Plasma A beta 42/40 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 (A beta)1-42/A beta 1-40 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 A beta 1-42, A beta 1-40, p-tau181, GFAP, and NfL were measured utilizing the Single Molecule Array (Simoa) platform and compared cross-sectionally across the AD continuum, wherein A beta-PET (positron emission tomography)-negative cognitively unimpaired (CU A beta-, n = 81) and mild cognitive impairment (MCI A beta-, n = 26) participants were compared with A beta-PET-positive participants across the AD continuum (CU A beta+, n = 39; MCI A beta+, n = 33; AD A beta+, 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 A beta-PET load were assessed over a 7 to 10-year duration. Results Lower plasma A beta 1-42/A beta 1-40 ratio and elevated p-tau181 and GFAP were observed in CU A beta+, MCI A beta+, and AD A beta+, whereas elevated plasma NfL was observed in MCI A beta+ and AD A beta+, compared with CU A beta- and MCI A beta-. Among the aforementioned plasma biomarkers, for models with and without AD risk factors (age, sex, and apolipoprotein E (APOE) epsilon 4 carrier status), p-tau181 performed equivalent to or better than other biomarkers in predicting a brain A beta-/+ status across the AD continuum. However, for models with and without the AD risk factors, a biomarker panel of A beta 1-42/A beta 1-40, p-tau181, and GFAP performed equivalent to or better than any of the biomarkers alone in predicting brain A beta-/+ status across the AD continuum. Longitudinally, plasma A beta 1-42/A beta 1-40, 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 A beta 1-42/A beta 1-40 and higher p-tau181, GFAP, and NfL were associated with prospective cognitive decline and lower plasma A beta 1-42/A beta 1-40, and higher p-tau181 and GFAP were associated with increased A beta-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 A beta-PET load. In addition, although p-tau181 performed equivalent to or better than other biomarkers in predicting an A beta-/+ status across the AD continuum, a panel of biomarkers may have superior A beta-/+ status predictive capability across the AD continuum. HIGHLIGHTS Area under the curve (AUC) of p-tau181 >= AUC of A beta 42/40, GFAP, NfL in predicting PET A beta-/+ status (A beta-/+). AUC of A beta 42/40+p-tau181+GFAP panel >= AUC of A beta 42/40/p-tau181/GFAP/NfL for A beta-/+. Longitudinally, A beta 42/40, p-tau181, and GFAP were altered in MCI versus CU. Longitudinally, GFAP and NfL were altered in AD versus CU. A beta 42/40, p-tau181, GFAP, and NfL are associated with prospective cognitive decline. A beta 42/40, p-tau181, and GFAP are associated with increased PET A beta load prospectively.