Amyloid beta aggregation seeding activity as a new biomarker for Alzheimer’s disease

BACKGROUND: Blood-based biomarkers would greatly facilitate the clinical diagnosis of Alzheimer's disease (AD) as minimally invasive measurements. While several blood biomarkers for AD have emerged, the potential of plasma β-amyloid (Aβ) aggregation seeding activity remains underexplored. In this study, we aim to evaluate the ability of this biomarker to distinguish AD and mild cognitive impairment (MCI) due to AD from cognitively unimpaired (CU) individuals and non-AD dementia. METHODS: A total of 549 participants were recruited from Xuanwu Hospital, Capital Medical University, between December 2020 and May 2024. Plasma Aβ aggregation seeding activity was measured using a real-time sonication-based protein misfolding cyclic amplification assay across discovery (n = 120: 30 CU, 30 MCI due to AD, 30 AD, 30 non-AD dementia) and validation (n = 429: 118 CU, 46 MCI due to AD, 141 AD, 124 non-AD dementia) stages. The diagnostic performance of plasma Aβ aggregation seeding activity as a biomarker was assessed using receiver operating characteristic (ROC) curves. RESULTS: In the validation stage, plasma Aβ aggregation seeding activity exhibited high diagnostic accuracy with optimal cutoff values (Thioflavin T fluorescence %) of 42.91 for distinguishing AD from CU (area under the ROC curve [AUC] = 0.93, 95% confidence interval [CI]: 0.91-0.96), 42.02 for AD from non-AD dementia (AUC = 0.91, 95% CI: 0.88-0.94), 43.17 for MCI due to AD from CU (AUC = 0.92, 95% CI: 0.87-0.96), and 43.24 for MCI due to AD from non-AD dementia (AUC = 0.90, 95% CI: 0.85-0.94). Plasma Aβ seeding activity significantly correlated with cognitive functions (Mini-Mental State Examination scores [MMSE]: rs = -0.68, P <0.001; Clinical Dementia Rating scores [CDR]: rs = 0.71, P <0.001). CONCLUSIONS: These findings indicate that plasma Aβ aggregation seeding activity could serve as a promising minimally invasive biomarker for identifying both AD and MCI due to AD. This biomarker potentially facilitates early detection and differential diagnosis of AD at different clinical stages.