Plasma phospho-tau in Alzheimer’s disease: towards diagnostic and therapeutic trial applications

Abstract

As the leading cause of dementia, Alzheimer's disease (AD) is a major burden on affected individuals, their families and caregivers, and healthcare systems. Although AD can be identified and diagnosed by cerebrospinal fluid or neuroimaging biomarkers that concord with neuropathological evidence and clinical symptoms, challenges regarding practicality and accessibility hinder their widespread availability and implementation. Consequently, many people with suspected cognitive impairment due to AD do not receive a biomarker-supported diagnosis. Blood biomarkers have the capacity to help expand access to AD diagnostics worldwide. One such promising biomarker is plasma phosphorylated tau (p-tau), which has demonstrated specificity to AD versus non-AD neurodegenerative diseases, and will be extremely important to inform on clinical diagnosis and eligibility for therapies that have recently been approved. This review provides an update on the diagnostic and prognostic performances of plasma p-tau181, p-tau217 and p-tau231, and their associations with in vivo and autopsy-verified diagnosis and pathological hallmarks. Additionally, we discuss potential applications and unanswered questions of plasma p-tau for therapeutic trials, given their recent addition to the biomarker toolbox for participant screening, recruitment and during-trial monitoring. Outstanding questions include assay standardization, threshold generation and biomarker verification in diverse cohorts reflective of the wider community attending memory clinics and included in clinical trials.

A novel ultrasensitive assay for plasma p-tau217: performance in individuals with subjective cognitive decline and early Alzheimer’s disease

“…Whilst previous studies have shown good biomarker accuracies for plasma p-tau217 17, 20 , performances among CU participants in population-based cohorts have been scanty and in the few available papers the results have been less consistent 6, 12, 34 . This can be mainly attributable to the weak analytical performance (e.g., lack of quantifiable signals, poor precision) of first-generation p-tau217 assays in individuals with very low concentrations including CU participants and those in early symptomatic stages 2, 3 . However, detection of incipient Aβ pathology in the early stages of the AD continuum is crucial not only for early disease identification but also to determine eligibility for the recently approved anti-amyloid therapies.…”

“…Meanwhile, the evaluation of individuals in early stages of the AD continuum continues to be difficult partly due to heterogeneity in how clinical manifestations compare with biological evidence of disease 4, 5 . The implementation of peripheral biomarkers that can provide biochemical evidence of early AD biological changes could help clinicians to provide specialised diagnostic and/or therapeutic care 2, 3 . In the era of new anti-amyloid-beta (Aβ) immunotherapy drugs for AD, early intervention will be critical for maximising treatment efficacy, and robust biomarkers that become abnormal in cognitively unimpaired individuals as well as patients in the early symptomatic phases will be essential for first-in-line screening of patients eligible for treatment 5, 6 .…”

“…While neuroimaging techniques, especially positron emission tomography (PET), and cerebrospinal fluid (CSF) analyses offer valuable insights into AD pathology, they are expensive, invasive, involve radioactive ligands, and have very limited accessibility for routine clinical use 7, 8 . Therefore, the search for minimally invasive and readily accessible biomarkers for AD has gained substantial momentum 2, 9 . Several plasma biomarkers have been shown to associate well with Aβ pathophysiology – whether assessed using Aβ PET or CSF Aβ42/40 ratio 8, 10 – as well as cognitive performance 11, 12 .…”

“…These high-performing biomarkers include plasma Aβ42/40 measured with immunoprecipitation-mass spectrometry, glial fibrillary acidic protein (GFAP), and p-tau variants [13][14][15][16] . Among the plasma p-tau biomarkers, p-tau181, p-tau217 and p-tau231 have all shown high performances to detect Aβ pathophysiology 2,3 . However, recent head-to-head studies suggest that p-tau217 has the largest between-diagnostic group fold increases and the strongest associations with both cross-sectional and longitudinal changes in Aβ pathophysiology 17 , explainable by a more pronounced longitudinal increase in symptomatic cases 18 .…”

Artificial intelligence for biomarker discovery in Alzheimer's disease and dementia

“…Numerous studies have sought plasma biomarkers relevant to AD diagnosis, and the past decades have seen several analytes being tested for this purpose 51 . For example, recent studies have demonstrated that AD hallmarks in plasma such as Aβ42/40, p‐tau181, p‐tau231, and p‐tau217 can identify brain pathology with high accuracy, further adding significant weight to the growing body of evidence in their use as a non‐invasive diagnostic tool for AD 52–54 . Apart from AD hallmarks in blood, an increasing number of studies have discovered a range of other proteins and metabolites in plasma that might also act as diagnostic biomarkers 55,56 .…”