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

BACKGROUND: A reduced amyloid-ß (Aß)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 Aß peptides originating from peripheral sources. We hypothesized that the observable effect in plasma can be accentuated to some extent by specifically measuring Aß1-42 and Aß1-40 instead of AßX-42 and AßX-40. METHODS: We assessed the plasma AßX-42/X-40 and Aß1-42/1-40 ratios in an idealized clinical sample by semi-automated Aß immunoprecipitation followed by closely related sandwich immunoassays. The amyloid-positive and amyloid-negative groups (dichotomized according to Aß42/40 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 Aß1-42/1-40 ratio was 20.86% lower in amyloid-positive subjects than in the amyloid-negative group, while the median AßX-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 Aß1-42/1-40 compared to -15.50% for AßX-42/X-40. Cohen's d was 1.73 for Aß1-42/1-40 and 1.48 for plasma AßX-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 Aß1-42/1-40 and AßX-42/X-40. CONCLUSIONS: Our findings support the hypothesis that the relatively small difference in the plasma Aß42/40 ratio between subjects with and without evidence of brain amyloidosis can be accentuated by specifically measuring Aß1-42/1-40 instead of AßX-42/X-40. A simplified theoretical model explaining this observation is presented.