Plasma Aß42/40 ratio, p-tau181, GFAP, and NfL across the Alzheimer's disease continuum: A cross-sectional and longitudinal study in the AIBL cohort.

ABSTRACT

INTRODUCTION: Plasma amyloid beta (Aß)1-42/Aß1-40 ratio, phosphorylated-tau181 (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) are putative blood biomarkers for Alzheimer's disease (AD). However, head-to-head cross-sectional and longitudinal comparisons of the aforementioned biomarkers across the AD continuum are lacking. METHODS: Plasma Aß1-42, Aß1-40, p-tau181, GFAP, and NfL were measured utilizing the Single Molecule Array (Simoa) platform and compared cross-sectionally across the AD continuum, wherein Aß-PET (positron emission tomography)-negative cognitively unimpaired (CU Aß-, n = 81) and mild cognitive impairment (MCI Aß-, n = 26) participants were compared with Aß-PET-positive participants across the AD continuum (CU Aß+, n = 39; MCI Aß+, n = 33; AD Aß+, n = 46) from the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL) cohort. Longitudinal plasma biomarker changes were also assessed in MCI (n = 27) and AD (n = 29) participants compared with CU (n = 120) participants. In addition, associations between baseline plasma biomarker levels and prospective cognitive decline and Aß-PET load were assessed over a 7 to 10-year duration. RESULTS: Lower plasma Aß1-42/Aß1-40 ratio and elevated p-tau181 and GFAP were observed in CU Aß+, MCI Aß+, and AD Aß+, whereas elevated plasma NfL was observed in MCI Aß+ and AD Aß+, compared with CU Aß- and MCI Aß-. Among the aforementioned plasma biomarkers, for models with and without AD risk factors (age, sex, and apolipoprotein E (APOE) ε4 carrier status), p-tau181 performed equivalent to or better than other biomarkers in predicting a brain Aß-/+ status across the AD continuum. However, for models with and without the AD risk factors, a biomarker panel of Aß1-42/Aß1-40, p-tau181, and GFAP performed equivalent to or better than any of the biomarkers alone in predicting brain Aß-/+ status across the AD continuum. Longitudinally, plasma Aß1-42/Aß1-40, p-tau181, and GFAP were altered in MCI compared with CU, and plasma GFAP and NfL were altered in AD compared with CU. In addition, lower plasma Aß1-42/Aß1-40 and higher p-tau181, GFAP, and NfL were associated with prospective cognitive decline and lower plasma Aß1-42/Aß1-40, and higher p-tau181 and GFAP were associated with increased Aß-PET load prospectively. DISCUSSION: These findings suggest that plasma biomarkers are altered cross-sectionally and longitudinally, along the AD continuum, and are prospectively associated with cognitive decline and brain Aß-PET load. In addition, although p-tau181 performed equivalent to or better than other biomarkers in predicting an Aß-/+ status across the AD continuum, a panel of biomarkers may have superior Aß-/+ status predictive capability across the AD continuum. HIGHLIGHTS Area under the curve (AUC) of p-tau181 ≥ AUC of Aß42/40, GFAP, NfL in predicting PET Aß-/+ status (Aß-/+).  AUC of Aß42/40+p-tau181+GFAP panel ≥ AUC of Aß42/40/p-tau181/GFAP/NfL for Aß-/+.  Longitudinally, Aß42/40, p-tau181, and GFAP were altered in MCI versus CU.  Longitudinally, GFAP and NfL were altered in AD versus CU.  Aß42/40, p-tau181, GFAP, and NfL are associated with prospective cognitive decline.  Aß42/40, p-tau181, and GFAP are associated with increased PET Aß load prospectively.