Plasma p-tau217 predicts cognitive impairments up to ten years before onset in normal older adults

ImportancePositron emission tomography (PET) biomarkers are the gold standard for detection of Alzheimer amyloid and tau in vivo. Such imaging can identify cognitively unimpaired (CU) individuals who will subsequently develop cognitive impartment (CI). Plasma biomarkers would be more practical than PET or even cerebrospinal fluid (CSF) assays in clinical settings. ObjectiveAssess the prognostic accuracy of plasma p-tau217 in comparison to CSF and PET biomarkers for predicting the clinical progression from CU to CI. DesignIn a cohort of elderly at high risk of developing Alzheimers dementia (AD), we measured the proportion of CU individuals who developed CI, as predicted by A{beta} (A+) and/or tau (T+) biomarker assessment from plasma, CSF, and PET. Results from each method were compared with (A-T-) reference individuals. Data were analyzed from June 2023 to April 2024. SettingLongitudinal observational cohort. ParticipantsSome 228 participants from the PREVENT-AD cohort were CU at the time of biomarker assessment and had 1 - 10 years of follow-up. Plasma was available from 215 participants, CSF from 159, and amyloid- and tau-PET from 155. Ninety-three participants had assessment using all three methods (main group of interest). Progression to CI was determined by clinical consensus among physicians and neuropsychologists who were blind to plasma, CSF, PET, and MRI findings, as well as APOE genotype. ExposuresPlasma A{beta}42/40 was measured using IP-MS; CSF A{beta} 42/40 using Lumipulse; plasma and CSF p-tau217 using UGOT assay. A{beta}-PET employed the 18F-NAV4694 ligand, and tau-PET used 18F-flortaucipir. Main OutcomePrognostic accuracy of plasma, CSF, and PET biomarkers for predicting the development of CI in CU individuals. ResultsCox proportional hazard models indicated a greater progression rate in all A+T+ groups compared to A-T-groups (HR = 6.61 [95% CI = 2.06 - 21.17] for plasma, 3.62 [1.49 - 8.81] for CSF and 9.24 [2.34 - 36.43] for PET). The A-T+ groups were small, but also characterized with individuals who developed CI. Plasma biomarkers identified about five times more T+ than PET. Conclusion and relevancePlasma p-tau217 assessment is a practical method for identification of persons who will develop cognitive impairment up to 10 years later. Key PointsO_ST_ABSQuestionC_ST_ABSCan plasma p-tau217 serve as a prognostic indicator for identifying cognitively unimpaired (CU) individuals at risk of developing cognitive impairments (CI)? FindingsIn a longitudinal cohort of CU individuals with a family history of sporadic AD, almost all individuals with abnormal plasma p-tau217 concentrations developed CI within 10 years, regardless of plasma amyloid levels. Similar findings were obtained with CSF p-tau217 and tau-PET. Fluid p-tau217 biomarkers had the main advantage over PET of identifying five times more participants with elevated tau. MeaningElevated plasma p-tau217 levels in CU individuals strongly indicate future clinical progression