Signs of Alzheimer’s disease in the blood 17 years before symptoms start

Summary: A newly developed immuno-infrared sensor allowed researchers to discover biomarkers of Alzheimer’s disease in blood samples 17 years before the onset of clinical symptoms. The sensory is able to detect the misfolding of beta-amyloid.

Source: TO RUB

The dementia disorder of Alzheimer’s disease has an asymptomatic evolution of 15 to 20 years before the appearance of the first clinical symptoms. Thanks to an immuno-infrared sensor developed in Bochum, a research team is able to identify the signs of Alzheimer’s disease in the blood up to 17 years before the appearance of the first clinical symptoms. The sensor detects the misfolding of the beta-amyloid biomarker protein. As the disease progresses, this misfolding causes characteristic 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 published the results obtained with the immuno-infrared sensor in the journal “Alzheimer’s and dementia: the journal of the Alzheimer’s Association” on July 19, 2022.

This study is supported by a comparative study published in the same journal on March 2, 2022, in which the researchers used SIMOA (Complementary Single Molecule Array) technology.

Early detection of asymptomatic people at high risk for Alzheimer’s disease

The researchers analyzed the blood plasma of participants in the ESTHER study conducted in Saarland for potential biomarkers of Alzheimer’s disease. The blood samples had been taken between 2000 and 2002 and then frozen.

At that 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 were selected who had been diagnosed with Alzheimer’s disease during the 17-year follow-up and compared with 240 control subjects without such a diagnosis.

The team led by Klaus Gerwert and Hermann Brenner aimed to find out whether signs of Alzheimer’s disease could already be found in the blood samples at the start of the study.

The immuno-infrared sensor was able to identify the 68 test subjects who later developed Alzheimer’s disease with a high degree of testing accuracy. For comparison, the researchers examined other biomarkers with the complementary and highly sensitive SIMOA technology – in particular the P-tau181 biomarker, which is currently being proposed as a promising 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.”

Yet, by combining beta-amyloid misfolding and GFAP concentration, the researchers were able to further increase the accuracy of the test at the symptom-free stage.

A start-up aims to bring the immuno-infrared sensor to market maturity

The Bochum researchers hope that early diagnosis based on beta-amyloid misfolding could help to apply Alzheimer’s disease drugs at such an early stage that they have a significantly better effect – 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 in the development phase, the invention has already been patented worldwide. BetaSENSE aims 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

Approved by the FDA in the United States in the spring of 2021, the drug Aduhelm has been shown to clear amyloid-beta plaques from the brain. However, previous studies have shown it to have only a minor effect on clinical symptoms such as memory loss and disorientation. Therefore, the European Medicines Agency decided in winter 2021 not to approve the drug in Europe.

“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.”

In the tests used to date, the plaques are either detected directly in the brain with the complex and expensive technology of PET scan, or indirectly determined in a less complex way using concentrations of protein biomarkers in the cerebrospinal fluid obtained in a way invasive with ELISA or mass spectrometry technology.

Unlike established plaque diagnostics, the immuno-infrared sensor indicates the early misfolding of beta-amyloid, which causes plaque to be deposited later.

“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.

It shows a brain
The researchers analyzed the blood plasma of participants in the ESTHER study conducted in Saarland for potential biomarkers of Alzheimer’s disease. Image is in public domain

“The precise timing of therapeutic intervention will become even more important in the future,” predicts Léon Beyer, first author and doctoral student in Klaus Gerwert’s team.

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This shows a mother's hand holding a baby's feet

“The success of future drug trials will depend on whether study participants are properly characterized and do not yet show irreversible harm at 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.

About this Alzheimer’s disease research news

Author: Julia Weiller
Source: TO RUB
Contact: Julia Weiler – RUB
Image: Image is in public domain

Original research: Free access.
“Amyloid-beta misfolding and GFAP predict the risk of clinical diagnosis of Alzheimer’s disease within 17 years” by Klaus Gerwert et al. Alzheimer’s and dementia


Summary

Beta-amyloid misfolding and GFAP predict risk of clinical diagnosis of Alzheimer’s disease within 17 years

Introduction

Blood biomarkers for Alzheimer’s disease (AD) are urgently needed. Here, four plasma biomarkers were measured at baseline in a community cohort followed for 17 years, and the association with clinical risk of AD was determined.

Methods

Amyloid beta (Aβ) misfolding status as a structure-based biomarker along with concentration levels of phosphorylated tau 181 (P-tau181), glial fibrillary acidic protein (GFAP), and neurofilament lumen (NfL) were determined at baseline in the heparinized plasma of 68 participants who were diagnosed with AD and 240 controls without a diagnosis of dementia throughout follow-up.

Results

Aβ misfolding showed high disease prediction accuracy of AD diagnosis within 17 years. Among concentration markers, GFAP showed the best performance, followed by NfL and P-tau181. The combination of Aβ misfolding and GFAP increased accuracy.

Discussion

Aβ misfolding and GFAP have shown strong ability to predict clinical risk of AD and may be important early markers of AD risk. Aβ misfolding illustrated its potential as a screening tool for AD risk stratification in the elderly.

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