Head‐to‐head comparison of plasma biomarkers across the AD continuum in an Australian population

Abstract Background Plasma amyloid‐β (Aβ) 1‐42/Aβ1‐40 ratio, phosphorylated‐tau181 (p‐tau181), glial fibrillary acidic protein (GFAP) and neurofilament light (NFL) are putative blood‐based biomarkers for Alzheimer’s disease (AD). However, head‐to‐head comparisons of the afore‐mentioned biomarkers across the AD continuum are lacking. Method Plasma Aβ1‐42, Aβ1‐40, p‐tau181, GFAP and NFL were measured using the Single Molecule Array platform and compared cross‐sectionally in models with and without AD risk factors (age, sex and APOE ε4 status) across the AD continuum in Aβ PET positive confirmed participants (CU Aβ+, n = 39; MCI Aβ+, n = 33; AD Aβ+, n = 46) and Aβ PET negative confirmed participants (CU Aβ‐, n = 81; MCI Aβ‐, n = 26) from the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL) cohort. Area under the receiver operating characteristic curves (AUCs) for predicting Aβ PET‐/+ status were compared using DeLong test. Associations between plasma biomarker levels at baseline and prospective cognitive decline (CDR‐SOB) and brain Aβ load were also assessed. Result Lower plasma Aβ1‐42/Aβ1‐40 ratio and higher p‐tau181 and GFAP were observed in preclinical AD (Aβ1‐42/Aβ1‐40 ratio: ∼19%; p‐tau181: ∼70%; GFAP: ∼52%), prodromal AD (Aβ1‐42/Aβ1‐40 ratio: ∼14%; p‐tau181: ∼69%; GFAP: ∼45%) and AD (Aβ1‐42/Aβ1‐40 ratio: ∼16%; p‐tau181: ∼91%; GFAP: ∼85%), and higher plasma NFL was observed in prodromal AD (∼27%) and AD (∼45%) (Figure 1). Based on the AUCs, p‐tau181 performed equivalent to or better than (≥) other biomarkers, in predicting Aβ PET‐/+ status across the AD continuum (p‐tau AUCs for CU Aβ‐ vs CU Aβ+ ∼81%/ MCI Aβ+ ∼86%/ AD ∼92%). A biomarker panel of Aβ1‐42/Aβ1‐40 ratio, p‐tau181 and GFAP performed ≥ the biomarkers alone in predicting Aβ PET‐/+ status across the AD continuum (biomarker panel AUCs for CU Aβ‐ vs CU Aβ+ 90%/ MCI Aβ+ 89%/ AD 96%). Higher p‐tau181 (β = 0.531, p = 3.18E‐08), GFAP (β = 0.530, p = 5.07E‐08) and NFL (β = 0.487, p = 4.76E‐06) were associated with cognitive decline prospectively and lower plasma Aβ1‐42/Aβ1‐40 ratio (β = ‐6.035, p = 1.56E‐04) and higher p‐tau181 (β = 2.823, p = 4.72E‐05) and GFAP (β = 2.075, p = 0.003) were associated with increased Aβ PET load prospectively. Conclusion These findings suggest that plasma biomarkers are altered across the AD continuum and are associated with cognitive decline and increased brain Aβ load prospectively.