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Julia Stockmann, Inge M.W. Verberk, Nina Timmesfeld, Robin Denz, Brian Budde, Julia Lange-Leifhelm, Philip Scheltens, Wiesje M. van der Flier, Andreas Nabers, Charlotte E. Teunissen, Klaus Gerwert

• \(\bf Background\) We evaluated A\(\beta\) misfolding in combination with A\(\beta_{42/40}\) 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). \(\bf Methods\) Baseline plasma samples (\(\it n\) = 203) from SCD subjects in the SCIENCe project and Amsterdam Dementia Cohort (age 61 \(\pm\) 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 A\(\beta\) folding; readouts at ≤ 1646 \(cm^{− 1}\) reflected low and at < 1644 \(cm^{− 1}\) high misfolding. We used Cox proportional hazard models to quantify Aβ\(\beta\) 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 \(APOE_{\epsilon}\)4 status. Additionally, plasma A\(\beta_{42/40}\) data measured by SIMOA were statistically analyzed and compared. \(\bf Results\) All 22 patients who converted to MCI or AD-dementia within 6 years exhibited A\(\beta\) 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 A\(\beta\) misfolding in an age, sex, and \(APOE_{\epsilon}\)4 model. A similar model with plasma A\(\beta_{42/40}\) 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 A\(\beta\) misfolding and the A\(\beta_{42/40}\) ratio. \(\bf Conclusions\) 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.