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Clinical study shows that misfolded amyloid beta proteins in the blood are an accurate risk marker for Alzheimer’s disease

Friday 11 October 2019

On 11 October, Dr Hannah Stocker and colleagues published a paper in the Alzheimer’s and Dementia journal, showing that the levels of misfolded amyloid beta (Aβ) protein in the blood can accurately predict a person’s risk of developing Alzheimer’s disease (AD).  During the progression of AD, Aβ proteins undergo distinct structural changes: starting off as single, ordered proteins, they become clustered, misfolded aggregates.  It is these misfolded aggregates that create amyloid plaques in the brain, kicking off the disease cascade. Recent work has shown that the amount of misfolded Aβ in the brain is correlated to misfolded Aβ in cerebrospinal fluid and blood plasma. However, studies have yet to assess the performance of Aβ misfolding as an early predictor of clinical AD, compared to more established predictors such asAPOE4status.  

To address this question, Dr Stocker and colleagues turned to the ongoing community-based ESTHER cohort study.  From 2000-2002, ESTHER recruited 9940 participants aged between 50-75 years, with regular clinical follow-up.  Of these participants, the researchers identified 150 people with a dementia diagnosis during the 14-year follow-up, and 620 healthy controls.  Using an immune-infrared sensor tool, Dr Stocker and colleagues measured the level of misfolded Aβ in blood plasma samples from these participants at baseline and over the 14-year follow-up period.  In line with previous studies,APOE4status was a good predictor of AD diagnosis: individuals with anAPOE4genotype had a 2.4-fold greater likelihood of being clinically diagnosed with AD.  However, Aβ misfolding far exceeded the predictive capability ofAPOE4genotype, with a 23-fold increased odds of clinical AD diagnosis even many years before the development of symptoms. Measurement of Aβ misfolding also allowed the researchers to discriminate between AD, vascular dementia and other mixed dementias. Limitations of the study included the relatively small number of participants with clinically confirmed AD; further large-scale studies are therefore required. Nevertheless, these results suggest that Aβ misfolding could be used to stratify AD risk and help clinicians distinguish between different types of dementia.