Researchers at Stanford Medicine led the study which discovered that approximately one in five individuals carry the gene variant, a protective allele identified as DR4 (aka, HLA-DR4). It’s one of a large number of alleles found in a gene known as DRB1.
DRB1 is part of a family of genes collectively known as the human lymphocyte antigen complex or HLA. The HLA-DRB1 gene plays a crucial role in the ability of the immune system to see a cell’s inner contents.
“In an earlier study, we’d found that carrying the DR4 allele seemed to protect against Parkinson’s disease,” said Emmanuel Mignot, MD, PhD (above), Director of the Stanford Center for Narcolepsy, in a Stanford press release. “Now, we’ve found a similar impact of DR4 on Alzheimer’s disease.” Clinical laboratories may soon have new vaccines for both neurodegenerative diseases. (Photo copyright: Stanford University.)
DR4 Found to Impact Both Parkinson’s and Alzheimer’s Diseases
To perform their research, the team examined a large collection of medical and genetic databases from 176,000 people who had either Alzheimer’s or Parkinson’s disease. The people involved in the study were from numerous countries located in East Asia, Europe, the Middle East and South America. Their genomes were then compared with people who did not have the diseases, focusing on the incidence and age of onset.
“In an earlier study we’d found that carrying the DR4 allele seemed to protect against Parkinson’s disease,” said Mignot in the Stanford press release. “Now, we’ve found a similar impact of DR4 on Alzheimer’s disease.”
The team found that about 20% to 30% of people carry DR4, and that they have around a 10% risk reduction for developing the two diseases.
“That this protective factor for Parkinson’s wound up having the same protective effect with respect to Alzheimer’s floored me,” said Emmanuel Mignot, MD, PhD, the Craig Reynolds Professor of Sleep Medicine in the Department of Psychiatry and Behavioral Sciences at Stanford University and the Director of the Stanford Center for Narcolepsy, in the Stanford Medicine press release. “The night after we found that out, I couldn’t sleep.”
The scientists also analyzed data from autopsied brains of more than 7,000 Alzheimer’s patients and discovered that individuals who carry DR4 had fewer neurofibrillary tangles and that those tangles are composed mainly of modified tau proteins, a common biomarker for Alzheimer’s.
The presence of these tangles corresponds with the severity of Alzheimer’s disease. They are not typically seen in Parkinson’s patients, but the Stanford team found that Parkinson’s patients who did carry DR4 experienced later onset of symptoms.
Mignot stated that tau, which is essential in Alzheimer’s, may also play a role in Parkinson’s, but that further research is required to prove its function.
Both diseases are characterized by the progressive loss of certain nerve cells or neurons in the brain and are linked to an accumulation of abnormal proteins. The Stanford researchers suggested that the DR4 gene variant may help protect individuals from Alzheimer’s and Parkinson’s by preventing the buildup of tau proteins.
“This is a very interesting study, providing additional evidence of the involvement of the immune system in the pathogenesis of Alzheimer’s and Parkinson’s,” neurologist Wassim Elyaman, PhD, Assistant Professor of Neurological Sciences in Neurology, the Taub Institute and the Institute for Genomic Medicine at Columbia University, told Live Science.
New Vaccines and Immunotherapies
According to the Alzheimer’s Association, more than six million Americans are currently living with Alzheimer’s disease and approximately one in three Americans die with Alzheimer’s or another dementia.
The Parkinson’s Foundation states that nearly one million Americans are currently living with Parkinson’s disease, and that number is expected to rise to 1.2 million by 2030. Parkinson’s is the second-most common neurodegenerative disease after Alzheimer’s disease.
Even though the genetic analysis of the Stanford research is strong, more immune cell and blood-based research is needed to definitively establish how tau is connected to the two diseases.
This research could have implications for clinical laboratories by giving them biomarkers for a useful new diagnostic test, particularly for diagnosing Alzheimer’s and Parkinson’s.
Further, Mignot suggested that an effective vaccine could delay the onset or slow the progression of both diseases. He hopes to test his hypothesis on genetically modified mice and eventually human subjects.
University of Cincinnati researchers hypothesize that low levels of amyloid-beta protein, not amyloid plaques, are to blame
New research from the University of Cincinnati (UC) and Karolinska Institute in Sweden challenges the prevailing theory about the causes of Alzheimer’s disease, suggesting the possibility of new avenues for the development of effective clinical laboratory assays, as well as effective therapies for treating patients diagnosed with Alzheimer’s.
“Yet the plaques remain the center of our attention as it relates to biomarker development and therapeutic strategies,” he added.
“It’s only too logical, if you are detached from the biases that we’ve created for too long, that a neurodegenerative process is caused by something we lose, amyloid-beta, rather than something we gain, amyloid plaques,” said Alberto Espay, MD (above), in a University of Cincinnati news story. “Degeneration is a process of loss, and what we lose turns out to be much more important.” The UC study could lead to new clinical laboratory diagnostics, as well as treatments for Alzheimer’s and Parkinson’s diseases. (Photo copyright: University of Cincinnati.)
High Levels of Aβ42 Associated with Lower Dementia Risk
The researchers found that study participants with high levels of a soluble amyloid-beta protein, Aβ42, were less likely to develop dementia than those with lower levels of the protein, regardless of the levels of amyloid plaques in their brains or the amount of tau protein—either as phosphorylated tau (p-tau) or total tau (t-tau)—in their cerebral spinal fluid. P-tau and t-tau are proteins that form “tau tangles” in the brain that are also associated with Alzheimer’s.
One limitation of the study was that the researchers were unable to include Aβ40, another amyloid-beta protein, in their analysis. But they noted that this “did not limit the testing of our hypothesis since Aβ40 exhibits lower fibrillogenicity and lesser depletion than Aβ42, and is therefore less relevant to the process of protein aggregation than Aβ42.” Fibrillogenicity, in this context, refers to the process by which the amyloid-beta protein hardens into plaque.
While the presence of plaques may be correlated with Alzheimer’s, “Espay and his colleagues hypothesized that plaques are simply a consequence of the levels of soluble amyloid-beta in the brain decreasing,” UC news stated. “These levels decrease because the normal protein, under situations of biological, metabolic, or infectious stress, transform into the abnormal amyloid plaques.”
The UC News story also noted that many attempts to develop therapeutics for Alzheimer’s have focused on reducing amyloid plaques, but “in some clinical trials that reduced the levels of soluble amyloid-beta, patients showed worsening in clinical outcomes.”
New Therapeutics for Multiple Neurodegenerative Diseases
Eisai, a Japanese pharmaceutical company, recently announced phase three clinical trial results of lecanemab, an experimental drug jointly developed by Eisai and Biogen, claiming that the experimental Alzheimer’s drug modestly reduced cognitive decline in early-stage patients, according to NBC News.
Espay noted that lecanemab “does something that most other anti-amyloid treatments don’t do in addition to reducing amyloid: it increases the levels of the soluble amyloid-beta.” That may slow the process of soluble proteins hardening into plaques.
Beyond their findings about Alzheimer’s, the researchers believe similar mechanisms could be at work in other neurodegenerative diseases such as Parkinson’s disease, where the soluble alpha-synuclein protein also hardens into deposits.
“We’re advocating that what may be more meaningful across all degenerative diseases is the loss of normal proteins rather than the measurable fraction of abnormal proteins,” Espay said. “The net effect is a loss not a gain of proteins as the brain continues to shrink as these diseases progress.”
Espay foresees two approaches to treating these diseases: Rescue medicine, perhaps based on increasing levels of important proteins, and precision medicine, which “entails going deeper to understand what is causing levels of soluble amyloid-beta to decrease in the first place, whether it is a virus, a toxin, a nanoparticle, or a biological or genetic process,” according to UC News. “If the root cause is addressed, the levels of the protein wouldn’t need to be boosted because there would be no transformation from soluble, normal proteins to amyloid plaques.”
Clinical Laboratory Impact
What does this mean for clinical laboratories engaged in treatment of both Alzheimer’s and Parkinson’s patients? A new understanding of the disease would create “the opportunity to identify new biomarkers and create new clinical laboratory tests that may help diagnose Alzheimer’s earlier in the disease progression, along with tests that help with the patient’s prognosis and monitoring his or her progression,” said Robert Michel, Editor-in-Chief of Dark Daily and its sister publication The Dark Report.
Given the incidence of Alzheimer’s disease in the population, any clinical laboratory test cleared by the FDA would be a frequently-ordered assay, Michel noted. It also would create the opportunity for pathologists and clinical laboratories to provide valuable interpretation about the test results to the ordering physicians.
Studies presented at the Alzheimer’s Association International Conference point to the p-tau217 protein as an especially useful biomarker
Researchers disclosed a potentially useful biomarker for Alzheimer’s Disease at a major conference this summer. The good news for clinical laboratories is that the biomarker is found in blood. If further research confirms these early findings, medical laboratories could one day have a diagnostic test for this condition.
That possibility emerged from the Alzheimer’s Association International Conference (AAIC), which was held online July 27-31. Researchers presented findings from multiple studies that suggested blood/plasma levels of a protein known as phospho-tau217 (p-tau217) can indicate brain anomalies associated with Alzheimer’s.“Changes in brain proteins amyloid and tau, and their formation into clumps known as plaques and tangles, respectively, are defining physical features of Alzheimer’s disease in the brain,” states an AAIC press release. “Buildup of tau tangles is thought to correlate closely with cognitive decline. In these newly reported results, blood/plasma levels of p-tau217, one of the forms of tau found in tangles, also seem to correlate closely with buildup of amyloid.”
At present, “there is no single diagnostic test that can determine if a person has Alzheimer’s disease,” the association states on its website. Clinicians will typically review a patient’s medical history and conduct tests to evaluate memory and other everyday thinking skills. That may help determine that an individual has dementia, but not necessarily that Alzheimer’s is the cause.
“Currently, the brain changes that occur before Alzheimer’s dementia symptoms appear can only be reliably assessed by positron-emission tomography (PET) scans, and from measuring amyloid and tau proteins in [cerebrospinal] fluid (CSF),” the association states. “These methods are expensive and invasive. And, too often, they are unavailable because they are not covered by insurance or difficult to access, or both.”
In the AAIC press release, Alzheimer’s Association Chief Science Officer Maria C. Carrillo, PhD, said that a clinical laboratory blood test “would fill an urgent need for simple, inexpensive, non-invasive and easily available diagnostic tools for Alzheimer’s.
“New testing technologies could also support drug development in many ways,” she added. “For example, by helping identify the right people for clinical trials, and by tracking the impact of therapies being tested. The possibility of early detection and being able to intervene with a treatment before significant damage to the brain from Alzheimer’s disease would be game changing for individuals, families, and our healthcare system.”
However, she cautioned, “these are early results, and we do not yet know how long it will be until these tests are available for clinical use. They need to be tested in long-term, large-scale studies, such as Alzheimer’s clinical trials.”
The study, led by Oskar Hansson, MD, of Lund University in Sweden, included 1,402 participants. About half of these were enrolled in BioFINDER-2, an ongoing dementia study in Sweden. In this group, researchers were most interested in the test’s ability to distinguish Alzheimer’s from other neurodegenerative disorders that cause dementia.
Diagnostic accuracy was between 89% and 98%, the researchers reported, which was similar to the performance of PET imaging and CSF tests. P-tau217 was more accurate than magnetic resonance imaging (MRI) as well as other biomarkers, such as p-tau181.
Here, the researchers’ primary goal was to determine the test’s ability to distinguish between individuals with and without Alzheimer’s. Researchers ran the p-tau217 test on plasma samples collected within 2.9 years of death and compared the results to postmortem examinations of the brain tissue. Accuracy was 89% in individuals with amyloid plaques and tangles, and 98% in individuals with plaques and more extensive tangles.
The third cohort consisted of 622 members of a large extended family in Colombia whose members share a genetic mutation that makes them susceptible to early-onset Alzheimer’s, The New York Times reported. Among the members, 365 were carriers of the mutation. In this group, levels of plasma p-tau217 increased by age, and “a significant difference from noncarriers was seen at age 24.9 years,” the researchers wrote in Jama Network. That’s about 20 years before the median age when mild cognitive impairment typically begins to appear in carriers.
Other Alzheimer Biomarker Studies Presented at AAIC
Suzanne Schindler, MD, PhD, a neurologist and instructor in the Department of Neurology at the Washington University School of Medicine (WUSM) in St. Louis, presented results of an Alzheimer’s Disease (AD) study that used mass spectrometry to analyze amyloid and p-tau variants in blood samples collected from participants. The researchers compared these with CSF and PET results and found that some of the of p-tau isoforms, especially p-tau217, had a strong concordance.
“These findings indicate that blood plasma Aβ and p-tau measures are highly precise biomarkers of brain amyloidosis, tauopathy, and can identify stages of clinical and preclinical AD,” stated an AAIC press release on the studies.
For decades, physicians have wanted a diagnostic test for Alzheimer’s Disease that could identify this condition early in its development. This would allow the patient and the family to make important decisions before the onset of severe symptoms. Such a clinical laboratory test would be ordered frequently and thus would be a new source of revenue for medical laboratories.
The AP story noted that “half a dozen research groups gave new results on various experimental tests, including one that seems 88% accurate at indicating Alzheimer’s risk.” And Richard Hodes, MD, Director of the National Institute on Aging, told AP, “In the past year, we’ve seen a dramatic acceleration in progress [on Alzheimer’s tests]. This has happened at a pace that is far faster than any of us would have expected.”
This could be a boon for medical laboratories seeking way to contribute more value to patient care. Especially among Alzheimer’s patients, who account for as many as 70% of all dementia cases.
Plasma Biomarker for Predicting Alzheimer’s
One of the experimental blood tests presented at the AAIC involved a 2018 study into “the potential clinical utility of plasma biomarkers in predicting brain amyloid-β burden at an individual level. These plasma biomarkers also have cost-benefit and scalability advantages over current techniques, potentially enabling broader clinical access and efficient population screening,” the researchers stated an article they published in Nature.
AP also reported that Japanese scientists at the AAIC
presented results of a validation test conducted on 201 people who had either
Alzheimer’s, other types of dementia, or little or no symptoms. They found that
the test “correctly identified 92% of people who had Alzheimer’s and correctly
ruled out 85% who did not have it, for an overall accuracy of 88%.”
Akinori Nakamura, MD, PhD, of the National Center for
Geriatrics and Gerontology in Obu, Japan, was a member of the research team and
first author of the research paper. He told the AP that the test results “closely
matched those from the top tests used now—three types of brain scans and a
mental assessment exam.”
Koichi Tanaka is a Japanese engineer who won the Nobel prize winner for chemistry. He heads the Koichi Tanaka Research Lab at Shimadzu Corp. (OTCMKTS:SHMZF) in Kyoto, Japan, and was on the team that developed the Amyloid beta biomarker test that was presented at AAIC. He told Bloomberg, “Our finding overturned the common belief that it wouldn’t be possible to estimate amyloid accumulation in the brain from blood. We’re now being chased by others, and the competition is intensifying.”
But Tanaka cautions that the test needs further study before
it is ready for clinical use, and that for now “it belongs in the hands of drug
developers and research laboratories,” Bloomberg reported.
Other Studies into Developing an Alzheimer’s Biomarker
Alzheimer’s is usually diagnosed after symptoms appear, such
as memory loss. To arrive at their diagnoses, doctors often rely on medical
history, brain imaging (MRI, CT), PET, and measurement of amyloid in spinal
An article published on Alzforum, a website and news service dedicated to the research and treatment for Alzheimer’s and other related disorders, noted a study by King’s College London researchers who, using mass spectrometry, “found a panel of biomarkers that predicted with almost 90% accuracy whether cognitively normal people had a positive amyloid scan.”
Nicholas Ashton, PhD, neuroscientist and Wallenberg Postdoctoral Fellow at University of Gothenburg in Sweden, and first author of the King’s College study, explained that “Amyloid-burden and neurofilament light polypeptide (NFL) peptides were important in predicting Alzheimer’s, but alone they weren’t as predictable as when we combined them with novel proteins related to amyloid PET.”
The researchers published their study earlier this year in Science Advances. “Using an unbiased mass spectrometry approach, we have found and replicated with high accuracy, specificity, and sensitivity a plasma protein classifier reflecting amyloid-beta burden in a cognitively unimpaired cohort,” the researchers wrote.
“This is something that would be easy to incorporate into a screening test in a neurology clinic,” Brian Gordon, PhD, Assistant Professor of Radiology at Washington University’s Mallinckrodt Institute of Radiology, and an author of the study, stated in the news release.
These parallel studies into screening for Alzheimer’s by
researchers worldwide are intriguing. The favorable results suggest that
someday there may be a screen for Alzheimer’s using a clinical laboratory blood
With Alzheimer’s affecting nearly six million Americans of all ages, such an assay would enable clinical laboratories to help many people.
Should greater attention be given to protein damage in chronic diseases such as Alzheimer’s and diabetes? One life scientist says “yes” and suggests changing how test developers view the cause of age-related and degenerative diseases
DNA and the human genome get plenty of media attention and are considered by many to be unlocking the secrets to health and long life. However, as clinical laboratory professionals know, DNA is just one component of the very complex organism that is a human being.
In fact, DNA, RNA, and proteins are all valid biomarkers for medical laboratory tests and, according to one life scientist, all three should get equal attention as to their role in curing disease and keeping people healthy.
Along with proteins and RNA, DNA is actually an “equal partner in the circle of life,” wrote David Grainger, PhD, CEO of Methuselah Health, in a Forbes opinion piece about what he calls the “cult of DNA-centricity” and its relative limitations.
Effects of Protein Damage
“Aging and age-related degenerative diseases are caused by protein damage rather than by DNA damage,” explained Grainger, a Life Scientist who studies the role proteins play in aging and disease. “DNA, like data, cannot by itself do anything. The data on your computer is powerless without apps to interpret it, screens and speakers to communicate it, keyboards and touchscreens to interact with it.”
“Similarly,” he continued, “the DNA sequence information (although it resides in a physical object—the DNA molecule—just as computer data resides on a hard disk) is powerless and ethereal until it is translated into proteins that can perform functions,” he points out.
According to Grainger, diseases such as cystic fibrosis and Duchenne Muscular Dystrophy may be associated with genetic mutation. However, other diseases take a different course and are more likely to develop due to protein damage, which he contends may strengthen in time, causing changes in cells or tissues and, eventually, age-related diseases.
“Alzheimer’s disease, diabetes, or autoimmunity often take decades to develop (even though your genome sequence has been the same since the day you were conceived); the insidious accumulation of the damaged protein may be very slow indeed,” he penned.
“But so strong is the cult of DNA-centricity that most scientists seem unwilling to challenge the fundamental assumption that the cause of late-onset diseases must lie somewhere in the genome,” Grainger concludes.
Shifting Focus from Genetics to Proteins
Besides being CEO of Methuselah Health, Grainger also is Co-Founder and Chief Scientific Advisor at Medicxi, a life sciences investment firm that backed Methuselah Health with $5 million in venture capital funding for research into disease treatments that focus on proteins in aging, reported Fierce CEO.
Methuselah Health, founded in 2015 in Cambridge, UK, with offices in the US, is reportedly using post-translational modifications for analysis of many different proteins.
“At Methuselah Health, we have shifted focus from the genetics—which tells you in an ideal world how your body would function—to the now: this is how your body functions now and this is what is going wrong with it. And that answer lies in the proteins,” stated Dr. David Grainger (above), CEO of Methuselah Health, in an interview with the UK’s New NHS Alliance. Click on this link to watch the full interview. [Photo and caption copyright: New NHS Alliance.]
How Does it Work?
This is how Methuselah Health analyzes damaged proteins using mass spectrometry, according to David Mosedale, PhD, Methuselah Health’s Chief Technology Officer, in the New NHS Alliance story:
Protein samples from healthy individuals and people with diseases are used;
Proteins from the samples are sliced into protein blocks and fed slowly into a mass spectrometer, which accurately weighs them;
Scientists observe damage to individual blocks of proteins;
Taking those blocks, proteins are reconstructed to ascertain which proteins have been damaged;
Information is leveraged for discovery of drugs to target diseases.
Mass spectrometry is a powerful approach to protein sample identification, according to News-Medical.Net. It enables analysis of protein specificity and background contaminants. Interactions among proteins—with RNA or DNA—also are possible with mass spectrometry.
Methuselah Health’s scientists are particularly interested in the damaged proteins that have been around a while, which they call hyper-stable danger variants (HSDVs) and consider to be the foundation for development of age-related diseases, Grainger told WuXi AppTec.
“By applying the Methuselah platform, we can see the HSDVs and so understand which pathways we need to target to prevent disease,” he explained.
For clinical laboratories, pathologists, and their patients, work by Methuselah Health could accelerate the development of personalized medicine treatments for debilitating chronic diseases. Furthermore, it may compel more people to think of DNA as one of several components interacting that make up human bodies and not as the only game in diagnostics.