The combination of and Aβ42/40 achieved a diagnostic accuracy of 0.937 in cognitively unimpaired individuals.
In cognitively unimpaired individuals, combining p-tau217 with Aβ42/40 significantly improved diagnostic accuracy compared to p-tau217 alone.
The area under the curve for the combined biomarkers was 0.937, indicating strong diagnostic performance.
In cognitively impaired individuals, the combination of biomarkers provided modest improvements in model fit but did not significantly enhance diagnostic accuracy.
GFAP and Neurofilament light chain did not significantly contribute to amyloid detection in either group.
Subgroup analyses indicated that older adults, females, and APOE4 non-carriers in the cognitively unimpaired group showed the greatest improvement in diagnostic accuracy.
Simplified
BACKGROUND: Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) pathology. Recently, plasma biomarkers, particularly , have emerged as promising tools for early diagnosis and risk stratification. In this retrospective study, we evaluated the diagnostic performance of p-tau217 combined with other plasma biomarkers in distinguishing Aβ Positron emission tomography (PET) positivity in cognitively unimpaired (CU) and cognitively impaired (CI) individuals across diverse clinical subgroups.
METHODS: We analyzed 2,497 participants from the Korea-Registries to Overcome dementia and Accelerate Dementia (K-ROAD) cohort, including 636 CU and 1,971 CI individuals. Plasma p-tau217 was measured using both SIngle MOlecule Array (SIMOA) and Meso Scale Discovery (MSD) assays, alongside Aβ42/40, Glial fibrillary acidic protein (GFAP), and Neurofilament light chain (NfL). We assessed the diagnostic performance of biomarker combinations for Aβ PET positivity through the area under the receiver operating characteristic curve (AUC), Akaike Information Criterion (AIC) and Bayesian Information Criterion (BIC), and performed subgroup analyses based on age, sex, body mass index (BMI), and Apolipoprotein E (APOE) ε4 status. To assess applicability, we stratified the cohort by recruitment site into a development set (Samsung Medical Center, n = 1,545) and a validation set (other centers, n = 952).
RESULTS: In CU individuals from the development cohort, the combination of p-tau217 and Aβ42/40 significantly improved diagnostic accuracy (AUC: ALZpath 0.937 vs. 0.905, MSD 0.901 vs. 0.861; p < 0.05, DeLong test; 95% CIs) and model fit (AIC /BIC, p < 0.001) compared to p-tau217 alone. In contrast, in CI individuals, the combination provided only modest improvements in model fit without significantly enhancing AUC. GFAP and NfL did not contribute significantly to amyloid detection in either group. These findings were successfully validated in an independent cohort from other centers. Subgroup analyses in CU individuals showed the greatest improvements in older adults, females, and APOE4 non-carriers, regardless of obesity status. In CI individuals, the combination had no significant impact on AUC except in males, where a small but significant increase was observed (p = 0.002).
CONCLUSION: Combining p-tau217 with Aβ42/40 enhances amyloid detection in CU individuals, improving both diagnostic accuracy and model fit, whereas its impact in CI individuals is limited. These results highlight the potential of plasma biomarker combinations for refining early AD diagnostics and individualized risk assessment.
Key numbers
0.937
Increase in
for the + model in individuals.
0.905
for alone
for alone in individuals.
0.936
for individuals
for the + model in individuals.
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