The association between plasma biomarkers, p‐tau181, glial fibrillary acidic protein, and neurofilament light and clinical AD risk: Results from prospective cohort study followed over 17 years

Abstract

AbstractBackgroundPlasma biomarkers for Alzheimer’s disease (AD) have emerged as the future of AD prescreening measures and/or clinical risk assessment. In order to confirm clinical utility of plasma biomarkers, further validation in longitudinal cohort studies is necessary. Therefore, the aim of this study was to investigate the relationship between plasma biomarkers, phosphorylated tau (p‐tau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) and incident clinical Alzheimer’s disease diagnosis in a community‐based cohort study prospectively followed over 17 years. Secondarily, disease specificity of these biomarkers was assessed with comparison to vascular (VD) and mixed dementia (MD), and the impact of fatal CVD risk on plasma biomarker prediction was explored.MethodP‐tau181, GFAP, and NfL concentration in plasma taken at baseline was measured using the SimoaTM HD‐X Analyzer and the 10‐year risk of fatal CVD using the Systematic Coronary Risk Evaluation (SCORE) was determined in 145 participants diagnosed with AD, 66 participants with VD, and 50 participants with MD during 17 years of follow‐up and 507 participants without dementia diagnosis. Cox regression models adjusted for age, sex, and education were used to assess the association between the plasma biomarker levels and risk of incident dementia subtypes.ResultHigher plasma levels of p‐tau181 and NfL were significantly associated to higher risk of AD development within the first nine years of follow‐up (p‐tau181, p=.02; NfL, p=.01) and were most elevated in AD cases in the first five years of follow‐up, however lacked associations between 9‐17 years. Contrastingly, GFAP levels were consistently elevated in AD cases and significant associations to higher AD risk were evident throughout the 17‐year follow‐up. NfL and GFAP levels additionally exhibited associations to a higher risk of VD and MD; while p‐tau181 did not. Significant interactions between fatal CVD risk and biomarker levels were evident for AD (p‐tau181, p=.03; NfL, p=.01).ConclusionHigher plasma p‐tau181 and NfL levels were associated with higher AD risk within nine years, while higher GFAP levels with higher AD risk consistently throughout 17 years. Plasma levels of p‐tau181 and NfL may be more suited to short‐term AD risk stratification; while GFAP may add important long‐term disease risk information.