Plasma Biomarkers for Early Detection and Staging of Alzheimer’s Disease: A Cross-Sectional Study in a Japanese Cohort

Background Plasma biomarkers offer a promising alternative to amyloid beta (Aβ) PET or cerebrospinal fluid (CSF) biomarkers for diagnosing Alzheimer’s disease (AD). This cross-sectional study assessed the utility of multiple plasma biomarkers in a Japanese cohort, including healthy controls (HC), individuals on the AD continuum, and those with non-AD cognitive impairment. Methods Participants were classified using Aβ PET imaging and neuropsychological tests into HC, the AD continuum (preclinical [preAD], mild cognitive impairment [AD-MCI], and mild dementia [AD-D]), and non-AD cognitive impairment groups. We conducted ROC analyses to predict Aβ PET status, correlation analyses with Centiloid (CL) values and cognitive scores, and biomarker comparisons across AD stages. Plasma biomarkers assessed included Aβ42/40, phosphorylated tau (p-tau181, p-tau217), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL), individually and in combination. Aβ42/40 was measured via High-Sensitivity Chemiluminescence Enzyme Immunoassay (HISCL), while all other biomarkers were measured using the Single Molecule Array (Simoa) platform. Results A total of 69 HC, 13 preAD, 37 AD-MCI, 44 AD-D, and 80 non-AD cognitive impairment participants were analyzed. AUCs for predicting Aβ PET status were 0.931 (Aβ42/40), 0.924 (p-tau217), and 0.944 (p-tau217/Aβ42). In the cognitively normal group, AUCs were 0.968 (Aβ42/40), 0.958 (p-tau217), and 0.979 (p-tau217/Aβ42), while in the cognitively impaired group, they were 0.907 (Aβ42/40), 0.890 (p-tau217), and 0.921 (p-tau217/Aβ42). Among HC and AD continuum participants, CL correlations were 0.75 (Aβ42/40), 0.81 (p-tau217), and 0.83 (p-tau217/Aβ42). All biomarkers correlated strongly with Logical Memory scores. Aβ42/40 levels declined sharply from HC to preAD, transitioning at a CL threshold of 19.3, while the Aβ PET positivity threshold was 32.9. P-tau217 exhibited a linear increase with disease progression. Conclusions Plasma biomarkers, Aβ42/40, p-tau217, and particularly their ratio (p-tau217/Aβ42), show strong potential as Aβ PET alternatives for AD diagnosis. HISCL-based plasma Aβ42/40 detects Aβ accumulation earlier (CL = 20) than Aβ PET visual reading threshold (CL = 32.9), underscoring its utility as an early diagnostic marker. P-tau217 consistently tracks disease progression, reinforcing its value in AD staging. Longitudinal validation of these findings is needed.