The nonlinear relationship between cerebrospinal fluid A beta(42) and tau in preclinical Alzheimer's disease

Abstract

Cerebrospinal fluid (CSF) studies consistently show that CSF levels of amyloid-beta 1-42 (A beta(42)) are reduced and tau levels increased prior to the onset of cognitive decline related to Alzheimer's disease (AD). However, the preclinical prediction accuracy for low CSF A beta(42) levels, a surrogate for brain A beta(42) deposits, is not high. Moreover, the pathology data suggests a course initiated by tauopathy contradicting the contemporary clinical view of an A beta initiated cascade. CSF A beta(42) and tau data from 3 normal aging cohorts (45-90 years) were combined to test both cross-sectional (n = 766) and longitudinal (n = 651) hypotheses: 1) that the relationship between CSF levels of A beta(42) and tau are not linear over the adult life-span; and 2) that non-linear models improve the prediction of cognitive decline. Supporting the hypotheses, the results showed that a u-shaped quadratic fit (A beta(2)) best describes the relationship for CSF A beta(42) with CSF tau levels. Furthermore we found that the relationship between A beta(42) and tau changes with age-between 45 and 70 years there is a positive linear association, whereas between 71 and 90 years there is a negative linear association between A beta(42) and tau. The quadratic effect appears to be unique to A beta(42), as A beta(38) and A beta(40) showed only positive linear relationships with age and CSF tau. Importantly, we observed the prediction of cognitive decline was improved by considering both high and low levels of A beta(42). Overall, these data suggest an earlier preclinical stage than currently appreciated, marked by CSF elevations in tau and accompanied by either elevations or reductions in A beta(42). Future studies are needed to examine potential mechanisms such as failing CSF clearance as a common factor elevating CSF A beta(xx) analyte levels prior to A beta(42) deposition in brain.