Early diagnostic accuracy and pathophysiologic relevance of an autopsy-confirmed Alzheimer's disease peripheral biomarker

Abstract

Treatment of Alzheimer's disease (AD) and the discovery of promising drug candidates depend on early diagnosis. Few currently available diagnostic tests have significantly improved this early uncertainty, while the "gold standard" diagnosis continues to require clinical dementia in life and the presence of pathologic brain lesions of amyloid plaques and neurofibrillary tangles in the brain at autopsy. Here, the inflammatory agonist bradykinin, a small nano-peptide, that induces PKC-mediated phosphorylation of Erk1 and Erk2 in fibroblasts, was applied to punch-biopsy-obtained human skin fibroblasts. Quantitative imaging of the phosphorylated Erk1 and Erk2 bands was then used in a ratio that is mathematically configured into an AD-Biomarker Index (AD-Index). In the population described here (N=264), there were 64 autopsy examinations. Demented individuals were clinically diagnosed as AD with an overall accuracy of 78%. Among the 42 autopsy-confirmed cases for which there were also AD-Biomarker measurements, the overall accuracy of the AD-Biomarker was 98%. Among both the autopsy-confirmed and the clinically diagnosed patients, the AD-Index values were inversely correlated with the duration of disease, i.e., the time from the onset of dementia symptoms. Among the autopsy-confirmed cases, the AD-Biomarker diagnosis showed remarkably high sensitivity (97%) and specificity (100%) compared to clinical diagnosis (sensitivity: 78% and specificity: 20%). Using autopsy validation, the clinical diagnosis was only accurate at 52% level vs. the AD-Biomarker accuracy of 100% for cases with dementia not larger than 4 years of duration. Finally, application of soluble Abeta(1-42) to the fibroblasts of normal controls induced the abnormal AD-Biomarker phenotype, suggesting the pathophysiologic relevance of this AD-Biomarker measurement. In summary, the AD-Biomarker, as confirmed by autopsy validation, showed significantly higher sensitivity and specificity than did clinical diagnosis, particularly at early stages of disease, and pathophysiological relevance was demonstrated for the mechanistic basis of the AD-Biomarker measurements.