Plasma phosphorylated tau 181 and 217 as biomarkers for multiple sclerosis diagnosis, subtyping, and prognosis

BackgroundBlood-based biomarkers are crucial for individualized management of multiple sclerosis (MS). Blood neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) have shown promising clinical utility in MS, but they are insufficient to guide clinical management. Plasma tau proteins remain underexplored despite the growing evidence of shared pathology in Alzheimers disease and MS. We aimed to: (1) assess the utility of plasma tau biomarkers (phosphorylated tau 181 [p-tau181], p-tau217, and total tau [t-tau]) in MS diagnosis, subtyping, and prognosis; and (2) compare their performance with NfL and GFAP. MethodsFrom a clinic-based prospective cohort, we included 160 people with MS (pwMS; 117 with relapsing-remitting MS [RRMS], 43 with progressive MS [PMS]) and 20 non-MS controls, all with baseline plasma samples. We measured baseline plasma concentrations of p-tau181, p-tau217, t-tau, NfL, and GFAP using ultrasensitive immunoassays. We collected demographics, clinical information, and longitudinal multi-modal outcomes (Patient Determined Disease Steps [PDDS], normalized age-related MS severity score [ARMSS], walking speed, manual dexterity, cognitive performance, retinal nerve fiber layer [RNFL] thickness, total brain volume, and gray matter volume) over a median follow-up of 3.0 years (IQR, 3.5). Adjusting for demographic and clinical covariates, we evaluated associations between biomarkers and MS diagnosis, subtypes, and prognosis. We examined the enhanced value of tau markers, in addition to NfL and GFAP, for subtype distinction and outcome prediction. Participants were enrolled between 2017 and 2023. Analyses were conducted in December 2024. ResultsParticipants (n=180) had a median age of 51 years and were predominantly women (68%) and non-Hispanic white (91%). Compared with controls, pwMS had higher levels of p-tau217 (1.0 vs 0.7 pg/mL; p=0.04) and NfL (14.1 vs 9.0 pg/mL; p<0.01). Among pwMS, higher p-tau181 (aOR [95%CI]=2.3 [1.4,4.1]) and p-tau217 (aOR [95%CI]=3.0 [1.8,5.7]) were associated with PMS. These markers improved MS subtype classification accuracy beyond clinical features, NfL, and GFAP. Higher baseline p-tau181 and p-tau217 predicted worse disability, functional outcomes, and imaging outcomes independent of other biomarkers. ConclusionsPlasma p-tau181 and p-tau217 are promising biomarkers for MS subtype classification and disability prediction, providing complementary information to NfL and GFAP. Further studies to validate their potential clinical utility in guiding MS management are warranted.