New recommendations from the Alzheimer’s Association call for Alzheimer’s blood tests to reach at least 90% sensitivity and specificity to be used in place of established diagnostic tools.
Alzheimer’s blood tests need to offer at least 90% sensitivity and 90% specificity before they can replace brain scans and spinal taps in diagnosis of the neurodegenerative disease, according to a new clinical practice guideline recommendation from the Alzheimer’s Association.
The health organization cautioned in a news release that “many commercially available blood-based biomarker tests do not meet these thresholds” for substituting amyloid PET imaging and cerebrospinal fluid (CSF) tests in Alzheimer’s diagnosis.
“The whole purpose of developing the clinical practice guideline is to try to create pragmatic recommendations for clinicians on how to choose the right test for the right patient at the right time,” Rebecca Edelmayer, PhD, Alzheimer’s Association Vice President of Scientific Engagement, told Medscape. “The blood- based biomarker area is still a burgeoning field,” added Edelmayer, a guideline Co-author.
Clinical laboratories may find the recommendations useful in making decisions about additions to lab test menus and in educating clinicians on appropriate test ordering.
“Pathologically, Alzheimer’s disease is defined by the accumulation of extracellular cortical plaques composed of amyloid-beta fibrils and intracellular neurofibrillary tangles containing abnormal hyperphosphorylated tau protein. These pathologies manifest many years or even decades before the onset of clinical symptoms,” the authors wrote.
Compared to “standard-of-care” amyloid PET imaging and CSF tests, blood-based biomarkers may cost less and reduce patients’ stress, the Alzheimer’s Association pointed out, adding that blood tests are not a replacement for clinical evaluations by healthcare providers.
“What we’ve learned from all of the evidence so far is that some of these biomarkers, like tau217, tend to be very accurate predictors of Alzheimer’s disease biology in the brain, and they can be used to aid in the diagnostic process early on—sometimes even before tau tangle formations can be visualized with brain imaging,” Rebecca Edelmayer, PhD, Alzheimer’s Association Vice President of Scientific Engagement, said in the Medscape article. (Photo credit: Alzheimer’s Association.)
Panel Reviews Phosphorylated-tau and Amyloid-beta
To discover the diagnostic accuracy of blood-based biomarkers in Alzheimer’s disease, a panel of 11 clinicians, convened by the Alzheimer’s Association, did a systematic review using this methodology described in the association’s statement:
Reviewed 49 observational studies and assessed 31 tests.
Focused on blood-based biomarkers including plasma phosphorylated-tau (p-tau) and amyloid beta (Aβ) tests measuring: p-tau217, ratio of p-tau217 to non-p-tau217 x 100, p-tau181, p-tau231, and ratio of Aβ42 to Aβ40.
Panelists, unaware of the tests they were reviewing, did not rank or endorse tests.
Diagnostic accuracy varied among the assays with sensitivity ranging from 49.31% to 91.41% and specificity from 61.54% to 96.72%, Neurology Advisorreported.
Tests evaluated included these, which were also recently reported on by Dark Daily:
Based on the systematic review, the panel released the following recommendations for use of blood-based biomarker tests when Alzheimer’s disease is suspected, according to the Alzheimer’s Association:
Tests with 90% sensitivity and 90% specificity or more may stand-in for PET amyloid imaging or CSF Alzheimer’s biomarker testing.
Tests with at least 90% sensitivity and 75% specificity can serve as triaging assays whereby negative results rule out Alzheimer’s “with high probability” while positive findings need confirmation with PET or CSF testing.
“For the first time, we have a rigorously evidence-based guideline that empowers clinicians to use blood biomarker tests confidently and consistently. Adoption of these recommendations will lead to quicker, more accessible, more accurate diagnoses, and better outcomes,” said Maria Carillo, PhD, Alzheimer’s Association Chief Science Officer and Medical Affairs Lead and a Co-author of the guideline.
The guideline is part of the Alzheimer’s Association resources to promote best practices. It plans development of other reports about cognitive assessment tools, clinical implementation of staging, and Alzheimer’s prevention.
Pharmaceutical and biotech researchers convened last week to discuss their latest work on targeting neurodegenerative diseases
With all the news this year alone on progress being made with diagnostic testing for Alzheimer’s disease, clinical laboratory professionals will be interested to know that drug discovery efforts to combat neurogenerative diseases are also at a heightened pitch.
Last week at the one-day Neuroimmunology in Drug Discovery forum in Boston, scientists learned about the latest advances in therapeutic research to better treat Alzheimer’s disease, multiple sclerosis, and Parkinson’s disease. As the treatments advance, demand for them will increase, which goes hand-in-hand with medical lab testing to detect signs of these illnesses.
The concern is urgent. The US Food and Drug Administration (FDA) noted that 10% of people age 65 and older have Alzheimer’s disease, and that number could double by 2050. The FDA recently cleared the first in vitro diagnostics device that tests blood to diagnose Alzheimer’s, and other IVD manufacturers and clinical labs are working on other Alzheimer’s tests, Dark Daily reported.
“It’s looking quite promising for NLRP3 inhibitors,” said Cheryl Leyns, PhD, associate principal scientist in discovery neuroscience at Merck Research Laboratories, in discussing how mutations of the NLRP3 protein can lead to neurodegenerative diseases. (Photo copyright: ELRIG.)
Much of the discussion at the Neuroimmunology in Drug Discovery forum centered on the idea that neuroinflammation—in other words, inflammation of the brain or spinal cord—starts well before neurodegenerative diseases arise. Neuroinflammation can accelerate Parkinson’s disease and other neurodegenerative disorders, said Cheryl Leyns, PhD, associate principal scientist, neuroimmunology, at Merck Research Laboratories in Boston, who spoke at the event.
From that perspective, drug discovery researchers are on the prowl for these early signs of future problems.
Leyns discussed NLRP3, a protein that aids the body’s inflammation process. A mutation of NLRP3 can lead to inflammatory problems, making the protein a prime target for researchers. “We have been interested, in the biopharma space, in the potential of NLRP3 inhibitors,” she noted.
Older Immune Systems Are Susceptible
While many in the public correctly associate Alzheimer’s with a person being outwardly older, a lesser-known aspect is that the body’s immune system also ages, becoming more susceptible over time to chronic inflammation.
Wailings’ assertion was not rhetorical. She pointed to numbers which showed scholarly research that involved the terms “inflammation,” “neurodegeneration,” and “aging” was only about 17% of the total amount of journal articles that addressed the first two terms, but which did not include “aging.”
As the pharmaceutical, biotech, and medical fields move aggressively forward to defend people against neurodegenerative diseases like Alzheimer’s, clinical laboratory scientists should take comfort that diagnostic testing trends are solidly in the mix.
Therapeutic advances, along with increased options for testing, show promising signs that patients and their caregivers will have more tools to use in the battle against these illnesses.
Lumipulse G pTau217/ß-Amyloid 1-42 Plasma Ratio test measures blood biomarkers associated with the disease
Clinical laboratories could soon find themselves playing a significant role in Alzheimer’s care as the US Food and Drug Administration (FDA) announced its first-ever clearance of a blood test to assist in diagnosing the cognitive disease.
The agency issued a 510(k) clearance for the Lumipulse G pTau217/ß-Amyloid 1-42 Plasma Ratio test from Fujirebio Diagnostics, Inc. The test is intended for “the early detection of amyloid plaques associated with Alzheimer’s disease in adult patients, aged 55 years and older, exhibiting signs and symptoms of the disease,” according to an FDA press release.
“Nearly seven million Americans are living with Alzheimer’s disease, and this number is projected to rise to nearly 13 million,” said FDA Center for Devices and Radiological Health Director Michelle Tarver, MD, PhD, in the press release. “Today’s clearance is an important step for Alzheimer’s disease diagnosis, making it easier and potentially more accessible for US patients earlier in the disease.”
“Alzheimer’s disease impacts too many people, more than breast cancer and prostate cancer combined,” said FDA Commissioner Martin A. Makary, MD, MPH, in the FDA press release.
“Knowing that 10% of people aged 65 and older have Alzheimer’s, and that by 2050 that number is expected to double, I am hopeful that new medical products such as this one will help patients,” said FDA Commissioner Martin A. Makary, MD, MPH, in the FDA press release. (Photo copyright: Johns Hopkins University.)
Blood Protein Test Details
Fujirebio’s test calculates the ratio of two blood proteins, pTau217 and β-amyloid 1-42. “This ratio is correlated to the presence or absence of amyloid plaques in the patient’s brain, reducing the need for a PET scan,” the press release states.
The FDA said it has already authorized or cleared similar tests that use cerebrospinal fluid (CSF) samples obtained through an invasive spinal tap. “This new Lumipulse test only requires a simple blood draw, making it less invasive and much easier for patients to access,” the FDA said.
In granting the clearance, the agency looked at data from a clinical study of 499 adults displaying signs of cognitive impairment. Close to 92% of participants with positive test results had amyloid plaques as determined by amyloid PET scan or CSF test results. Approximately 97% with negative results from the Lumipulse test were also shown to be negative in the PET scan or CSF test. Fewer than 20% of the patients received indeterminate results, which would require additional testing.
The primary risks of the test are false positive or false negative results, the federal agency noted.
“Importantly, the Lumipulse G pTau217/ß-Amyloid 1-42 Plasma Ratio is not intended as a screening or stand-alone diagnostic test and other clinical evaluations or additional tests should be used for determining treatment options,” the FDA said.
‘Wild West’ Marketplace
In their reporting of this story,MedPage Today and the Associated Press both noted that some laboratory-developed tests can already measure plasma biomarkers associated with Alzheimer’s.
“But those tests aren’t reviewed by the FDA and generally aren’t covered by insurance,” the AP reported. “Doctors have also had little data to judge which tests are reliable and accurate, leading to an unregulated marketplace that some have called a ‘wild west.’”
Neurologist Richard S. Isaacson, MD, told CNN that he’s already using the test for research purposes. “It can provide better clarity into whether a person experiencing memory loss may have Alzheimer’s disease,” he said.
However, he cautioned that more research is needed to allow doctors to make best use of the test.
“I think the next step as a field is, we need to advance education about what these tests mean and what they don’t and who they should be used for,” he told CNN. “Because they mean different things in different people depending on their risk factors and whether they have symptoms. So, we’re still early.”
“The results must be interpreted in conjunction with other patient clinical information,” the FDA acknowledged in their press release.
Other Alzheimer’s Tests
The FDA said it reviewed the Lumipulse test through the 510(k) premarket notification pathway, in which the federal agency determines if a device is “substantially equivalent to a legally marketed predicate device.”
In this case, the agency found that the test is substantially equivalent to Fujirebio’s Lumipulse G β-amyloid Ratio (1-42/1-40), which measures the same proteins in CSF samples. The FDA authorized that device in 2022, according to a Fujirebio press release. That test uses Fujirebio’s automated Lumipulse G1200 instrument system.
Other companies including Roche, Eli Lilly, and C2N Diagnostics are also developing Alzheimer’s tests they intend to submit for FDA review, the AP reported.
Findings could lead to clinical laboratory test that can both track the disease’s progress and differentiate it from other forms of dementia
Another research study is underway with hopes of developing a new clinical laboratory blood test to aid in the diagnoses of Alzheimer’s disease and help physicians determine the best course of treatment.
Researchers at the Washington University School of Medicine (WashU Medicine) in St. Louis and Lund University in Sweden have developed a test that focuses on the presence of a protein called MTBR-tau243, a potential biomarker for Alzheimer’s. This protein is correlated to the toxic accumulation of tau aggregates in the brain and the severity of the disease, according to a WashU new release.
Cognitive tests and brain imaging are also used to diagnose the condition. However, existing tests cannot establish how far the illness has progressed. Alzheimer’s therapies are most effective during early stages, so determining the disease’s progression could provide insights doctors need to devise the most effective treatment protocols.
Washington University’s new blood test that identifies MTBR-tau243 protein could lead to new biomarkers as well as identifying how far the disease has progressed.
“This blood test clearly identifies Alzheimer’s tau tangles [aka, neurofibrillary tangles], which is our best biomarker measure of Alzheimer’s symptoms and dementia,” said co-senior author Randall J. Bateman, MD, professor of neurology at WashU Medicine in the WashU news release.
“In clinical practice right now, we don’t have easy or accessible measures of Alzheimer’s tangles and dementia, and so a tangle blood test like this can provide a much better indication if the symptoms are due to Alzheimer’s and may also help doctors decide which treatments are best for their patients,” said co-senior author Randall J. Bateman, MD, professor of neurology at WashU Medicine in a news release. (Photo copyright: Washington University.)
Distinguishing between Alzheimer’s and Other Forms of Dementia
The WashU scientists tested the study participants in three main stages of Alzheimer’s disease:
Pre-symptomatic.
Early stage with mild cognitive impairment.
Late symptomatic where patients have been diagnosed with dementia.
The study included 108 volunteers from WashU Medicine’s Charles F. and Joanne Knight Alzheimer Disease Research Center and a subset of 55 people from the Swedish BioFINDER-2 study, which aims to discover key mechanisms in neurodegenerative disorders. The scientists validated their results in an independent dataset involving 739 other people in the BioFINDER-2 database. The patient information used for the study represented patients from all stages of the disease.
Alzheimer’s disease involves an accumulation of amyloid into plaques in the brain, which turn into tangles of tau proteins. When these tau tangles become detectable, cognitive symptoms begin to occur and exacerbate as the tangles spread. WashU’s new blood test can detect MTBR-tau243 levels in the brain with 92% accuracy. The researchers also found that MTBR-tau243 levels were significantly higher for patients in the mild cognitive stage of the disease and up to 200 times higher for patients in the late symptomatic stage.
“MTBR-tau243 is a chipped (off) piece of the protein in Alzheimer’s tau tangles,” Bateman told Medical News Today. “The blood test measures this piece of tau tangles in the blood as a measure of how many tangles are in the brain.”
The researchers also found that MTBR-tau243 levels were normal in patients with cognitive symptoms attributed to diseases other than Alzheimer’s, suggesting that the test can distinguish Alzheimer’s dementia from other forms of dementia.
“We’re about to enter the era of personalized medicine for Alzheimer’s disease,” said Kanta Horie, PhD, voluntary research associate professor of neurology at WashU Medicine, co-first and co-corresponding author of the study, in the WashU news release.
More Studies Needed
According to the Centers for Disease Control and Prevention (CDC), Alzheimer’s is the seventh leading causes of death in the US. It accounted for more than 120,000 deaths in 2022, the most recent year for available data. With the ebbing of COVID-19, which was ranked number four in 2022, Alzheimer’s is assumed to be higher in ranking for more recent years.
Washington University’s new blood test for Alzheimer’s may one day enable earlier detection of the disease, earlier intervention, and slowing of its advancement. However, more research and trials are needed into the theory behind this study.
“The initial study needs to be replicated in larger and more diverse populations to confirm its accuracy and reliability across different demographics, ethnicities, and stages of the disease,” Manisha Parulekar, MD, director of the Division of Geriatrics at Hackensack University Medical Center, told Medical News Today. “This includes testing individuals with other neurological conditions to ensure specificity. Clear and standardized protocols for blood collection, processing, and analysis must be established to ensure consistent and reproducible results across different laboratories and healthcare settings.”
Findings may lead to new clinical laboratory testing and treatments for Parkinson’s patients
Gut bacteria have repeatedly been proven to perform critical roles in the development of certain diseases. And many clinical laboratory tests use human microbiota as biomarkers.
Now, researchers at Nagoya University Graduate School of Medicine in Japan have discovered a link between microbes in the gut and the brain. The connection may play a part in the development of Parkinson’s disease, according to a Nagoya University news release.
The researchers found that a reduction in the genes responsible for synthesizing riboflavin (vitamin B2) and biotin (vitamin B7) may increase the likelihood of developing Parkinson’s.
They also determined that the lack of these genes may lessen the integrity of the intestinal barrier that prevents toxins from entering the bloodstream causing the inflammation often seen in Parkinson’s patients.
“Supplementation therapy targeting riboflavin and biotin holds promise as a potential therapeutic avenue for alleviating Parkinson’s symptoms and slowing disease progression,” said lead researcher Hiroshi Nishiwaki, PhD, Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, in a news release. (Photo copyright: Nagoya University.)
Key Deficiencies in Parkinson’s Patients
According to the Parkinson’s Foundation, nearly one million people in the US are living with Parkinson’s and that number is expected to increase to 1.2 million by the year 2030. Approximately 90,000 new cases of Parkinson’s are diagnosed in the US each year, and more than 10 million people are living with the disease worldwide.
To perform their research, the Nagoya University team analyzed stool samples from 94 Parkinson’s patients from Japan, the US, Germany, China, and Taiwan. They also included 73 relatively healthy controls from Japan. They then used shotgun sequencing (a laboratory technique for determining the DNA sequence of an organism’s genome) to gain a better understanding of the microbial community and genetic makeup of each sample.
The scientists discovered a decrease in B2 and B7 vitamins in patients diagnosed with Parkinson’s. B vitamins promote the production and functions of short-chain fatty acids (SCFA) and polyamines.
“Supplementation of riboflavin and/or biotin is likely to be beneficial in a subset of Parkinson’s disease patients, in which gut dysbiosis plays pivotal roles,” the authors wrote in NPJ-Parkinson’s Disease.
The examination of fecal metabolites in Parkinson’s patients revealed a reduction in both components.
“Deficiencies in polyamines and SCFAs could lead to thinning of the intestinal mucus layer, increasing intestinal permeability, both of which have been observed in Parkinson’s,” said Hiroshi Nishiwaki, PhD, a professor at Nagoya University Graduate School of Medicine and a lead researcher for the study, in the news release.
“This higher permeability exposes nerves to toxins, contributing to abnormal aggregation of alpha-synuclein, activating the immune cells in the brain, and leading to long-term inflammation,” he added.
The team surmises that the weakened protective layer in the gut exposes the intestinal nervous system to more of the toxins people experience in everyday life, such as chemicals, pesticides, and herbicides. These types of toxins lead to the overproduction of alpha-synuclein fibrils. These molecules are aggregates of the α-synuclein protein that form into long, thread-like structures which are primarily found in the brains of individuals with neurodegenerative diseases like Parkinson’s.
Alpha-synuclein fibrils amass in dopamine-producing cells in the brain and increase the type of inflammation that leads to the debilitating motor skills and dementia symptoms of Parkinson’s.
Precision Medicine Analysis Suggested
Due to their research, the team proposes that high doses of vitamin B may help reduce the damage of toxins on the gut microbiome, help protect against neurodegenerative diseases like Parkinson’s, and aid in the creation of personalized therapy plans for patients.
“We could perform gut microbiota analysis on patients or conduct fecal metabolite analysis,” Nishiwaki noted. “Using these findings, we could identify individuals with specific deficiencies and administer oral riboflavin and biotin supplements to those with decreased levels, potentially creating an effective treatment.”
The results of the Nagoya University study illustrate the importance of a healthy gut microbiome in the prevention of disease. Altering the bacterial level in the gut may enable doctors to stave off the progression of neurodegenerative illnesses like Parkinson’s disease.
