In a recent issue of Neurology, Suzanne E. Schindler, MD, PhD, from the Washington University School of Medicine in St. Louis, and colleagues reported in their recent completed research study (Schindler et al., 2019) that the ratio of plasma beta-amyloid (Aβ) 42 to plasma Aβ40, as measured by a high-precision assay, can accurately predict current and future brain amyloidosis, one of the hallmarks of Alzheimer disease (AD) pathology. This study used amyloid positron-emission tomography (amyloid-PET) or cerebrospinal fluid (CSF) phosphorylated-tau (p-tau)/Aβ42 as reference standards. CSF p-tau /Aβ42 is a measure that incorporates both Aβ pathology-mediated reduction of Aβ42 and the neuronal response to the pathology in the form of increased secretion of p-tau.
Using plasma samples collected in 158 mostly cognitively normal participants who had undergone amyloid PET imaging or CSF collection, the research group found that a lower ratio of plasma Aβ42/Aβ40 had a high correspondence with amyloid PET status (receiver operating characteristic area under the curve [AUC] 0.88) and CSF p-tau /Aβ42 (AUC 0.85). When age and APOE gene e4 status, both of which are strong AD risk factors, were added to the model, plasma Aβ42/Aβ40 can predict amyloid PET status with a higher AUC of 0.94. In a small subset of individuals with a negative amyloid PET scan at baseline, patients with a lower plasma Aβ42/Aβ40 ratio had a 15-fold greater risk of conversion to amyloid positivity on PET imaging.
The results of this study are impressive and significant, matching well with earlier studies done by the same group (Ovod et al., 2017) and by another group from Japan and Australia (Nakamura et al., 2018). The later, using similar immunoprecipitation mass spectrometry-based methods, reported that plasma Aβ42 derived measurements can predict brain amyloidosis (measured by amyloid PET) with close to 90% accuracy.
The good performance of plasma Aβ42/Aβ40 for detection of brain amyloidosis makes it an excellent screening tool for those at risk of AD dementia. Moreover, this study suggests that plasma Aβ42/Aβ40 may become positive earlier than the amyloid PET scan.
This is a very promising study that would add another strong piece of scientific evidence that we are one step closer to getting blood-based biomarker test available for clinical trials and practice, particularly for the development of screening tools needed for the design of prevention clinical trial, in which case, the cost and burden of clinical trial screening by using amyloid PET are extremely high. However we should be more cautious when interpreting the results. The plasma Aβ42/Aβ40 is a promising screening test for brain amyloidosis, but not a screening test for symptomatic AD, so it should not be considered as a diagnostic test, which requires the test to be not only highly sensitive, but also highly specific. The new assays still need validation, including replication, optimization, and generalization to different populations. Head to head comparison between the proposed assay and different other plasma assays may be needed as well.
References
Nakamura A, Kaneko N, Villemagne VL, et al: High performance plasma amyloid-beta biomarkers for Alzheimer’s disease. Nature 554:249–254, 2018.
Ovod V, Ramsey KN, Mawuenyega KG, et al: Amyloid β concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis. Alzheimers Dement 13:841–849, 2017.
Schindler SE, Bollinger JG, Ovod V, et al: High-precision plasma β-amyloid 42/40 predicts current and future brain amyloidosis. Neurology 2019 Aug 1. pii: 10.1212/WNL.0000000000008081. doi: 10.1212/WNL.0000000000008081. [Epub ahead of print]
