A new two-step diagnostic process is maintaining to firmly detect Alzheimer's disease nearly 10 years before clinical symptoms appear. It's expected that the method, which involves the measurement of both amyloid and tau proteins in the blood and cerebrospinal fluid, will improve the results of clinical trials by helping better identify patients at the earliest stages of the disease.
The general hypothesis explaining the cause of Alzheimer's disease is that the aggregation of toxic amyloid and tau proteins in the brain results in neurodegenerative damage associated with cognitive decline. However, a near-constant parade of clinical trial failures targeted at reducing the build-up of those toxic proteins has led to critical reconsiderations from many Alzheimer's researchers. While some scientists are investigating dramatically different hypotheses, others are suggesting the original protein hypothesis could still be correct, but simply needs to be targeted before any symptoms appear.
Andreas Nabers, from Ruhr-Universität Bochum in Germany, suggests the key to effective treatments is targeting the disease before the amyloid proteins can accumulate in the brain. The idea is that once the neurodegenerative damage has been done it cannot simply be reversed by reducing the amyloid or tau burden in the brain.
"Once amyloid plaques have formed, it seems that the disease can no longer be treated," says Nabers.
So it is vital scientists have a reliable early detection tool that can confidently identify patients with Alzheimer's before major neurodegeneration occurs. This new study builds on prior work indicating a simple blood test that can detect misfolding amyloid proteins. This earlier test reported the ability to detect Alzheimer's cases about eight years before clinical symptoms appeared in about 71 percent of subjects. This accuracy rate was not high enough for useful clinical applications so the researchers developed a second diagnostic tool to optimize overall accuracy. This second step in the process involves tracking levels of the other toxic protein implicated in the disease, tau.
"Through the combination of both analyses, 87 of 100 Alzheimer's patients were correctly identified in our study," explains Klaus Gerwert, corresponding author on the new research. "And we reduced the number of false positive diagnoses in healthy subjects to three of 100. The second analysis is carried out in cerebrospinal fluid that is extracted from the spinal cord."
At this stage, the second diagnostic test for tau proteins can only be measured using cerebrospinal fluid. Due to the invasive nature of collecting cerebrospinal fluid, the researchers admit this is not ideal, and work is underway to find effective ways to detect tau in blood samples. However, the two-step process can be rolled out relatively soon in its current form, with the suggestion the second cerebrospinal fluid test be only carried out on subjects testing positive in the first blood test.
While the research ultimately may lead to a clinical test for the general public, the initial goal is more focused on optimizing patients for clinical trials. If a confident early-stage Alzheimer's diagnosis can be made using the process, anti-amyloid treatments can be investigated at a point in the disease progression where they may be more effective.
"Now, new clinical studies with test participants in very early stages of the disease can be launched," says Gerwert. "Recently, two major promising studies have failed, especially Crenezumab and Aducanumab - not least because it had probably already been too late by the time therapy was taken up. The new test opens up a new therapy window."
