Amyloid-β misfolding as a plasma biomarker indicates risk for future clinical Alzheimer’s disease in individuals with subjective cognitive decline

Abstract

Background 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). Methods 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. Results 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. 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.

State-of-the-Art Methods and Emerging Fluid Biomarkers in the Diagnostics of Dementia—A Short Review and Diagnostic Algorithm

“…Furthermore, a recent meta-analysis by Koychev and colleagues [ 27 ] did not find any difference in plasma Aβ42 levels between AD patients and controls, based on two previously published reports describing SIMOA-based measurements [ 26 , 28 ]. Also, the Aβ42/40 ratio did not significantly differ between AD patients and healthy controls [ 26 ], but it might be able to discriminate those mild cognitive impairment (MCI) patients that convert to AD in the follow-up [ 29 ] and associate with positive amyloid-PET imaging in preclinical AD patients [ 30 ].…”

Biomarkers and Their Implications in Alzheimer’s Disease: A Literature Review

“…119 Another Aβ related plasma biomarker that has shown prognostic value in AD is the detection of Aβ mis-folding using immuneinfrared-sensor technology. 121 In one cohort study, the presence of Aβ mis-folding and Aβ42/Aβ40 plasma levels were tracked in patients with only subjective cognitive decline. The presence of mis-folding and positive Aβ ratios were strongly correlated with the progression to MCI and dementia due to AD.…”

“…The presence of mis-folding and positive Aβ ratios were strongly correlated with the progression to MCI and dementia due to AD. 121…”

Aβ misfolding in blood plasma is inversely associated with body mass index even in middle adulthood

“…Structural misfolding of Aβ in blood plasma can be measured by an immuno-infrared-sensor (iRS) [ 5 , 6 ]. In previous studies, we have shown that Aβ misfolding in blood plasma is correlated to CSF AD biomarkers and amyloid PET imaging and is highly predictive of Alzheimer’s clinical syndrome (clinical AD) many years before clinical diagnosis [ 6 – 8 ]. Most recently, we were able to show that Aβ misfolding in blood plasma might be an early risk marker of AD that is independent of age [ 9 ].…”