Phosphorylated tau-Aβ₄₂ ratio as a continuous trait for biomarker discovery for early-stage Alzheimer's disease in multiplex immunoassay panels of cerebrospinal fluid

Background Identification of the physiologic changes that occur during the early stages of Alzheimer's disease (AD) may provide critical insights for the diagnosis, prognosis, and treatment of disease. Cerebrospinal fluid (CSF) biomarkers are a rich source of information that reflect the brain proteome. Methods A novel approach was applied to screen a panel of ~190 CSF analytes quantified by multiplex immunoassay, and common associations were detected in the Knight Alzheimer's Disease Research Center (N = 311) and the Alzheimer's Disease Neuroimaging Initiative (N = 293) cohorts. Rather than case-control status, the ratio of CSF levels of tau phosphorylated at threonine 181 (ptau₁₈₁) and Aβ₄₂ was used as a continuous trait in these analyses. Results The ptau₁₈₁-Aβ₄₂ ratio has more statistical power than traditional modeling approaches, and the levels of CSF heart-type fatty acid binding protein (FABP) and 12 other correlated analytes increase as AD progresses. These results were validated using the traditional case-control status model. Stratification of the dataset demonstrated that increases in these analytes occur very early in the disease course and were apparent even in nondemented individuals with AD pathology (low ptau₁₈₁, low Aβ₄₂) compared with elderly control subjects with no pathology (low ptau₁₈₁, high Aβ₄₂). The FABP-Aβ₄₂ ratio demonstrates a similar hazard ratio for disease conversion to ptau₁₈₁-Aβ₄₂ even though the overlap in classification is incomplete suggesting that FABP contributes independent information as a predictor of AD. Conclusions Our results indicate that the approach presented here can be used to identify novel biomarkers for AD correctly and that CSF heart FABP levels start to increase at very early stages of AD.