Anti-Correlated Cerebrospinal Fluid Biomarker Trajectories in Preclinical Alzheimer's Disease.

Abstract

The earliest stage of preclinical Alzheimer's disease (AD) is defined by low levels of cerebrospinal fluid (CSF) amyloid-β (Aβ42). However, covariance in longitudinal dynamic change of Aβ42 and tau in incipient preclinical AD is poorly understood. To examine dynamic interrelationships between Aβ42 and tau in preclinical AD. We followed 47 cognitively intact participants (CI) with available CSF data over four years in ADNI. Based on longitudinal Aβ42 levels in CSF, CI were classified into three groups: 1) Aβ42 stable with normal levels of Aβ42 over time (n = 15); 2) Aβ42 declining with normal Aβ42 levels at baseline but showing decline over time (n = 14); and 3) Aβ42 levels consistently abnormal (n = 18). In the Aβ42 declining group, suggestive of incipient preclinical AD, CSF phosphorylated tau (p-tau) showed a similar longitudinal pattern of increasing abnormality over time (p = 0.0001). Correlation between longitudinal slopes of Aβ42 and p-tau confirmed that both trajectories were anti-correlated (rho = -0.60; p = 0.02). Regression analysis showed that Aβ42 slope (decreasing Aβ42) predicted p-tau slope (increasing p-tau) (R2 = 0.47, p = 0.03). Atrophy in the hippocampus was predicted by the interaction of Aβ42 and p-tau slopes (p < 0.0001) only in this incipient preclinical AD group. In all groups combined, memory decline was predicted by p-tau. The evolution of Aβ42 and p-tau CSF biomarkers in CI subjects follows an anti-correlated trajectory, i.e., as Aβ42 declined, p-tau increased, and thus was suggestive of strong temporal coincidence. Rapid pathogenic cross-talk between Aβ42 and p-tau thus may be evident in very early stages of preclinical AD.