Blood-based biomarkers for brain pathologies other than amyloid accumulation: beyond the ATN system.

There is still a substantial unmet need for less invasive and lower-cost molecular biomarkers, namely blood-based biomarkers, for the diagnosis and stratification of patients with dementia including Alzheimer\u27s disease (AD). We developed the world\u27s first immunoassay to quantify plasma tau phosphorylated at threonine 181 (p-tau181) in 2017 by using an ultrasensitive digital array technology (Simoa system, Quanterix, USA). With this original assay, we reported that the plasma levels of p-tau181 were significantly higher in AD patients than those in the controls. Our study suggested that plasma p-tau181 is a promising blood biomarker for brain AD pathology. After our study, substantial evidence of the usefulness of plasma p-tau assays in the diagnosis of AD has been accumulating internationally. Besides, usefulness of various p-tau species for brain AD pathologies has been reported by many laboratories, and the list of blood-based biomarker candidates for brain pathologies related to dementia is growing more rapidly than we used to recognize. Now, we are developing other blood biomarkers for AD and other dementias, such as Aβ40/42, neurofilament light (NfL), p-tau species other than p-tau181 as well as molecules related to other dementing disorders including TDP-43 and α-synuclein. Furthermore, for the validation and future use of those biomarkers in the clinical settings, it is essential that we should collect large-scale blood samples obtained from patients with a highly reliable diagnosis of underlying diseases. Such a "reliable diagnosis" used to mean the pathological diagnosis of the patients, but now neuroimaging techniques, such as PET imaging, of pathognomonic accumulation of abnormal protein aggregates can be used as a substitute for the pathological diagnosis. From this recognition, we have launched the Multicenter Alliance for Brain Biomarkers (MABB) in August 2020 and have started to enroll patients with cognitive impairment and controls to collect both PET imaging data and blood samples. In my talk, I will present our results and recent findings reported from other groups regarding tau species and other dementia-related molecules in human blood as the candidates of blood-based biomarkers for AD and neurodegenerative dementias. Furthermore, I will propose “ProVEN” system that is a novel framework of biomarkers, which is more comprehensive than current “ATN” system, for dementing disorders including various brain diseases.The 16th International Symposium on Geriatrics and Gerontolog