Alzheimer’s disease dementia has a symptom-free course of 15 to 20 years before the first clinical symptoms appear. Using an immune infrared sensor developed in Bochum, the research team is able to identify signs of Alzheimer’s disease in the blood up to 17 years before the first clinical symptoms appear. The sensor detects an abnormality in the biomarker of amyloid-beta protein. As the disease progresses, this imbalance causes distinct 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 even before toxic plaques form in the brain, in order to ensure that treatment can be started in a timely manner,” says Professor Klaus Gerwirt, founding director of the Center for Proteomics Diagnostics (PRODI). In Ruhr-Universität Bochum. His team collaborated on the study with a group at the German Cancer Research Center in Heidelberg (DKFZ) headed by Professor Hermann Brenner.
The team published the results obtained with the immunofluorescence infrared sensor in the journal “Alzheimer’s and Dementia: Journal of the Alzheimer’s AssociationOn July 19, 2022.
This study is supported by a comparative study published in the same journal on March 2, 2022, in which researchers used complementary single molecule array (SIMOA) technology.
Early detection of asymptomatic people who are at high risk of Alzheimer’s disease
Researchers analyzed blood plasma from participants in the Esther Study conducted in Saarland for potential biomarkers of Alzheimer’s disease. Blood samples were taken between 2000 and 2002 and then frozen.
At the time, the test participants were between 50 and 75 years old and had not yet been diagnosed with Alzheimer’s disease. For the current study, 68 participants diagnosed with Alzheimer’s disease during 17 years of follow-up were selected and compared with 240 people who were not diagnosed.
The team, led by Klaus Giroert and Hermann Brenner, aims to find out if signs of Alzheimer’s disease can indeed be found in blood samples at the start of the study.
The immunological infrared sensor was able to identify 68 test subjects who later developed Alzheimer’s disease with a high degree of test accuracy. For comparison, the researchers screened for other biomarkers using the highly sensitive complementary SIMOA technology – specifically the biomarker P-tau181, which is currently proposed as a promising biomarker candidate in various studies.
“Unlike the clinical stage, however, this marker is not appropriate for the early, asymptomatic stage of Alzheimer’s disease,” Klaus Gerwort summarizes the results of the comparative study.
“Surprisingly, we found that glial fibrillation protein (GFAP) concentration can signal disease up to 17 years before the clinical stage, although it is much less accurate than the immunological infrared sensor.”
However, by combining the disruption of amyloid-beta formation and GFAP concentration, the researchers were able to increase the accuracy of the test in the asymptomatic phase.
Start-up aims to bring the immune infrared sensor to market maturity
The Bochum researchers hope that early diagnosis based on the disruption of amyloid-beta formation will help in applying Alzheimer’s drugs at an early stage so that they have a significantly better effect – for example, the drug Aduhelm, which was recently approved in the USA.
“We plan to use the malformation test to establish a screening method for older adults and determine their risk of Alzheimer’s dementia,” says Klaus Gerwirt.
“The vision of the newly started betaSENSE is that the disease can be stopped in an asymptomatic stage before irreversible damage occurs.”
Although the sensor is still in the development stage, the invention has already been patented worldwide. BetaSENSE aims to bring the Immunological Infrared Sensor to market and adopt it as a diagnostic device so that it can be used in clinical laboratories.
Clinical trials of Alzheimer’s drugs often fail
Aduhelm was approved by the FDA in the USA in the spring of 2021 and has been shown to remove beta-amyloid plaques from the brain. However, previous studies showed that it had only a slight effect on clinical symptoms such as memory loss and confusion. As a result, the European Medicines Agency decided in the winter of 2021 not to approve the drug in Europe.
“So far, dozens of clinical trials of Alzheimer’s drugs have failed, apparently because the plaque tests used in the trials do not detect the disease in a timely manner,” says Gerort.
“It appears that once plaques are deposited, they cause irreversible damage to the brain.”
In the tests used to date, plaques are either detected directly in the brain using complex and expensive PET scanning technology or determined indirectly in a less sophisticated way using concentrations of a protein biomarker in cerebrospinal fluid obtained surgically using ELISA or spectrometry technology. mass spectrometry.
In contrast to well-established plaque diagnoses, the immunofluorescence IR sensor indicates a pre-existing defect in amyloid-beta, causing late plaque deposition.
“However, the debate remains controversial as to whether this error is the cause of Alzheimer’s disease or if it is just an accompanying factor,” Gerwirt notes.
For a therapeutic approach, this question is important, but irrelevant to the diagnosis. The imbalance signals the onset of Alzheimer’s disease.”
Léon Beyer, first author and doctoral student on Klaus Gerwert’s team, predicts that “the exact timing of a therapeutic intervention will become even more important in the future.”
“The success of future drug trials will depend on study participants being correctly prescribed and not showing irreversible harm upon entry into the study.”
Biomarkers of Parkinson’s disease and amyotrophic lateral sclerosis
Misfolded proteins play a major role in many neurodegenerative diseases, such as Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis (ALS).
As the researchers explain, the immunofluorescence infrared sensor could in principle also be used to detect other denatured proteins, such as TDP-43, that are characteristic of ALS. They do not measure the concentration of a specific protein, but detect its imbalance using disease-specific antibodies.
“Importantly, this platform technology enables us to perform a differential and accurate biomarker-based diagnosis in the early stages of neurodegenerative diseases, where the currently applied symptom-based diagnosis is very difficult and prone to errors,” emphasizes Gerwirt.
About this research on Alzheimer’s disease news
author: Julia Wheeler
Contact: Julia Weiler – RUB
picture: The image is in the public domain
original search: open access.
“Impairment of amyloid-beta and GFAP predicts risk of clinical Alzheimer’s diagnosis within 17 years” by Klaus Gerwirt et al. Alzheimer’s disease and dementia
Disruption of amyloid beta and GFAP predicts risk of clinical Alzheimer’s diagnosis within 17 years.
Blood-based biomarkers of Alzheimer’s disease (AD) are urgently needed. Here, four plasma biomarkers were measured at baseline in a community group followed over a 17-year period, and the association with clinical Alzheimer’s risk was determined.
Dysfunctional status of amyloid beta (Aβ) was determined as a structure-based biomarker in addition to phosphorylation of tau 181 (P-tau181), glial fibrillary acidic protein (GFAP), and neuronal capillary light (NfL) concentration levels at baseline in the heparinized plasma of 68 participants. who were diagnosed with Alzheimer’s disease and 240 controls without a diagnosis of dementia throughout the follow-up period.
Malformations demonstrated high disease prediction accuracy for AD diagnosis within 17 years. Among the focus markers, GFAP showed the best performance, followed by NfL and P-tau181. The combination of Aβ misfolding and GFAP increased accuracy.
Impairment of Aβ and GFAP has demonstrated a strong ability to predict clinical Alzheimer’s disease risk and may be early risk markers of Alzheimer’s disease. Aβ misfolding has demonstrated its potential as a prescreening tool for Alzheimer’s risk classification in the elderly.