Misfolded protein biomarkers are found in the blood by a sensor.
Before the appearance of the first clinical symptoms, Alzheimer’s the disease has a symptom-free period of 15 to 20 years. A research team has discovered that it is possible to detect Alzheimer’s disease in the blood for up to 17 years before outward symptoms appear. This is done using an immuno-infrared sensor developed in Bochum. The sensor detects the amyloid-beta misfolding of the protein biomarker. As the disease progresses, this misfolding leads to distinctive deposits in the brain called plaques.
“Our goal is to determine the risk of developing Alzheimer’s dementia at a later stage with a simple blood test before the toxic plaques can even form in the brain, to ensure that therapy can be initiated. on time”, explains Professor Klaus Gerwert. , founding director of the Center for Protein Diagnostics (PRODI) at the Ruhr-Universität Bochum. His team cooperated for the study with a group from the German Cancer Research Center in Heidelberg (DKFZ) led by Professor Hermann Brenner.
The team recently published the results obtained with the immuno-infrared sensor in the journal Alzheimer’s and dementia: the journal of the Alzheimer’s Association. This finding is supported by a comparative study that was conducted using SIMOA (Complementary Single Molecule Array) technology and published in the same journal on March 2, 2022.
Early detection of asymptomatic people at high risk for Alzheimer’s disease
The researchers analyzed the blood plasma participants in the ESTHER study conducted in Saarland on potential biomarkers of Alzheimer’s disease. Blood samples were taken and frozen between 2000 and 2002. The test participants were then between the ages of 50 and 75 and had not yet been diagnosed with Alzheimer’s disease.
The current study compared 68 people who had been diagnosed with Alzheimer’s disease during 17-year follow-up with 240 control subjects who had not been diagnosed. The researchers, led by Klaus Gerwert and Hermann Brenner, wanted to see if symptoms of Alzheimer’s disease could be detected in blood samples early in the study.
The immuno-infrared sensor correctly identified the 68 people tested who eventually developed Alzheimer’s disease. For comparison, the researchers used the complementary and extremely sensitive SIMOA technology to analyze other biomarkers, in particular the P-tau181 biomarker, which is now being proposed as a potential biomarker candidate in various studies.
“However, unlike the clinical phase, this marker is not suitable for the asymptomatic early phase of Alzheimer’s disease”, summarizes Klaus Gerwert in the results of the comparative study. “Surprisingly, we found that glial fiber protein (GFAP) concentration can indicate disease up to 17 years before the clinical phase, although it does so much less accurately than the immuno-infrared sensor.”
Nevertheless, by combining the misfolding of beta-amyloid with the concentration of GFAP, the researchers were able to improve the quality of the test. precision at the asymptomatic stage.
The start-up aims to bring immuno-infrared sensors to maturity on the market
Bochum researchers hope that early diagnosis based on beta-amyloid misfolding could allow Alzheimer’s drugs to be used at such an early stage that they have a significantly greater impact – for example, the drug Aduhelm, which was recently approved in the United States.
“We plan to use the misfolding test to establish a method for screening older people and determining their risk of developing Alzheimer’s dementia,” explains Klaus Gerwert. “The vision of our newly founded start-up betaSENSE is that the disease can be stopped at an asymptomatic stage before irreversible damage occurs.”
Although the sensor is still under development, the technology has already been patented worldwide. BetaSENSE’s goal is to commercialize the immuno-infrared sensor and have it approved as a diagnostic device so that it can be used in clinical laboratories.
Clinical trials with Alzheimer’s drugs often fail
The drug Aduhelm, which was approved by the US FDA in the spring of 2021, has been shown to clear amyloid-beta plaques from the brain. However, previous research found it had only a minor effect on clinical symptoms such as memory loss and disorientation. As a result, the European Medicines Agency has chosen not to approve the drug in Europe in winter 2021.
“So far, clinical trials of Alzheimer’s drugs have failed by the dozens, apparently because the established plaque tests used in trials don’t flag the disease in time,” says Gerwert. “It appears that once the plaques are deposited, they induce irreversible damage in the brain.”
To date, plaques have been detected directly in the brain using complex and expensive PET technology, or indirectly using concentrations of protein biomarkers in cerebrospinal fluid obtained invasively using ELISA or mass spectrometry technologies. Unlike conventional plaque diagnostics, the immuno-infrared sensor detects early amyloid-beta misfolding, resulting in later plaque deposition.
“However, it is still controversial whether this misfolding is the cause of Alzheimer’s disease or just an accompanying factor,” Gerwert points out. “For the therapeutic approach, this question is crucial, but it is not relevant for the diagnosis. Misfolding indicates the onset of Alzheimer’s disease.
“The exact timing of therapeutic intervention will become even more important in the future,” predicts Léon Beyer, first author and Ph.D. student in Klaus Gerwert’s team. “The success of future drug trials will depend on whether study participants are properly characterized and do not yet show irreversible harm upon study entry.”
Biomarkers for Parkinson’s disease and ALS
Misfolded proteins play a central role in many neurodegenerative diseases, such as Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis (ALS). As the researchers have shown, the immuno-infrared sensor can in principle also be used to detect other misfolded proteins, such as TDP-43, which is characteristic of ALS. They do not measure the concentration of a specific protein but detect its misfolding using disease-specific antibodies.
“Most importantly, this platform technology enables us to establish differential and accurate biomarker-based diagnosis in the early stages of neurodegenerative diseases, in which the symptom-based diagnosis currently applied is very difficult and error-prone. », points out Gerwert.
Reference: “Amyloid-beta misfolding and GFAP predict the risk of clinical diagnosis of Alzheimer’s disease within 17 years” by Léon Beyer, Hannah Stocker, Dan Rujescu, Bernd Holleczek, Julia Stockmann, Andreas Nabers , Hermann Brenner and Klaus Gerwert, July 19, 2022, Alzheimer’s and dementia: the journal of the Alzheimer’s Association.
Donors: Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg, Bundesministerium für Bildung und Forschung, Bundesministerium für Familie, Senioren, Frauen und Jugend, Ministerium für Arbeit, Soziales, Frauen und Gesundheit des Saarlands, Network Aging Research Universität Heidelberg, Alzheimer Forschung Initiative, and Ministerium für Kultur und Wissenschaft des Landes Nordrhein-Westfalen.