Preclinical Cerebrospinal Fluid and Volumetric Magnetic Resonance Imaging Biomarkers in Swedish Familial Alzheimer's Disease

Background: It is currently believed that therapeutic interventions will be most effective when introduced at the preclinical stage of Alzheimer's disease (AD). This underlines the importance of biomarkers to detect AD pathology in vivo before clinical disease onset. Objective: To examine the evolution of cerebrospinal fluid (CSF) biomarker and brain structure changes in the preclinical phase of familial AD. Methods: The study included members from four Swedish families at risk for carrying an APP(swe), APP(arc), PSEN1 H163Y, or PSEN1 I143T mutation. Magnetic resonance imaging (MRI) scans were obtained from 13 mutation carriers (MC) and 20 non-carriers (NC) and analyzed using vertex-based analyses of cortical thickness and volume. CSF was collected from 10 MC and 12 NC from familial AD families and analyzed for A beta(42), total tau (T-tau) and phospho-tau (P-tau). Results: The MC had significantly lower levels of CSF A beta(42) and higher levels T-tau and P-tau than the NC. There was a trend for a decrease in A beta(42) 15-20 years before expected onset of clinical symptoms, while increasing T-tau and P-tau was not found until close to the expected clinical onset. The MC had decreased volume on MRI in the left precuneus, superior temporal gyrus, and fusiform gyrus. Conclusions: Aberrant biomarker levels in CSF as well as regional brain atrophy are present in preclinical familial AD, several years before the expected onset of clinical symptoms.