1. Introduction
Progress in biomarkers of Alzheimer’s disease (AD) in the last ten years has been remarkable. Biomarkers for amyloid-β and tau have reconceptualized AD and become an integral part of its operational definition. There is recognition of the close link between amyloid-β and tau pathology in the process leading to dementia due to AD [Citation1]. There has thus been interest in measuring both pathological features of AD using PET imaging, CSF examination, and plasma.
A specific issue with p-tau plasma biomarkers is the contribution of the periphery vs the brain in generating elevated levels. Bathélemy et al. [Citation2] estimate that CNS tau contributes up to 20% of overall plasma t-tau levels in cognitively unimpaired controls. They argue for use of CNS tau isoforms such as p-tau181 and p-tau217 to overcome the contribution of peripheral tau and to monitor CNS tau in plasma.
Cohort studies have demonstrated the sensitivity and specificity of p-tau181 plasma levels to distinguish AD from other dementias [Citation3–5] (), and correlate with neurofibrillary tangle distribution at autopsy [Citation6].
Table 1. Illustration of sensitivity analysis of p–tau isoforms in different cohorts
A postmortem study involving 115 individuals showed that elevated levels of p-tau181 were present eight years before death, with a plateau over time four years before death [Citation7].
An analysis of p-tau181 in data generated from the ADNI longitudinal cohort has demonstrated that elderly participants without dementia but with elevated p-tau181 levels had greater memory decline at baseline and greater rates of progression to dementia [Citation8]. Furthermore, the addition of plasma p-tau181 increased the prediction of memory decline above readily available clinical and genetic information.
There are other p-tau phosphorylated peptides such as p-tau217 that have also demonstrated sensitivity and specificity in the differential diagnosis of AD [Citation9]. The extent to which plasma p-tau217 may be more effective than p-tau181, and how this differs across disease stages [Citation10], is not yet known. When both plasma p-tau peptides are measured simultaneously they have been found to be specific to the brain amyloid-β status as reflected by CSF measures, with the superiority of p-tau217 over p-tau181 [Citation2].
2. Potential immediate impact
The transformative potential of plasma phosphorylated tau has been quite appropriately emphasized by C. Jack in a commentary: useful for enrollment in clinical trials that target amyloid-β, tau or both, increasing efficacy and decreasing costs currently encountered with negative PET or CSF examinations [Citation11].
One might ask whether measures of plasma phosphorylation will face the same methodological issues from CSF measures of biomarkers. In fact, methodological issues hampered the dissemination of fluid biomarkers in clinical practice. It is expected that the challenges faced during the clinical implementation of CSF biomarkers will accelerate the harmonization protocols and rapid dissemination of the new technology for plasma p-tau181 and 217 in research and clinical settings.
In research, several questions remain to be answered. Is the dynamic range of plasma phosphorylated tau species sufficient to stage disease? Furthermore, it remains unclear how plasma p-tau181 (or p-tau217) would perform as a direct measure of the removal or slowing of tau protein deposition, hence the need for quantification using PET imaging to measure changes in regional tau deposition across the Braak stages [Citation12].
3. Potential long-term impact
In the near future, one can easily envision the use of plasma phosphorylated tau species in conjunction with an MMSE or MoCA as a screening work-up. The use of these techniques as diagnostic method to rule in AD as a cause of cognitive decline might be helpful due to the frequent co-morbidities between AD with other protein aggregates and cerebrovascular disease.
If and when anti-amyloid and anti-tau drugs are proven effective in AD, there will be a requirement to confirm that specific persons with MCI or dementia are amyloid-β and tau positive. Elevation beyond a threshold still to be determined of these plasma p-tau isoforms could thus be required prior to initiating treatment, avoiding the need for more invasive and costly CSF examination and/or PET scanning. Another potential possibility is to use plasma tau assessments as pre-screening, with CSF examination or PET imaging used to confirm the presence of pathology before initiating treatment.
The trajectory of AD biomarker discovery serves as a blueprint for translating basic science to tangible advances in clinical diagnosis. This blueprint will lead to the discovery of biomarkers to other age-related neurodegenerative conditions.
4. Conclusion
Elevated p-tau isoforms plasma levels correlate with the brain content of amyloid-β and tau, at least in symptomatic stages of AD. This will accelerate progress in drug development and future use of effective drugs.
5. Expert opinion
We are fortunate to see evidence that plasma p-tau181 and p-tau217 correlate so well with brain amyloid-β and tau content. We are thus closer to an operational use of the AT(N) concept of AD with a combination of p-tau isoforms, a sensitive measure of amyloid-ß pathology such as plasma Aβ42/Aβ40 ratio [Citation13,Citation14] and a neurodegeneration biomarker such as neurofilament light chain in a blood sample. Such measures will be standard in tertiary diagnostic and care clinics when a biological early diagnosis of AD is needed in clinical situations such as MCI in persons who need early etiologic diagnosis, in enrollment into randomized clinical trials or in observational studies. These plasma biomarkers may prove to have the same specificity and sensitivity as CSF amyloid-β and tau levels in a follow-up validation study. It is premature to use these plasma markers in primary care practice, particularly in asymptomatic persons.
6. Five-year view
Memory clinics will be able to use blood samples for the etiological diagnosis of MCI and dementia due to AD, and offer treatments proven to delay progression, at least at certain stages of the disease.
Article highlights
There is a need for non-invasive and low-cost biomarkers of AD pathology in order to accelerate the development of new therapies
There is good evidence that elevated plasma tau isoforms p-tau181 and p-tau217 correlate with abnormal brain amyloid-β and tau content
These plasma tau isoforms should be used in the screening of candidates for therapeutic randomized clinical trials with anti-amyloid-β and anti-tau drugs
The natural history of changes over time of these isoforms should be established in longitudinal observational studies
Individual-level variability over time and test-retest stability are needed to determine confidence in individual-level diagnostic accuracy
Plasma p-tau assays should be used in combination with ultrasensitive plasma assays for amyloid-β
Potential changes of plasma levels of these isoforms in response to anti-amyloid-β and anti-tau drugs should be looked for
Prospective studies testing the impact of plasma marker results on physicians’ decision-making when evaluating patients with suspected AD pathophysiology are needed to understand the contribution of these markers to clinical practice.
The utility of plasma p-tau231 14 remains to be determined
It will be helpful to have postmortem data on more variants of tauopathies to further confirm the extent to which plasma p-tau181 and 217 differentiate AD from other dementia syndromes.
Declaration of interests
The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
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References
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