Is plasma amyloid-β 1-42/1-40 a better biomarker for Alzheimer's disease than AβX-42/X-40?

Background A reduced amyloid-beta (A beta)42/40 peptide ratio in blood plasma represents a peripheral biomarker of the cerebral amyloid pathology observed in Alzheimer's disease brains. The magnitude of the measurable effect in plasma is smaller than in cerebrospinal fluid, presumably due to dilution by A beta peptides originating from peripheral sources. We hypothesized that the observable effect in plasma can be accentuated to some extent by specifically measuring A beta 1-42 and A beta 1-40 instead of A beta X-42 and A beta X-40.Methods We assessed the plasma A beta X-42/X-40 and A beta 1-42/1-40 ratios in an idealized clinical sample by semi-automated A beta immunoprecipitation followed by closely related sandwich immunoassays. The amyloid-positive and amyloid-negative groups (dichotomized according to A beta 42/40 in cerebrospinal fluid) were compared regarding the median difference, mean difference, standardized effect size (Cohen's d) and receiver operating characteristic curves. For statistical evaluation, we applied bootstrapping.Results The median A beta 1-42/1-40 ratio was 20.86% lower in amyloid-positive subjects than in the amyloid-negative group, while the median A beta X-42/X-40 ratio was only 15.56% lower. The relative mean difference between amyloid-positive and amyloid-negative subjects was -18.34% for plasma A beta 1-42/1-40 compared to -15.50% for A beta X-42/X-40. Cohen's d was 1.73 for A beta 1-42/1-40 and 1.48 for plasma A beta X-42/X-40. Unadjusted p-values < 0.05 were obtained after .632 bootstrapping for all three parameters. Receiver operating characteristic analysis indicated very similar areas under the curves for plasma A beta 1-42/1-40 and A beta X-42/X-40.Conclusions Our findings support the hypothesis that the relatively small difference in the plasma A beta 42/40 ratio between subjects with and without evidence of brain amyloidosis can be accentuated by specifically measuring A beta 1-42/1-40 instead of A beta X-42/X-40. A simplified theoretical model explaining this observation is presented.

Automated summary

Our findings suggest that the relatively small difference in the plasma A beta 42/40 ratio between subjects with and without evidence of brain amyloidosis can be accentuated by specifically measuring A beta 1-42/1-40 instead of A beta X-42/X-40.