Autopsy‐confirmed minimally invasive biomarker identifies Alzheimer’s Disease even in the presence of co‐morbid pathologies

Abstract

AbstractBackgroundThere are currently no FDA‐approved tests that are highly sensitive and highly specific for Alzheimer’s disease (AD). Diagnostic Accuracy has been even more difficult due to recent findings that >50% of AD brains show co‐morbid pathologies such as multi‐infarct dementia and Frontal Lobe Dementia. Here, we describe an autopsy‐confirmed AD Biomarker that identifies AD pathology even with co‐morbid brain pathology.MethodA Morphometric Imaging (MI) assay was previously shown to correlate the dementia and presence of AD pathology in the brains of AD patients (Chirila et al., 2013) with abnormalities of skin fibroblasts isolated with routine punch biopsies (∼3mm). Cells were cultured on a thick layer of 3‐D Matrigel matrix and subjected to image analysis. AD cell lines formed large aggregates in contrast to non‐AD dementia (non‐ADD) or non‐demented control (NDC) cell samples. Typically skin fibroblasts formed “networks” analogous to networks formed by neurons isolated in cell culture and AD networks were slower and less connected Quantitative image analyses enabled the calculation of average unit aggregate area (A) in terms of ln(A/N). Samples were collected with a double‐blind protocol for demented patients > 55 years old who eventually reached blinded autopsy examination. NDC samples were collected for Biomarker assay only.ResultThe total fibroblast patient sample (N = 74) consisted of AD (N = 26) patients and non‐ADD (N = 21) patients (all were autopsy confirmed and had blinded biomarker data); and NDC, N = 27 that had biomarker data. The cut‐off value of ln(A/N) = 6.98 was determined from the biomarker values for NDC patient samples. For the Biomarker AD vs. Non‐ADD data, True Positive = 26, False Negative = 0, False Positive = 0, with Sensitivity and Specificity calculated as 100 and 100, respectively. (AD vs. Non‐ADD, p < .000001). The NDC MI assay values closely superimposed with the non‐ADD sample values.ConclusionIn these autopsy‐confirmed results, the MI Biomarker distinguished AD from Non‐ADD patients and correctly diagnosed AD even in the presence of other co‐morbid pathologies at autopsy. This highly, accurate, minimally invasive AD biomarker, therefore, was validated by rigorous reference to the NIH gold standard criteria for an AD Diagnosis, dementia in life and the presence of plaques and hyperphosphorylated tau at autopsy.