Plasma Aβ42/40 ratio, p‐tau181, GFAP, and NfL across the Alzheimer's disease continuum: A cross‐sectional and longitudinal study in the AIBL cohort

Introduction Plasma amyloid beta (Aβ)1‐42/Aβ1‐40 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 Aβ1‐42, Aβ1‐40, p‐tau181, GFAP, and NfL were measured utilizing the Single Molecule Array (Simoa) platform and compared cross‐sectionally across the AD continuum, wherein Aβ‐PET (positron emission tomography)–negative cognitively unimpaired (CU Aβ−, n = 81) and mild cognitive impairment (MCI Aβ−, n = 26) participants were compared with Aβ‐PET–positive participants across the AD continuum (CU Aβ+, n = 39; MCI Aβ+, n = 33; AD Aβ+, 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 Aβ‐PET load were assessed over a 7 to 10‐year duration. Results Lower plasma Aβ1‐42/Aβ1‐40 ratio and elevated p‐tau181 and GFAP were observed in CU Aβ+, MCI Aβ+, and AD Aβ+, whereas elevated plasma NfL was observed in MCI Aβ+ and AD Aβ+, compared with CU Aβ− and MCI Aβ−. 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 Aβ−/+ status across the AD continuum. However, for models with and without the AD risk factors, a biomarker panel of Aβ1‐42/Aβ1‐40, p‐tau181, and GFAP performed equivalent to or better than any of the biomarkers alone in predicting brain Aβ−/+ status across the AD continuum. Longitudinally, plasma Aβ1‐42/Aβ1‐40, 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 Aβ1‐42/Aβ1‐40 and higher p‐tau181, GFAP, and NfL were associated with prospective cognitive decline and lower plasma Aβ1‐42/Aβ1‐40, and higher p‐tau181 and GFAP were associated with increased Aβ‐PET load prospectively. Discussion These findings suggest that plasma biomarkers are altered cross‐sectionally and longitudinally, along the AD continuum, and are prospectively associated w