CSF tau phosphorylation at T217 and T205 are improved biomarkers of amyloid and tau pathology in Alzheimer disease

CSF Aβ42/Aβ40 and tau phosphorylated at site 181 (p-tau181) are well-established biomarkers of Alzheimer disease (AD). This study used mass spectrometry to measure concentrations of 9 phosphorylated and 5 non-phosphorylated species, and phosphorylation occupancies (phosphorylated/non-phosphorylated [%]) at 10 sites. In 750 individuals with a median age of 71.2 years, CSF pT217/T217 (%) predicted amyloid PET status slightly better than Aβ42/Aβ40 (p=0.02). In amyloid PET positive individuals (n=263), CSF pT217/T217 (%) was more strongly correlated with amyloid PET Centiloid (Spearman ρ=0.69) than Aβ42/Aβ40 (ρ = -0.42, p<0.0001). CSF pT217/T217 (%) and pT205/T205 (%) were superior to Aβ42/Aβ40 and similar to tau PET in prediction of cognitive impairment. In two independent cohorts with symptomatic AD (n=55 and n=90), CSF pT217/T217 (%) and pT205/205 (%) were better correlated with tau PET measures than CSF p-tau181 concentration. CSF pT217/T217 (%) and pT205/205 (%) represent improved CSF biomarkers of amyloid and tau pathology in AD.