Using a blood test, a German-Dutch research team has predicted the risk of Alzheimer's disease in people who were clinically diagnosed as not having Alzheimer's disease but who perceived themselves as cognitively impaired (Subjective Cognitive Decline, SCD).
The researchers analysed blood samples from an SCD cohort supervised at the Alzheimer Centre Amsterdam. Using a test developed at Ruhr-Universität Bochum (RUB) called the Immuno-Infrared Sensor, they identified all 22 subjects at study entry who developed Alzheimer's dementia, thus the clinical symptoms, within six years. The test also showed which subjects were at very low risk to develop Alzheimer's dementia within six years.
For the study, the team led by biophysics Professor Klaus Gerwert and Julia Stockmann of the Bochum Research Centre for Protein Diagnostics (Prodi) collaborated with RUB statistician Professor Nina Timmesfeld, department of medical informatics, biometry and epidemiology, and researchers from the Amsterdam University Medical Centres, Location Vrije University (VUmc) led by Professor Charlotte Teunissen and Professor Philip Scheltens.
The SCD cohort included 203 individuals. At study entry, blood samples were taken from all the participants and analysed using the patented immuno-infrared sensor that detects misfolding of the amyloid-beta (Aβ) peptide, which is a biomarker for Alzheimer's disease. In addition, the subjects underwent extensive Alzheimer's disease diagnostic testing; at study entry, this did not provide a diagnosis of Alzheimer's disease in any of the subjects studied. The immuno-infrared sensor, on the other hand, detected misfolded Aβ peptides at study entry in all 22 subjects who developed the clinical disease in the following six years. In subjects who showed mild misfolding, it took on average longer (3.4 years) for conversion to clinical Alzheimer than in subjects with severe Aβ misfolding (2.2 years).
Together with statistician Nina Timmesfeld, the researchers predicted the risk of developing clinical Alzheimer's disease. According to the statistical model, SCD subjects with mild misfolding have an 11-fold higher risk and SCD subjects with severe misfolding have a 19-fold higher risk of developing clinical Alzheimer's in the following six years than subjects without misfolded Aβ peptide. "Misfolding of Aβ is therefore a very precise prognostic plasma biomarker," concludes Klaus Gerwert.
In addition, the team checked whether the combination of two different measurement methods in the plasma biomarker panel could further improve the prediction of disease risk. For this purpose, they combined the misfolding of all Aβ isoforms with a concentration decrease for Aβ42 as ratio to Aβ40 in plasma. The Amsterdam group measured Aβ concentrations using the new single-molecule array (SIMOA) technology. This increased the assay accuracy from an AUC (area under the ROC curve) of 0.94 to 0.99.
"We can now very accurately predict the risk of developing clinical Alzheimer's disease in the future, with a simple blood test on symptom-free individuals with subjective concerns," explains Klaus Gerwert. "However, we can just as confidently give the all-clear for SCD patients who have a very low probability of developing Alzheimer's disease in the next six years."
"Through the plasma biomarker panel, we can monitor disease progression over 14 years, beginning in the asymptomatic state with misfolding of Aβ and subsequent plaque deposition of Aβ42 in the brain associated with the first cognitive impairments," Julia Stockmann adds.
Such a blood test, which can detect the onset of Alzheimer's dementia even in the asymptomatic state, would be particularly useful if an active substance were available to treat the disease. In March 2021, the US Food and Drug Administration will decide whether to approve the drug aducanumab. "Our results indicate that Alzheimer's drugs should be applied as early as possible in a non-clinical stage to improve therapy response," Klaus Gerwert said. The Bochum researcher is promoting the immuno-infrared sensor to be used in the selection of trial participants in the future to achieve a significantly better therapy response.
Amyloid-β misfolding as a plasma biomarker indicates risk for future clinical Alzheimer’s disease in individuals with subjective cognitive decline.
Julia Stockmann, Inge MW Verberk, Nina Timmesfeld, Robin Denz, Brian Budde, Julia Lange-Leifhelm, Philip Scheltens, Wiesje M van der Flier, Andreas Nabers, Charlotte E Teunissen, Klaus Gerwert
Published in Alzheimer's Research & Therapy, 24 December 2020
We evaluated Aβ misfolding in combination with Aβ42/40 ratio as a prognostic tool for future clinical progression to mild cognitive impairment (MCI) or dementia due to Alzheimer’s disease (AD) in individuals with subjective cognitive decline (SCD).
Baseline plasma samples (n = 203) from SCD subjects in the SCIENCe project and Amsterdam Dementia Cohort (age 61 ± 9 years; 57% male, mean follow-up time 2.7 years) were analyzed using immuno-infrared-sensor technology. Within 6 years of follow-up, 22 (11%) individuals progressed to MCI or dementia due to AD. Sensor readout values > 1646 cm− 1 reflected normal Aβ folding; readouts at ≤ 1646 cm− 1 reflected low and at < 1644 cm− 1 high misfolding. We used Cox proportional hazard models to quantify Aβ misfolding as a prognostic biomarker for progression to MCI and dementia due to AD. The accuracy of the predicted development of MCI/AD was determined by time-dependent receiver operating characteristic (t-ROC) curve analyses that take individual follow-up and conversion times into account. Statistical models were adjusted for age, sex, and APOEε4 status. Additionally, plasma Aβ42/40 data measured by SIMOA were statistically analyzed and compared.
All 22 patients who converted to MCI or AD-dementia within 6 years exhibited Aβ misfolding at baseline. Cox analyses revealed a hazard ratio (HR) of 19 (95% confidence interval [CI] 2.2–157.8) for future conversion of SCD subjects with high misfolding and of 11 (95% CI 1.0–110.1) for those with low misfolding. T-ROC curve analyses yielded an area under the curve (AUC) of 0.94 (95% CI 0.86–1.00; 6-year follow-up) for Aβ misfolding in an age, sex, and APOEε4 model. A similar model with plasma Aβ42/40 ratio yielded an AUC of 0.92 (95% CI, 0.82–1.00). The AUC increased to 0.99 (95% CI, 0.99–1.00) after inclusion of both Aβ misfolding and the Aβ42/40 ratio.
A panel of structure- and concentration-based plasma amyloid biomarkers may predict conversion to clinical MCI and dementia due to AD in cognitively unimpaired subjects. These plasma biomarkers provide a noninvasive and cost-effective alternative for screening early AD pathological changes. Follow-up studies and external validation in larger cohorts are in progress for further validation of our findings.
Ruhr-University Bochum material
Alzheimer's Research & Therapy study (Open access)