The area under the curves (AUCs) for predicting amyloid beta PET status were 0.946 for the ratio of to Aβ42.
Plasma biomarkers Aβ42/40 and p-tau217, as well as their ratio, may serve as effective alternatives to amyloid PET imaging for diagnosing Alzheimer's disease.
In cognitively normal participants, the AUCs for Aβ42/40 and p-tau217 were 0.968 and 0.958, respectively, indicating strong predictive capability.
Cognitively impaired individuals showed AUCs of 0.919 for Aβ42/40 and 0.893 for p-tau217, reflecting the potential utility of these biomarkers in different stages of cognitive decline.
Correlations between biomarker levels and cognitive performance were strong, particularly with logical memory scores, suggesting a relationship between these biomarkers and cognitive function.
Aβ42/40 levels demonstrated a bimodal distribution among healthy controls and participants in the Alzheimer's continuum, highlighting its potential for early detection.
P-tau217 levels increased linearly with disease progression, indicating its association with advancing Alzheimer's disease.
Simplified
BACKGROUND: Plasma biomarkers offer a promising alternative to amyloid beta (Aβ) positron emission tomography (PET) or cerebrospinal fluid (CSF) biomarkers for diagnosing Alzheimer's disease (AD). This cross-sectional study assessed the utility of multiple plasma biomarkers for diagnosing and staging AD in a Japanese cohort.
METHODS: The assessed plasma biomarkers included Aβ42/40, phosphorylated tau (p-tau181 and ), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL), individually and in combination. Aβ42/40 was measured using the HISCLplatform, while all other biomarkers were measured using the Simoaplatform. Participants were classified based on Aβ PET imaging and neuropsychological testing into healthy controls (HC), AD continuum (preclinical AD, mild cognitive impairment [AD-MCI], and mild dementia [AD-D]), and non-AD cognitive impairment (CI) groups. Receiver operating characteristic analyses were performed to predict the Aβ PET status, correlation with Centiloid (CL) values and cognitive scores, and biomarker comparisons across AD stages. ® ®
RESULTS: Sixty-nine HC, 13 preclinical AD, 38 AD-MCI, 44 AD-D, and 79 non-AD CI participants were included. The area under the curves (AUCs) for predicting Aβ PET status were 0.937 (Aβ42/40), 0.926 (p-tau217), and 0.946 (p-tau217/Aβ42); results of pair-wise DeLong tests revealed no significant differences among these three metrics (all p > 0.05). In the cognitively normal group, the AUCs were 0.968 (Aβ42/40), 0.958 (p-tau217), and 0.979 (p-tau217/Aβ42), while in the cognitively impaired group, they were 0.919 (Aβ42/40), 0.893 (p-tau217), and 0.923 (p-tau217/Aβ42). Among HC and AD continuum participants, CL correlations were - 0.74 (Aβ42/40), 0.81 (p-tau217), and 0.83 (p-tau217/Aβ42). In the HC and AD continuum, Aβ42/40 levels showed a bimodal distribution (cutoff = 0.096), with a shift from high to low occurring at 19.3 CL, compared to the PET positivity threshold of 32.9 CL. P-tau217 exhibited a linear increase with disease progression. All biomarkers correlated strongly with logical memory scores.
CONCLUSIONS: Plasma biomarkers, Aβ42/40 and 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 than Aβ PET visual reading threshold, underscoring its utility as an early diagnostic marker.
Key numbers
0.937
AUC for Aβ42/40
Area under the curve for Aβ42/40 predicting AD status.
0.926
AUC for
Area under the curve for predicting AD status.
0.946
AUC for /Aβ42 ratio
Area under the curve for the biomarker ratio predicting AD status.
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Declarations. Ethics approval and consent to participate: The Certified Review Board of Keio University (#N20170237) approved the study design and protocol. The study was conducted in accordance with the Declaration of Helsinki. All participants (plus their proxies as needed) provided written informed consent for participation in the study. The study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; https://www.umin.ac.jp/ctr/index.htm , ID# UMIN000032027) and Japan Registry of Clinical Trials (jRCT; https://jrct.niph.go.jp/ , ID# jRCTs031180225). Consent for publication: Not applicable. Competing interests: DI has received honorariums from Daiichi Sankyo, Nihon Medi-Physics, Kowa, PDRadiopharma, Otsuka Pharmaceutical, Lilly and Eisai and has a joint research agreement with Sysmex. There are no other relationships or activities that could appear to have influenced the submitted work.
