A new blood test for Alzheimer’s disease has been developed under the leadership of researchers at the University of Gothenburg, Sweden.
The method is based on measuring a specific variant of tau protein in ordinary blood samples, which makes the test relatively simple and cheap to perform.
The research behind the test was headed by Kaj Blennow, Professor of Clinical Neurochemistry, and Henrik Zetterberg, Professor of Neurochemistry, at Sahlgrenska Academy, University of Gothenburg. The results are published in an article in The Lancet Neurology.
Alzheimer’s disease is characterized by two pathological changes in the tissue of the nervous system. One is the formation of extracellular clumps of a protein called beta-amyloid.
The other is neurofibrils, composed of tau protein, that have stuck together in tiny lesions (“neurofibrillary tangles”) in the brain neurons through a biochemical process known as phosphorylation.
The newly developed method is based on measurement of phosphorylated tau – specifically, the P-tau181 variant – in ordinary blood samples, performed with an ultrasensitive method known as Single Molecule Array (Simoa).
Simoa can measure considerably lower levels of protein biomarkers than other analytical methods.
P-tau181 has long been measurable through testing of cerebrospinal fluid, in which it is found at a considerably higher level than in blood samples.
For the past few years, it has also been possible to demonstrate neurofibrils by using the advanced positron emission tomography (PET) medical imaging technique.
Tests of cerebrospinal fluid are, however, difficult to perform in primary care, and the high costs of PET scans restrict their use. Being able to establish tau pathology through ordinary blood tests will therefore be highly valuable.
The results now published show that the level of P-tau181 is greatly elevated in Alzheimer’s, including at its early stage, known as mild cognitive impairment. However, this raised level was found only in the patients who also had amyloid plaques, as revealed by the PET camera.
The level of specific P-tau181 in blood plasma also proved to correspond very closely with the level of tau tangles in the brain registered with the PET-technique.
The blood test also identified people early on in the course of the disease who had plaques, but in whom the PET technique discerned no increased tau levels.
The blood test showed a very good capacity to distinguish Alzheimer’s from other brain diseases, such as frontotemporal dementia and Parkinson’s disease, where the blood level of P-tau181 was entirely normal.
The blood test developed at the University of Gothenburg produces results similar to those from the blood test that was developed at the U.S. pharmaceutical company Eli Lilly. Results from the latter were recently published in Nature Medicine, with Kaj Blennow and Henrik Zetterberg as coauthors.
“We believe that, in the future, one very important use of our blood test will be for screening in primary care. We demonstrated this in one of the studies forming part of our article, in which we looked at patients in primary care with concerns about their failing memory,” Blennow says.
“We also think the level of P-tau181 in blood plasma may be a very important marker to show and monitor the efficacy of the new drugs against Alzheimer’s that are currently being developed,” says Henrik Zetterberg.
Plasma levels of tau phosphorylated at residue 181 (P-tau181) are a marker of Alzheimer disease (AD), according to two new studies published in Nature Medicine.
The measure could form the basis of a diagnostic blood test for AD that would transform clinical practice and AD drug development.
Currently, a biomarker-supported diagnosis of AD can only be obtained with use of amyloid-β (Aβ)-PET, which is expensive and not widely available, or by analysis of Aβ and tau in the cerebrospinal fluid (CSF), which is invasive. A diagnostic blood test for AD would provide a widely available and more affordable alternative.
Previous work has shown that blood levels of P-tau181 are higher in patients with AD than in healthy individuals, but whether this measurement is sufficiently specific to diagnose AD has been unclear. The two new studies aimed to provide some clarity.
In the first study, Adam Boxer and colleagues aimed to determine whether plasma levels of P-tau181 can differentiate AD from frontotemporal lobar degeneration (FTLD), a tauopathy that underlies frontotemporal dementia (FTD).
“Particularly in younger patients with mild symptoms, differential diagnosis between AD and FTLD can be challenging,” explains Boxer. “Current biomarkers are expensive and/or invasive, therefore limiting their usefulness in routine practice, particularly when screening large populations.”
The study involved 293 individuals with mild cognitive impairment (MCI), a clinical diagnosis of AD or a variant of FTD, and 69 healthy controls. The researchers measured levels of P-tau181 in the blood of participants and compared these with Aβ-PET findings and CSF measurements of P-tau181.
Blood levels of P-tau181 were higher among patients with clinically diagnosed AD than among any of the other groups, and the difference was sufficient to distinguish clinically diagnosed or autopsy-confirmed AD from clinically diagnosed or autopsy-confirmed FTLD.
Blood levels of P-tau181 were strongly associated with Aβ-PET and CSF P-tau181 measures and enabled identification of patients with positive Aβ-PET scans, regardless of their clinical diagnosis.
The findings suggest that measurement of P-tau181 could be used as a diagnostic blood test for AD, thereby facilitating not only clinical management but also development of treatments.
“We are particularly interested in how the test might be used to find participants in clinical trials of disease modifying agents for AD,” says Boxer.
In the other study, Oskar Hansson and colleagues also assessed how useful plasma levels of P-tau181 are for diagnosis and prognosis in AD.
They conducted a prospective study of two cohorts including 526 individuals who had AD, mild cognitive impairment, non-AD neurodegenerative diseases or no neurological disease. Blood levels and CSF levels of P-tau181 were measured, and participants underwent Aβ-PET and tau-PET.
Plasma levels of P-tau181 correlated with CSF levels and with levels of pathology identified with PET. Blood levels of P-tau181 also enabled individuals on the AD spectrum to be distinguished from healthy controls and distinguished AD from non-AD neurodegenerative disease with a sensitivity of 92% and a specificity of 87%.
P-tau181 levels increased with progression from mild cognitive impairment to late AD, and among patients without cognitive impairment at baseline, higher blood levels of P-tau181 were associated with a higher risk of subsequent AD, indicating that the measure can predict development of AD.
In a third cohort of 63 patients, antemortem plasma levels of P-tau181 were associated with post-mortem neuropathology. This observation confirmed that the blood test reflects pathology in the brain.
References
- Janelidze, S. et al. Plasma P-tau181 in Alzheimer’s disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer’s dementia. Nat. Med. https://doi.org/10.1038/s41591-020-0755-1 (2020)
Source:
University of Gothenburg
