The nonlinear relationship between cerebrospinal fluid Aβ(42) and tau in preclinical Alzheimer’s disease

Cerebrospinal fluid (CSF) studies consistently show that CSF levels of amyloid-beta 1–42 (Aβ(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 Aβ(42) levels, a surrogate for brain Aβ(42) deposits, is not high. Moreover, the pathology data suggests a course initiated by tauopathy contradicting the contemporary clinical view of an Aβ initiated cascade. CSF Aβ(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 Aβ(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 (Aβ(2)) best describes the relationship for CSF Aβ(42) with CSF tau levels. Furthermore we found that the relationship between Aβ(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 Aβ(42) and tau. The quadratic effect appears to be unique to Aβ(42), as Aβ(38) and Aβ(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 Aβ(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 Aβ(42). Future studies are needed to examine potential mechanisms such as failing CSF clearance as a common factor elevating CSF Aβ(xx) analyte levels prior to Aβ(42) deposition in brain.