Changes in Plasma Amyloid β 1-42 Peptide and Total Tau Protein from Normal Cognition to Sever-Stage Alzheimer's...

Measurements of plasma biomarkers are included in current guidelines for the diagnosis of Alzheimer's disease. Amyloid β 1-42 peptide (Aβ_1-42) and tau protein are the key analytes. By using the ultrasensitive immunomagnetic reduction (IMR) assay, the combination of Aβ_1-42 and total tau protein (T-Tau), i.e., Aβ_1-42xT-Tau, effectively discriminates cognitively unimpaired (CU) individuals from patients with amnestic mild cognitive impairment (aMCI) and early-stage Alzheimer's disease dementia (eADD). However, the accuracy of plasma Aβ_1-42xT-Tau in distinguishing mild/severe ADD (m-sADD) decreases. In this work, the dynamic changes in individual and combined plasma Aβ_1-42 and T-Tau in CU, aMCI, eADD, and m-sADD individuals were investigated. One hundred thirty-nine individuals, including 66 CU, 24 aMCI, 26 eADD, and 23 m-sADD patients, were enrolled to investigate the distributions of plasma Aβ_1-42 and T-Tau using IMR. In addition, 13 autopsies were performed to investigate the evolution of plasma Aβ_1-42 and T-Tau with increasing Aβ plaque density in the brain. CU subjects had 249.8 ± 103.7 (pg/mL)² for plasma Aβ_1-42xT-Tau. aMCI, eADD, and m-sADD patients had plasma Aβ_1-42xT-Tau of 583.4 ± 139.2, 1061.1 ± 402.9, and 884.7 ± 488.9 (pg/mL)², respectively. Plasma Aβ_1-42xT-Tau levels clearly increase from CU to aMCI to eADD patients. Similar changes in plasma Aβ_1-42xT-Tau are correlated with high densities of Aβ plaques in the postmortem brain. Further analysis revealed that the dynamic changes in plasma Aβ_1-42xT-Tau from CU to m-sADD patients are mainly attributed to T-Tau neuropathology. The results of the autopsy study suggest that the fibrillization of soluble tau proteins is accelerated at high Aβ plaque densities, possibly contributing to the dynamic change in plasma biomarkers from eADD to m-sADD. Measurements of individual or combined plasma Aβ_1-42 and T-Tau using IMR show high sensitivity (>0.9) and high specificity (>0.9) for assessing aMCI and eADD patients. By using stepwise cutoff values, the prediction of staging CU, aMCI, or eADD is feasible in clinical practice.