How Are Blood-Based Biomarkers Reshaping Alzheimer’s Disease Diagnostics and Treatment?

The escalating global challenge of Alzheimer’s disease (AD) demands new approaches to detection, diagnosis and treatment.

Alzheimer’s disease is a progressive neurodegenerative disorder and is the most common cause of dementia among older adults. It’s characterized by cognitive decline, memory loss and impairment in daily living activities.

In the US, more than 6 million people are living with Alzheimer’s and the disease affects millions more worldwide, posing a significant social and economic burden. As the global population ages, the number of people with Alzheimer’s is expected to increase, underscoring the urgency to find effective treatments and interventions.

Awareness and understanding of Alzheimer’s disease are essential to support affected individuals and their families. Early diagnosis can also provide an opportunity for those with the disease and their caregivers to make informed decisions about care and future planning.

The use of blood-based biomarkers has tremendous potential to transform the diagnosis and treatment of Alzheimer’s disease. Non-invasive blood tests can make early detection more accessible, promoting early intervention even before symptoms appear.

Blood-based diagnostics and monitoring can also foster cost-effectiveness, as a simple blood test is more accessible and economical, which can promote its widespread adoption. Given their ease of use and low cost, the tests can also facilitate longitudinal monitoring by the continuous tracking of disease progression, which can help in the design of more personalized therapeutic strategies.

This Xtalks Spotlight edition features Michael K. Racke, MD, Medical Director of Neurology at Quest Diagnostics, discussing recent advancements in the Alzheimer’s disease diagnostic landscape. Dr. Racke shares insights into the promise of blood-based biomarker testing for Alzheimer’s, particularly in the early stages of the disease and use in clinical trials.

Dr. Racke’s research focuses on developing novel tests for neurologic disorders, including monitoring therapeutic responses in diseases such as multiple sclerosis. He has over three decades of leadership experience in academia and clinical practice and continues to serve on several national professional society committees. This has also included several editorial boards, including JAMA Neurology, Annals of Neurology as well as serving as the former Editor-in-Chief of the Journal of Neuroimmunology.

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Register for this free webinar to learn about a blood-based diagnostic test that has the potential to help accelerate and simplify Alzheimer’s clinical trials. Find out how the new blood-based test works and the promise it holds for identifying individuals at risk of developing Alzheimer’s disease even before the onset of noticeable symptoms and irreparable brain damage occurs.

The Road to an Alzheimer’s Disease Blood Test

Blood-based tests offer the power of convenience, flexibility and cost effectiveness in the detection, diagnosis and monitoring of disease. At present, Alzheimer’s disease is diagnosed using a combination of medical history, neurological exams, cognitive and functional assessments, brain imaging (MRI, CT, PET) as well as cerebrospinal fluid (CSF) and blood tests. Blood tests for Alzheimer’s diagnosis are in advanced developmental stages, with significant strides having been made for their implementation in clinical settings.

The development of blood-based tests begins with the identification of robust disease biomarkers. Amyloid beta (Aβ) plaques and neurofibrillary tangles composed of the tau protein in the brain are both hallmarks of Alzheimer’s and are used as biomarkers to help diagnose the disease using different methodologies. Dr. Racke says previously, these markers were usually only identified during autopsies after a patient had passed away. However, about 20 years ago, the advent of amyloid PET scans was game-changing, as Aβ plaques could now be seen in living patients. Subsequently, tracers were also discovered that could bind to neurofibrillary tangles and phosphorylated tau protein in the neurofibrillary tangles, leading to the tau PET scan, explained Dr. Racke.

Through technological advances, Aβ and tau could now be identified through imaging and also in CSF. Then the question became whether they could be measured in the blood. Dr. Racke explains that the detection of these proteins in the blood represented “a significant technological breakthrough. That technological breakthrough was because the amount in the blood was a log lower than in the spinal fluid, and there were many more competing proteins in the blood, which made it quite difficult.”

But now that the technology is here, we now have Alzheimer’s blood testing diagnostics that could make their way into clinics soon. A simple blood test for Alzheimer’s offers non-invasiveness compared to a PET scan or lumbar puncture and provides significant cost savings. Such a test would greatly enhance disease monitoring and reduce patient burden.

“It’s unusual to do more than perhaps two PET scans in a patient’s lifetime and patients don’t like to do lumbar punctures — to get somebody to do multiple lumbar punctures would be quite difficult. But to do, say every six months, a blood draw, that would not be much of a burden on a patient at all. All those things have made the ability to do monitoring of these markers much easier, much more cost-effectively, than what was previous.”

Quest is currently developing the AD-Detect Amyloid-Beta 42/40 Ratio test. The LC-MS/MS assay measures beta-amyloid 40 (Aβ40) and Aβ42 in plasma, rather than Aβ42 alone. Quest says this allows for the normalization of Aβ levels circulating in plasma in different patients, and the ratio of Aβ42/Aβ40 improves sensitivity and specificity for detecting Alzheimer’s disease. While the test has not been cleared or approved by the US Food and Drug Administration (FDA) yet, the assay has been validated pursuant to the Clinical Laboratory Improvement Amendments (CLIA) regulations and is used for clinical purposes.

Overcoming Challenges in Alzheimer’s Disease Detection

Quest has been working on Alzheimer’s testing with CSF for over a decade, but Dr. Racke says the biggest advance has been in blood. Key to this has been gaining a greater understanding of the pathophysiologic trajectory of the disease and coupling that information to the use of new technologies that can enable the detection of changes in the brain at different stages.

Dr. Racke explains that Quest’s AD-Detect and apolipoprotein E (ApoE) combination testing in the blood allows one to identify people who are at risk for Alzheimer’s disease.

Technological advances have allowed for both CSF and blood tests to get better. Dr. Racke explains that things like antibodies weren’t necessarily as good 20 years ago as they are now for the treatment of Alzheimer’s disease.

Another big piece is that methods to identify patients were also not very good in the past. For example, Dr. Racke explains that “in the early Alzheimer’s disease trials, up to as much as a third of the patients actually didn’t have Alzheimer’s disease. And so you can imagine if you have a treatment, but you don’t really have Alzheimer’s, you have some other form of dementia, it’s not likely that it’s going to be successful. Recently, there have been several successful clinical trials and one of the important factors has been that we are now much better in identifying patients who really have Alzheimer’s disease, based on those biomarkers.”

“Recently, there have been several successful clinical trials and one of the important factors has been that we are now much better in identifying patients who really have Alzheimer’s disease, based on those biomarkers,” explains Dr. Racke.

The Aβ hypothesis for Alzheimer’s is that amyloid plaque buildup in the brain probably occurs decades before you become symptomatic for the disease. The amyloid plaques begin to cause some toxicity to neurons that results in neurofibrillary tangles. The combination of these events results in neuronal loss and neurodegeneration. The loss of neurons adds up over time leading to the clinical manifestations of Alzheimer’s disease. Detecting changes in Aβ levels early, before symptoms appear, using a non-invasive, inexpensive blood test would be the ideal approach for early detection.

Dr. Racke revealed that Quest is participating in studies where one identifies people who are cognitively normal but already seem to have some of the characteristics of early changes in Alzheimer’s disease to see whether treatment in those early stages might be beneficial.

Blood Biomarkers for the Early Detection of Alzheimer’s Disease

It is being increasingly recognized that the development of Alzheimer’s disease occurs on a continuum, with an early asymptomatic phase that may be 20 to 25 years long. Identifying and tracking changes during this period is key, as interventions such as lifestyle changes may be introduced at this stage to delay or even prevent disease onset.

The significance of this is that the different markers can identify patients along more of an Alzheimer’s continuum. Dr. Racke says this is particularly important as “if there is a 20-to-25-year preclinical phase, with these other markers, I can more accurately determine where you are along that pathway and how soon it may be that you have clinical symptoms, or if you have clinical symptoms, how much damage has already occurred to the brain.”

Therefore, different markers and their combinations can be used to identify specific stages of the disease, which is an important goal of biomarker testing for early detection.

Given the ease of use of blood-based tests, they can be readily used over time, which is integral to the early detection of progressive diseases like Alzheimer’s. The risk for Alzheimer’s disease increases with age and therefore by following one’s amyloid ratio over time, you can identify when it becomes abnormal. If a marker suggests a risk for the disease, monitoring becomes easier to think about, and perhaps either getting involved in clinical trials or other strategies to try to reduce the amyloid burden in the brain, explains Dr. Racke.

“The World Health Organization (WHO) has a number of recommendations for things people can do to try to prevent Alzheimer’s disease, as this is something they’re worried about becoming a public health crisis globally,” says Dr. Racke.

A significant change to diagnostic guidelines this year was revealed at the Alzheimer’s Association International Congress (AAIC) held in Amsterdam this summer where for the first time, you could use plasma-based biomarkers to help in disease diagnosis. What remains a constant suggestion says Dr. Racke, is that you need to show if there is an abnormal 42/40 ratio in the plasma, you still need to have a plasma test that shows that abnormality for p-tau as well. Meaning, you must have both amyloid and p-tau. Alternatively, a CSF test could be used to show the same abnormality to confirm the plasma finding i.e., of amyloid abnormality. And a diagnosis can only be made with the appropriate clinical information to go along with the biomarkers.

While p-tau and amyloid remain the hallmarks of Alzheimer’s disease, there are now many other biomarkers. These include neurofilament that is suggestive of neurodegeneration and glial fibrillary acidic protein (GFAP), which is a manifestation of gliosis.

In addition to different biomarkers, there are also different isoforms of them — for example, for tau, there are p-tau231, p-tau217 and p-tau181 among others, some of which can appear early on, which can allow for the identification of people at risk for Alzheimer’s earlier in the Alzheimer’s continuum.

Alzheimer’s Diagnostics: Informing Innovations in Treatment

Improved Alzheimer’s diagnostics can pave the way towards innovative new treatments. Greater insights into the pathology of the disease are critical for the identification of disease biomarkers that can be used in diagnostics, as therapeutic targets and as markers for monitoring disease progression and/or therapeutic responses.

The utility of a biomarker depends on what it can identify biologically and clinically, and how readily it can be assessed. Biomarker assessments via blood-based tests are ideal given their non-invasive nature, which can allow for more frequent testing for continuous monitoring over time.

For clinical trials, accessible biomarker testing can allow for more appropriate identification of patient populations.

Dr. Racke says this is key to a successful study evaluating a treatment. He explains that in trials for lecanemab and donanemab, which target amyloid, having abnormal amyloid could not determine when or even if a patient would develop clinical manifestations of Alzheimer’s disease. That’s why it’s important to combine amyloid information with another marker, in this case, p-tau, which typically arises closer to clinical onset and signifies that the pathologic process is perhaps accelerating.

In the donanemab study, Dr. Racke says by making sure that people had both amyloid positivity and p-tau positivity, bigger differences could be observed between treated and untreated groups. “In other words, it appeared that the treatment had a greater effect because they did a better job perhaps in selecting patients whose cognitive deterioration was accelerating. And so, I think one of the things that is very clear is that by using these different biomarkers, we’re becoming very good at knowing where you are in the Alzheimer’s continuum,” he says.

Another important piece in Alzheimer’s diagnostics is improvements in imaging. Corroborating changes in biomarkers in CSF or plasma with imaging continues to be important, as no one diagnostic alone can be used for a diagnosis. This warrants the continued need for better, more fine-tuned and new diagnostics, including imaging. For example, if a blood test shows positivity for a biomarker, the MRI may not show Alzheimer’s-related changes in the brain until later, and a PET even later than the MRI. Hence, different imaging modalities and different biomarkers can be utilized to map disease onset and progression, including early stages.

Early detection is important not just for Alzheimer’s disease, but almost any neurodegenerative disease, says Dr. Racke. The earlier you identify when there’s been less damage done and interrupt the pathophysiologic process, the better you can prevent more damage earlier, which can lead to better clinical outcomes for patients.

This article was created in collaboration with the sponsoring company and the Xtalks editorial team.

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