A recent study shows that a blood test can detect Alzheimer’s disease early in its progression. It’s as accurate as other more invasive, expensive methods, such as cerebrospinal fluid (CSF) markers and positron emission tomography (PET) scans. We spoke with experts Bill Holt, DO, Exec Director of Therapeutic Expertise, and Ly Ngo, MD, Medical Director, about this exciting news and what it means for the future of clinical Alzheimer’s research.
At the Alzheimer’s Association International Conference this year, researchers presented some positive findings around a biomarker test for Alzheimer’s. Can you tell us about what was presented?
LN: The presentation summarized initial findings for a biomarker called Phosphorylated Tau 217 (p-tau217). This biomarker, which is more specifically a plasma marker (found in the blood), is able to discriminate Alzheimer's from other neurodegenerative conditions. The researchers found that p-tau217 had higher accuracy than other plasma markers that they've used previously. They also found that there was no significant difference between p-tau217 and CSF markers or PET findings. However, because p-tau217 testing is less invasive and less expensive, this is an exciting finding for the Alzheimer’s community.
BH: P-tau has been used as a biomarker for Alzheimer's for the past decade. There are two different variations of tau. Phosphorylated tau causes neurofibrillary tangles in Alzheimer’s disease. The concentration of p-tau is significantly higher in cerebrospinal fluid than in plasma. Assays are now available that are sensitive enough to pick up p-tau in plasma that has the potential of identifying Alzheimer’s disease or those at high risk to develop this disorder.
It will be a while before this method can be introduced in a clinical setting. It is a long process for diagnostics to be approved, especially for Alzheimer's disease, because the specificity and sensitivity has to be high in order to avoid false positive or negative results.
This research still must go through several validation trials. p-tau in plasma was just one exciting breakthrough, but there's also another protein called neurofilament light (nFL). This protein is also amenable to a plasma-based assay. When you combine the methods of analyzing both p-tau and nFL in plasma, the predictive ability is about 90%. That percentage is great for a clinical trial, but for general use, it’s probably not sensitive enough. The same group of investigators also reported that for some patients who have increased body mass index (BMI), this combination plasma-based assay is not as sensitive. We still need to figure out why that's the case.
These biomarkers will likely be used as inclusion criteria for Alzheimer's clinical trials long before they're used in clinical practice. One of the barriers to developing new drugs for Alzheimer's disease is slow enrollment rates in clinical trials. Finding volunteers for Alzheimer’s clinical trials is challenging since most now require lumbar punctures for CSF biomarker analysis. To make it even more onerous to the patient, the trials usually require two or three lumbar punctures throughout the course of the trial. Most patients who have early Alzheimer's disease, or even mild cognitive impairment (MCI) are reluctant to undergo spinal taps.
Will this new method ultimately replace the current standard of CSF sampling and PET imaging?
BH: Yes, but gradually so. I would predict that most trials will still require CSF and PET imaging. There needs to be some correlation between the findings from those analyses with plasma biomarkers. With time, if there's a tight correlation, you'll see the CSF sampling and PET imaging less commonly used as clinical trial procedures.
LN: Both CSF and PET imaging are typically used more in clinical research. In clinical practice, when a patient is diagnosed, this is usually based on cognitive testing. These include the Mini Mental Status Exam (MMSE) and the Montreal Cognitive Assessment (MOCA), as well as labs and MRI to rule out other possible diagnoses.
BH: All of these methods for diagnosing Alzheimer's disease will become critical once we develop a disease-modifying therapy and can treat patients with early disease. Currently, there's no disease-modifying drug out there, so there's less of a reason to do an invasive test like CSF sampling for something you can't actually treat.
What benefits will this discovery bring to patients?
BH: It’s a slow march forward. Even with Alzheimer’s trials that produce negative results, we learn something about the pathophysiology in almost every single trial. To give an example, just a few years ago the hot topic was beta amyloid precursor protein cleaving-based inhibitors (BACE). There were several large Phase III trials that were looking at inhibitors of BACE, which is the first enzymatic reaction that leads to accumulation of beta amyloid in the brain. It was thought that clearing beta amyloid from the brain would lead to improvement in Alzheimer's signs and symptoms. That turned out not to be the case, in part because of several off-target effects of BACE inhibitors. That avenue of research has dwindled. Now we're seeing more treatments targeting tau or other upstream biochemical reactions that lead to both tau and beta amyloid deposition. Others are pursuing combinations of drugs targeting multiple neurochemical pathways.
Do you think finding better ways to diagnose Alzheimer’s earlier on might help us figure out how to treat it?
BH: Ultimately, if we can come up with a plasma-based biomarker, then we'll be able to substantially increase the research participants in clinical trials. That's been a big barrier. To get these trials completed, we need volunteers to do it. I think this is a step forward in the clinical trial machinery that will hopefully lead to a treatment.
In trials that have requirements for CSF studies versus those that don't, the enrollment rates are at least half as much in the trials requiring CSF. If we could double the rate of entry of patients into clinical trials, then it would speed up the whole clinical trial machine.
As researchers, we know that early diagnosis of Alzheimer’s—before the dementia stage—is important for clinical trials evaluating novel therapies that might halt or slow the disease. Do CSF and imaging also facilitate early detection?
BH: Yes. CSF biomarker can identify people at high risk of developing Alzheimer's disease with a high degree of accuracy, >10-15 years before they develop clinical symptoms.
When will the use of these blood-based biomarkers become routine clinical practice?
BH: Part of it has to do with the pre-assay procedures. When you draw the blood, you have to freeze it. It must be frozen from the point of collection to the lab. The labs use mass spectrometry equipment, which isn’t commonly used in hospital labs, so few labs will be able to perform the technical sample analysis. The proper collection, storage and transport of samples must be validated.
Could you tell us about any new developments in Alzheimer’s disease research and development? Does the amyloid hypothesis prevail?
BH: From a scientific standpoint, tons of evidence suggest that amyloid deposition might not cause Alzheimer's disease, but it certainly causes neuron damage. If we can remove the beta amyloid, it seems like it should be effective. We haven’t started that process yet in clinical trials.
Many clinical trials were performed more than 10 years ago on patients who had moderate Alzheimer's disease. The drugs used actually did clear amyloid. We can demonstrate that by the CSF biomarkers in PET scans. The problem is, those patients didn’t have any change in the trajectory of their illness.
At the time we thought that maybe we're treating patients too far in their disease process. We thought that maybe once amyloid starts to build up, the neurons are destined to die no matter what. That's why over the past decade, we've been looking at clinical trials gearing towards treating the pre-symptomatic or MCI population group. However, problems arise if you have someone with pre-Alzheimer's disease and you're treating them with the drug to hopefully prevent Alzheimer's disease. You have to follow them sometimes for several years before they would become demented.
Those trials are challenging because they must be conducted over several years. Many of those trials have failed as well, so there's been a shift in the past few years to look at different targets. Tau's been a big topic of clinical trials over the past two years or so.
LN: And then there's a recent trial looking at glucose metabolism as well.
BH: There's also a camp of researchers who think that we might need to do a combined approach, andtreat patients with two or three drugs simultaneously.
What sorts of studies are we focused on here at PRA?
BH: We’ve done several trials in complications of Alzheimer's disease, such as psychosis. That’s a big step forward for more advanced Alzheimer's patients. About two thirds of the trials we look at are for disease modification and one third are for mitigation of symptoms associated with Alzheimer's disease.
To support those advances, what can we do to help patients participate in clinical research?
LN: With the development of this blood test, if trials can incorporate that instead of CSF and PET testing, that would help Alzheimer's trials tremendously in terms of cost and efficiency. The pandemic has made this a difficult time because patients are understandably hesitant to leave their homes. In this specific situation, mobile health platforms and tele-assessments have been key to help address this.
BH: From PRA’s standpoint, we work with both advocacy groups and the Alzheimer's Association. We look carefully at protocols that are sent to us from a standpoint of reducing barriers for patient participation in clinical research.
Patients need to understand that clinical research is a care option for them. In my role, l look at a protocol in early development. Often, it’s the result of 10-15 consultants putting their heads together. Sometimes these protocols are way too onerous for a patient. For example, they have so many cognitive tests that patients would be in a clinic for seven or eight hours. We try to focus on streamlining these processes by looking at them from the patient's perspective. We always keep the patient in mind.
PRA continuously strives for new treatment programs for those suffering from a neurodegenerative or neuro-inflammatory condition. Conducting diagnostic, preventive, and curative research, we bring significant commitment and experience to every clinical study, with particular expertise in Alzheimer’s disease and related dementias and mild cognitive impairment, Parkinson’s disease, motor neurone disease, and multiple sclerosis.
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