The first blood plasma test to identify hallmarks of Alzheimer’s disease was cleared in May by the U.S. Food and Drug Administration (FDA), and University of Wisconsin researchers provided a portion of the samples used in the clinical validation test.
The blood test measures concentrations of two Alzheimer’s disease–related biomarkers, tau and amyloid, in plasma and calculates their ratio. Clinicians are interested in early and accurate diagnosis because currently available therapies are most effective in the early stages of the disease. Amyloid begins to accumulate and form toxic plaques in the brain approximately 20 years before symptoms of cognitive impairment. Tau accumulates later, forming tangles in the brain that damage nerve cells and are more closely associated with the memory loss and cognitive decline in later stages of Alzheimer’s disease.
Nathaniel Chin
“A blood test of this kind is going to greatly expand clinicians’ ability to confirm that Alzheimer’s is present,” said Dr. Nathaniel Chin, associate professor of medicine at the University of Wisconsin School of Medicine and Public Health. “When you address Alzheimer’s earlier in the disease, during mild cognitive impairment versus later on with dementia, the people earlier in the disease respond better to the therapy, as they have more slowing of the disease progression,” Chin said.
Chin also serves as medical director and clinical core co-leader for the Alzheimer’s Disease Research Center (ADRC) and medical director for the Wisconsin Registry for Alzheimer’s Prevention (WRAP) study.
A blood test of this kind is going to greatly expand clinicians’ ability to confirm that Alzheimer’s is present.
Nathaniel Chin
Currently, doctors use PET scans, a form of advanced medical imaging, to visualize amyloid plaques in the brain. They may also use lumbar punctures that require inserting a needle into the spinal canal to collect cerebrospinal fluid (CSF) and then measure amyloid levels in CSF samples. Both approaches have drawbacks as PET scans require specialized equipment and expertise, and the lumbar puncture is considered an invasive procedure.
This new blood test is for the early detection of amyloid plaques associated with Alzheimer’s disease in adult patients, aged 50 years and older, exhibiting signs and symptoms of cognitive impairment. Its commercial name is Lumipulse G pTau217/β-Amyloid 1-42 Plasma Ratio.
The FDA issued clearance on May 16 of the test, classified as a diagnostic device by the FDA, under the 501(k) premarket notification pathway to Fujirebio Diagnostics Inc., the company that is commercializing it.
UW–Madison data powers 510(k) approval
The 510(k) process requires proof that a device is substantially equivalent to another device that is already on the market. The FDA found the blood test was substantially equivalent to the Lumipulse G β-amyloid Ratio (1-42/1-40), the previously approved test that uses cerebrospinal fluid to detect amyloid plaques in the brain.
Fujirebio conducted a clinical study of 499 patients aided by samples and data from five different previous studies or cohorts.
The Wisconsin Alzheimer’s Disease Research Center and WRAP provided paired cerebrospinal fluid and plasma blood samples to Fujirebio. These carefully curated biospecimens enabled the company to compare the performance of their new plasma test to the FDA-authorized CSF test and FDA-approved PET tracers.
The WRAP study, which has been conducted by UW researchers since 2001, focuses on asymptomatic individuals who enroll in the study when they are middle-aged, many of whom have one or both parents with a history of diagnosis with Alzheimer’s disease or related dementias.
The observational study allows researchers to assess disease incidence and progression over time. This enables them to link trends with lifestyle and exposure to known risk factors, for example. Volunteers also agree to periodically give blood samples, CSF samples, and undergo brain scans and memory testing.
In Fujirebio’s clinical study, 92% of individuals testing positive for amyloid plaque also had confirmed presence of amyloid plaque by PET scan or CSF test, and 97% of individuals with negative results were also negative by other tests.
In comparison, clinical evaluations for Alzheimer’s disease that do not involve biomarker-based testing are 73% accurate at identifying Alzheimer’s disease when done in specialty memory clinics, and only 61% accurate when done in primary care settings, according to an article posted by the National Institutes of Health.
Rachael Wilson
In a separate study, UW researchers independently validated Fujireibo’s findings. Led by Rachael Wilson, a PhD researcher at the ADRC, the study confirmed strong agreement between the blood plasma test results and PET imaging within the UW cohort. Results were reported at the Alzheimer’s Association International Conference in late July by Julie Oomens, PhD, a postdoctoral researcher working with Sterling Johnson, PhD, professor of medicine in the UW School of Medicine and Public Health. Johnson also serves as associate director of the Wisconsin Alzheimer’s Disease Research Center and associate director of the Wisconsin Alzheimer’s Institute.
Approximately 20% of individuals in the clinical validation study conducted by Fujirebio had plasma ratio values within the indeterminate range, meaning the result was not clearly positive or negative. In such cases, doctors may perform additional confirmatory testing, such as CSF analysis or amyloid PET imaging, to determine amyloid status.
The future of neurodegenerative treatment
More than 110,900 people live with Alzheimer’s or related dementias in Wisconsin, and it is estimated that number will increase to 213,000 people by 2040 without breakthroughs in treatment[1]. They are cared for by 205,000 unpaid family caregivers who provide the equivalent of $6 billion in care annually.
While the test is only approved as a diagnostic tool for people exhibiting signs of disease who are over 50 and is not intended as a screening or stand-alone test, experts say a tool like this could be used to track disease progression over time.
“If we have sensitive enough blood tests, we can implement a treatment to slow progression of Alzheimer’s and get a blood test to show that we’ve removed amyloid successfully,” Chin said. “Then when amyloid starts to increase again and it reaches a certain threshold, we would provide additional intervention.”
If a blood test was to be approved for screening, in theory it could be used in a predictive manner, providing an Alzheimer’s risk score like a cardiovascular disease risk score. Researchers are also pursuing biomarker testing for other neurodegenerative diseases like Parkinson’s disease and Lewy body dementia. Many of these diseases have similar pathological features.
“It’s going to become a very nuanced field where one blood test gives you all these biomarkers and then you have to figure out the right treatments,” Chin said. “In the next five years, Alzheimer’s research is going to be accelerating at an unbelievable rate.”
Chin noted that such research wouldn’t be possible without the participants, their caregivers, research staff and members of the health care community. Some volunteers have been involved with the WRAP study for over two decades.
“We are able to show them, ‘Yes, what you have done is meaningful and it has contributed,’” Chin said. “We now have a test that will help all of us in the future because of what [participants have] done.”
