Last month the US Food and Drug Administration approved fresh blood test to support diagnose Alzheimer’s disease. The Elecsys pTau181 test, produced by Roche, measures the concentration of a specific molecule – the phosphorylated form of tau protein – in the blood. Tau is one of two proteins (the other is amyloid) that become deformed and accumulate in the brains of patients with certain types of dementia. The buildup of these proteins is thought to disrupt brain cell communication, leading to the symptoms in these patients.
The test was approved for marketing in Europe in July and is therefore the first early detection system for Alzheimer’s disease for operate in primary care facilities, approved in two major pharmaceutical markets in the world. This is an introduction to a field that should soon become crowded as several other tests are in advanced stages of testing and validation.
How do such tests work?
Elecsys pTau181 checks for the form of tau protein in blood plasma with an attached phosphate group, which is often found in elevated amounts in Alzheimer’s disease patients. This molecule is an indirect marker of amyloid plaques and neurofibrillary tau tangles observed in the brains of diseased patients.
Other tests have also been approved, although not for early screening purposes. They evaluate other biomarkers associated with these two proteins. One of the tests, called Lumipulse and made by the Japanese company Fujirebio, examines the relationship between another form of phosphorylated tau (pTau217) and a key fragment of the protein that forms amyloid plaques (amyloid beta peptide 1-42).
The bottom line is that these studies provide clues to the likely presence of amyloidosis in the brain, which then needs to be diagnosed with greater accuracy using more invasive tests such as PET (positron emission tomography) scanning and cerebrospinal fluid analysis via lumbar puncture, considered the clinical gold standard for diagnosing amyloid pathology in living patients. However, even these involve a degree of uncertainty; true diagnostic certainty can only be obtained after a brain autopsy.
Why validate these tests now?
In the past, confirming a diagnosis of Alzheimer’s disease was not as significant because there were no drugs or treatments that could change the course of the disease. However, with the approval of fresh monoclonal antibody treatments for Alzheimer’s disease, the situation has changed over the past few years.
In order to operate these drugs, we need a way to know which patients might benefit from them. And because drugs work best when used early in the disease’s progression, a relatively inexpensive and minimally invasive diagnostic test will be extremely useful. It is impractical to subject all older adults with suspected symptoms of cognitive decline to PET scans and CSF sampling, which is where Alzheimer’s blood testing comes into play.
How useful are these tests?
Elecsys pTau181 is the first test to be validated for operate as a community screening tool. The idea is that the medicine will be administered at the primary care level, for example by a primary care physician or general practitioner. The test has been shown to have good “negative predictive value”, that is, it is effective in indicating who NO suffer from amyloid disease. In settings where the overall incidence of amyloid disease is low, a negative result on this test is 97.9% reliable. This makes it useful in selecting patients who should be referred for further testing.
The results are similar to those of other tests that have already been approved in recent months, such as Lumipulse from the Japanese company Fujirebio, which in studies showed a negative predictive value of about 97%.
However, there is an significant limitation to note: For all Alzheimer’s disease blood tests, a relatively huge percentage of patients (commonly estimated at 15-30 percent) fall into a gray zone of uncertainty, where the levels of identified biomarkers do not allow for a positive or negative response.