Cerebrospinal Fluid β-Amyloid and Phospho-Tau Biomarker Interactions Affecting Brain Structure in Preclinical Alzheimer Disease

Objective: To assess the relationships between core cerebrospinal fluid (CSF) biomarkers and cortical thickness (CTh) in preclinical Alzheimer disease (AD). Methods: In this cross-sectional study, normal controls (n = 145) from the Alzheimer's Disease Neuroimaging Initiative underwent structural 3T magnetic resonance imaging (MRI) and lumbar puncture. CSF beta-amyloid(1-42) (A beta) and phospho-tau(181p) (p-tau) levels were measured by Luminex assays. Samples were dichotomized using published cutoffs (A beta(+)/A beta(-) and p-tau(+)/ptau(-)). CTh was measured by Freesurfer. CTh difference maps were derived from interaction and correlation analyses. Clusters from the interaction analysis were isolated to analyze the directionality of the interaction by analysis of covariance. Results: We found a significant biomarker interaction between CSF Ab and CSF p-tau levels affecting brain structure. Cortical atrophy only occurs in subjects with both A beta(+) and p-tau(+). The stratified correlation analyses showed that the relationship between p-tau and CTh is modified by A beta status and the relationship between A beta and CTh is modified by p-tau status. p-Tau-dependent thinning was found in different cortical regions in A beta(+) subjects but not in A beta(-) subjects. Cortical thickening was related to decreasing CSF A beta values in the absence of abnormal p-tau, but no correlations were found in p-tau(+) subjects. Interpretation: Our data suggest that interactions between biomarkers in AD result in a 2-phase phenomenon of pathological cortical thickening associated with low CSF A beta, followed by atrophy once CSF p-tau becomes abnormal. These interactions should be considered in clinical trials in preclinical AD, both when selecting patients and when using MRI as a surrogate marker of efficacy.