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

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.