Site-Specific Phospho-Tau Aggregation-Based Biomarker Discovery for AD Diagnosis and Differentiation

Abstract

Tau aggregates are present in multiple neurodegenerative diseases known as "tauopathies," including Alzheimer's disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). Such misfolded tau aggregates are therefore potential sources for tauopathy biomarker discovery. Using the tau antibody screening approach targeting high-molecular-weight misfolded tau aggregates, we tested several tau antibodies and a comprehensive set of site-specific phospho-tau (p-tau) antibodies targeting tau phosphorylation sites showing high frequencies in AD subjects. Our screens revealed that site-specific p-tau antibodies can not only differentiate AD from non-AD brains, but also discriminate AD from rare tauopathies PiD, PSP, and CBD brains. Differential detection of tau aggregates identified several novel p-tau sites as potential new biomarkers. As a proof-of-principle example, we showed that p-tau198 is a novel promising AD biomarker with sensitivity and specificity comparable with the existing biomarkers p-tau181 and p-tau217. Our results demonstrated that p-tau198 detection can not only differentiate AD from non-AD controls, but also diagnose AD from related 4R tauopathies PSP and CBD with AUCs of 0.96−0.99 (95% CI ranges from 0.90 to 1.00). Promisingly, p-tau198 was able to discriminate mild cognitive impairment from cognitively normal brains with an AUC of 0.75 (95% CI = 0.58−0.92). Our work provides a new avenue for developing diagnosis and differentiation tools for AD and related tauopathies.

Seeding Activity of Skin Misfolded Tau as a Novel Biomarker for Tauopathies

“…Skin homogenates from cadavers with AD (n=5), PSP (n=4), CBD (n=4), PiD (n=4) and NC (n=4) were examined by western blotting with antibodies directed against phosphorylated tau (Anti-pT231 and Anti-pS396). P-tau231 and p-tau396 epitopes were previously identified from a systematic p-tau antibody screening in differential detection with AD and control brains [51]. Both the pThr231 (Fig.…”

“…In order to find an appropriate tau substrate for setting up our seed-amplification assay of skin tau (sTau-SAA) with the ultrasensitive RT-QuIC technique, based on our recent finding with autopsy brain tissues from cadavers with AD and other non-AD tauopathies [53], we first examined 4 types of tau substrates including 2 full-length tau isoforms (2N3R/2N4R) and 2 truncated tau fragments consisting of 4RCF (cysteine-free, equivalent to K18CFh)/3RCF (equivalent to K19CFh) using autopsy skin samples from AD cadavers. 4RCF represents the core aggregation sequences of the 4R tau isoforms [51, 53]. Correspondingly, 3RCF fragment represents the core aggregation sequences of the 3R tau isoforms.…”

Differential diagnosis of mild cognitive impairment of Alzheimer’s disease by Simoa p-tau181 measurements with matching plasma and CSF

“…A recent meta-analysis suggested that p-tau217 had better discriminative accuracy for MCI than p-tau181 and p-tau231 ( Chen et al, 2022 ). We recently showed that a new neuropathological biomarker p-tau198 had capability to diagnose MCI cohorts from cognitively normal subjects in brain tissues ( Wu et al, 2022a ). Therefore, it will be interesting in the future to evaluate these promising p-tau biomarkers or to develop novel p-tau biomarkers for plasma and CSF tests.…”

Breakthroughs in Alzheimer’s Research: A Path to a More Promising Future?

“…They found an intriguing new biomarker, p-tau 198, beneficial for spotting abnormal tau protein in the brain at the early stages of AD. 21 Early detection and effective AD treatment may be revolutionized by a simple, affordable, and accurate blood test for p-tau 198. According to a different study, tiny nucleotides that attach to mRNAs can be found in the blood and detect a cellular imbalance in the brain.…”