's disease (AD). The authors developed two novel Simoa immunoassays to measure these phosphorylations and evaluated their performance in three independent cohorts: a discovery cohort (n = 47), a clinical cohort (Paris cohort, n = 212), and a research cohort (TRIAD cohort, n = 262). Key findings include: 1. **CSF p-tau205 and p-tau202 Levels Across Diagnostic Groups**: - CSF p-tau205 levels increased progressively across the AD continuum, while CSF p-tau202 was only increased in AD and amyloid (Aβ) and tau pathology positive (A+T+) cases. - CSF p-tau205 showed high diagnostic accuracy in distinguishing AD, non-AD+ and MCI+ from CU-, MCI– and non-AD–, with an AUC of 99.5% and 85.9%, respectively. - CSF p-tau202 showed modest accuracies in all scenarios, with an AUC of 72.7–81.6% for AD, 50.7–61.5% for non-AD+, and 62.8–72.8% for MCI+. 2. **CSF p-tau205 and p-tau202 Across AT Groups**: - CSF p-tau205 increased progressively across AT groups, while CSF p-tau202 was only increased in A+T+ cases. - CSF p-tau205 showed higher accuracies in discriminating AT groups, with a stepwise increase across tau-PET Braak stages. - CSF p-tau202 displayed a stepwise increase but only in Braak stages V-VI. 3. **Associations with Aβ and Tau Pathology**: - CSF p-tau205 showed strong correlations with Aβ-PET SUVRs and tau-PET SUVRs, with a stronger association with tau-PET. - CSF p-tau202 also correlated with tau-PET SUVRs but to a lesser extent. - Both biomarkers were significantly increased in tau-PET positive individuals and showed higher accuracies in discriminating tau-PET positivity. 4. **Associations with Neurodegeneration and Cognition**: - CSF p-tau205 and p-tau202 showed significant negative correlations with global grey matter volume and cognitive performance (MMSE score). 5. **Conclusion**: - CSF p-tau205 has superior performance in discriminating