Summary: Researchers using a novel immuno-infrared sensor have identified blood-based biomarkers that indicate Alzheimer’s disease up to 17 years before clinical symptoms appear. The sensor detects misfolding of the amyloid-beta protein, an early event that later leads to plaque formation in the brain.
Source: RUB
Alzheimer’s disease has a long preclinical phase that can span 15 to 20 years before cognitive symptoms become evident. A research team in Bochum has developed an immuno-infrared sensor capable of detecting misfolded amyloid-beta in blood samples, revealing signs of the disease up to 17 years prior to clinical diagnosis. Because misfolded amyloid-beta is the precursor to the characteristic amyloid plaques in the brain, detecting this structural change early may enable much earlier intervention.
“Our aim is to identify individuals at increased risk of Alzheimer’s dementia with a simple blood test long before toxic plaques accumulate in the brain, so that therapies can be started in time,” says Professor Klaus Gerwert, founding director of the Centre for Protein Diagnostics (PRODI) at Ruhr-Universität Bochum. For this study, his team collaborated with researchers led by Professor Hermann Brenner at the German Cancer Research Centre (DKFZ) in Heidelberg.
The findings were published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association on 19 July 2022.
A related comparative study, published in the same journal on 2 March 2022, used complementary single-molecule array (SIMOA) technology to assess conventional concentration-based blood biomarkers alongside the structural biomarker measured by the immuno-infrared sensor.
Early detection in symptom-free individuals
The team analysed archived blood plasma from participants in the ESTHER cohort study in Saarland. Samples were originally collected between 2000 and 2002 and stored frozen. At the time of collection, participants were aged 50 to 75 and had no diagnosis of Alzheimer’s disease. For this analysis, researchers selected 68 individuals who later received an Alzheimer’s diagnosis over a 17-year follow-up and compared them with 240 control participants who remained free of a dementia diagnosis.
The primary goal was to determine whether the blood taken at baseline already contained signals that differentiate those who would go on to develop Alzheimer’s disease. The immuno-infrared sensor, designed to detect structural misfolding of amyloid-beta rather than simply measuring its concentration, identified the 68 future cases with high predictive accuracy.
For comparison, the researchers measured established concentration-based biomarkers using highly sensitive SIMOA assays, focusing in particular on phosphorylated tau 181 (P-tau181), which many studies have suggested as a promising blood biomarker for Alzheimer’s. In this preclinical cohort, however, P-tau181 did not perform well in predicting long-term risk.
“In the symptom-free stage, P-tau181 appears less suitable for early prediction,” Gerwert summarizes. “Surprisingly, we found that glial fibrillary acidic protein (GFAP) concentrations can also indicate increased risk up to 17 years before clinical diagnosis, though GFAP alone is less precise than the misfolding readout.”
Combining the structural amyloid-beta misfolding measure with GFAP concentration improved test accuracy in the preclinical phase, suggesting a complementary role for both types of biomarkers in early risk stratification.
From lab to market: start-up advancing the sensor
The Bochum team hopes that identifying amyloid-beta misfolding early could allow clinicians to apply disease-modifying treatments at a stage when they are more likely to be effective. They cite therapies such as Aduhelm, which was approved in the United States and shown to reduce amyloid plaques, as examples where earlier treatment might yield greater clinical benefit.
“We envision using the misfolding test as a screening tool for older adults to determine their risk of developing Alzheimer’s dementia,” says Gerwert. His newly founded start-up, betaSENSE, aims to commercialize the immuno-infrared sensor and obtain regulatory approval so the test can be implemented in clinical laboratories. The technology has been patented globally and is being advanced toward market readiness.
Why trials fail and the importance of early diagnosis
Many Alzheimer’s drug trials have failed, in part because participants are often enrolled after plaques and irreversible brain damage have already formed. Current plaque diagnostics either rely on costly PET imaging or on cerebrospinal fluid biomarkers obtained through lumbar puncture and measured by ELISA or mass spectrometry. These approaches typically detect pathology later in the disease process.
By contrast, the immuno-infrared sensor identifies earlier structural misfolding of amyloid-beta—the molecular event that precedes plaque deposition. Gerwert notes that whether amyloid misfolding is the direct cause of Alzheimer’s disease or an associated hallmark remains debated, but for diagnostic purposes the presence of misfolding clearly signals the start of the disease process.
“The timing of therapeutic intervention will become even more critical,” says Léon Beyer, the study’s first author and a PhD student in Gerwert’s group. “The success of future clinical trials will depend on recruiting participants who are correctly characterised and who have not yet sustained irreversible brain damage.”
Potential beyond Alzheimer’s: other neurodegenerative diseases
Protein misfolding is central to many neurodegenerative disorders, including Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis (ALS). The immuno-infrared sensor platform can, in principle, be adapted to detect other disease-specific misfolded proteins—for example, TDP-43 in ALS—by using targeted antibodies that recognise structural changes rather than measuring protein concentration alone.
“This platform technology could enable precise, differential biomarker-based diagnosis in the early stages of neurodegenerative diseases, where symptom-based diagnosis is often difficult and error-prone,” Gerwert emphasizes.
About this Alzheimer’s disease research news
Author: Julia Weiler
Source: RUB
Contact: Julia Weiler – RUB
Image: The image is in the public domain
Original Research: Open access. “Amyloid-beta misfolding and GFAP predict risk of clinical Alzheimer’s disease diagnosis within 17 years” by Klaus Gerwert et al., Alzheimer’s & Dementia
Abstract
Amyloid-beta misfolding and GFAP predict risk of clinical Alzheimer’s disease diagnosis within 17 years
Introduction
Blood-based biomarkers for Alzheimer’s disease are urgently needed for early detection and risk stratification. In this study, four plasma biomarkers were measured at baseline in a community-based cohort and participants were followed for 17 years to determine associations with clinical Alzheimer’s disease risk.
Methods
The investigators measured amyloid-beta (Aβ) misfolding as a structure-based biomarker using an immuno-infrared sensor, alongside concentrations of phosphorylated tau 181 (P-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) in heparin plasma. Samples were taken at baseline from 68 participants who were later diagnosed with Alzheimer’s disease and 240 control participants who did not receive a dementia diagnosis during follow-up.
Results
Aβ misfolding demonstrated high predictive accuracy for Alzheimer’s disease diagnosis within 17 years. Among the concentration markers, GFAP performed best, followed by NfL and P-tau181. Combining Aβ misfolding with GFAP further increased predictive accuracy in the preclinical phase.
Discussion
Aβ misfolding and elevated GFAP levels both show strong potential to predict long-term clinical Alzheimer’s disease risk and may serve as important early markers. The structural Aβ misfolding readout, in particular, shows promise as a prescreening tool to stratify risk among older adults and to improve selection for preventative or early therapeutic interventions.