This study compared the diagnostic accuracy of plasma and cerebrospinal fluid (CSF) p-tau217 with p-tau181 and p-tau231 in identifying Alzheimer's disease (AD) pathology in a memory clinic cohort. The study included 114 participants (33 with cognitive unimpaired [CU], 67 with mild cognitive impairment [MCI], and 14 with dementia). The p-tau variants were correlated with amyloid (A) and tau (T)-PET measures. Plasma p-tau217 showed stronger correlations with A-PET and T-PET (r range 0.64–0.83) compared to p-tau181 (r range 0.44–0.79) and p-tau231 (r range 0.46–0.76). Plasma p-tau217 demonstrated significantly higher diagnostic accuracy than p-tau181 and p-tau231 in terms of differences between diagnostic and biomarker groups (δrange: p-tau217 = 0.55–0.96; p-tau181 = 0.51–0.67; p-tau231 = 0.53–0.71) and ROC curves (AUCaverage: p-tau217 = 0.96; p-tau181 = 0.76; p-tau231 = 0.79). However, CSF p-tau217 did not show significant differences in A-PET and T-PET AUC compared to p-tau181 and p-tau231. The findings suggest that plasma p-tau217 has better performance in identifying AD pathology and clinical phenotypes compared to other p-tau variants, with comparable performance in plasma and CSF. These results highlight the potential of plasma p-tau217 as a valuable biomarker for the diagnosis and screening of AD.This study compared the diagnostic accuracy of plasma and cerebrospinal fluid (CSF) p-tau217 with p-tau181 and p-tau231 in identifying Alzheimer's disease (AD) pathology in a memory clinic cohort. The study included 114 participants (33 with cognitive unimpaired [CU], 67 with mild cognitive impairment [MCI], and 14 with dementia). The p-tau variants were correlated with amyloid (A) and tau (T)-PET measures. Plasma p-tau217 showed stronger correlations with A-PET and T-PET (r range 0.64–0.83) compared to p-tau181 (r range 0.44–0.79) and p-tau231 (r range 0.46–0.76). Plasma p-tau217 demonstrated significantly higher diagnostic accuracy than p-tau181 and p-tau231 in terms of differences between diagnostic and biomarker groups (δrange: p-tau217 = 0.55–0.96; p-tau181 = 0.51–0.67; p-tau231 = 0.53–0.71) and ROC curves (AUCaverage: p-tau217 = 0.96; p-tau181 = 0.76; p-tau231 = 0.79). However, CSF p-tau217 did not show significant differences in A-PET and T-PET AUC compared to p-tau181 and p-tau231. The findings suggest that plasma p-tau217 has better performance in identifying AD pathology and clinical phenotypes compared to other p-tau variants, with comparable performance in plasma and CSF. These results highlight the potential of plasma p-tau217 as a valuable biomarker for the diagnosis and screening of AD.