Amyloid-β Seeding as a Basis for a Blood Test for Alzheimer's Disease
Blood tests to assess Alzheimer's disease risk and progression exist, for example based on the presence of circulating varieties of tau protein, but there is a great deal of room for improvement. Researchers here provide evidence for an approach to the measurement of very small amounts of misfolded amyloid-β in blood to work reasonably well in patients. The amyloid cascade hypothesis continues to steer much of the field of research and development for Alzheimer's disease; misfolded amyloid-β spreads slowly in the brain over years, and eventually causes sufficient dysfunction to promote a subsequent disease stage characterized by a feedback loop between chronic inflammation and tau aggregation. Tracking this growth in misfolded amyloid-β make sense as an approach to assessing risk and progression of the early stages of Alzheimer's disease.
A hallmark of Alzheimer's disease (AD) pathophysiology is the misfolding and aggregation of β-amyloid (Aβ) protein in the brain, which results in tau pathology, neuroinflammation, synaptic loss, neurodegeneration, and cognitive decline. The misfolded Aβ aggregates, or "seeds", range from small, soluble oligomers to large, insoluble fibrils that have a rich β-sheet secondary structure and are generally stable. Because of its specific structure, Aβ seeds corrupt natively folded Aβ and promote the aggregation and formation of pathogenic assemblies, which is a process similar to prion-like aggregation. Such a process follows a secondary nucleation mechanism in which new aggregates generate at a rate dependent on the concentration of existing seeds.
Based on this seeding nucleation mechanism, protein misfolding cyclic amplification (PMCA) has been developed to amplify trace amounts of misfolded proteins to a detectable level in biological samples. It uses repeated cycles of incubation and amplification for seed multiplication. However, the application of these techniques to AD diagnosis is relatively limited. In the present study, we detected plasma Aβ aggregation seeding activity using a real-time sonication-based PMCA method. A total of 549 participants were recruited between December 2020 and May 2024. Plasma Aβ aggregation seeding activity was measured using a real-time sonication-based protein misfolding cyclic amplification assay. The diagnostic performance of plasma Aβ aggregation seeding activity as a biomarker was assessed.
In the validation stage, plasma Aβ aggregation seeding activity exhibited high diagnostic accuracy with optimal cutoff values of 42.91 for distinguishing AD from cognitively unimpaired (area under the curve [AUC] = 0.93), 42.02 for AD from non-AD dementia, and 43.24 for mild cognitive impairment due to AD from non-AD dementia. Plasma Aβ seeding activity significantly correlated with cognitive functions (Mini-Mental State Examination [MMSE] scores: rs = -0.68; Clinical Dementia Rating [CDR] scores: rs = 0.71).
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.