Cognition, Brain Atrophy, and Cerebrospinal Fluid Biomarkers Changes from Preclinical to Dementia Stage of Alzheimer's Disease and the Influence of Apolipoprotein E

Background: Knowledge of Alzheimer's disease (AD) manifestation in the pre-dementia stage facilitates the selection of appropriate measures for early detection and disease progression. Objective: To examine the trajectories of cognitive performance, gray matter volume (GMV), and cerebrospinal fluid (CSF) biomarkers, together with the influence of apolipoprotein E (APOE) in subjects with amyloid-beta (A beta) deposits across the pre-clinical to dementia stages of AD. Methods: 356 subjects were dichotomized into A beta+ and A beta- groups based on their CSF A beta(1-42) level. We derived AD-related atrophic regions (AD-ROIs) using the voxel-based morphometry approach. We characterized the trajectories of cognitive scores, GMV at AD-ROIs, and CSF biomarkers from preclinical to disease stages in A beta+ subjects. The effect of APOE epsilon 4 genotype on these trajectories was examined. Results: Impairments in executive functioning/processing speed (EF/PS) and atrophy at the right supramarginal/inferior parietal gyrus were detected in cognitively normal A beta+ subjects. Together with the APOE epsilon 4 carrier status, these measures showed potential to identify cognitively normal elderly with abnormal CSF A beta(1-42) level in another independent cohort. Subsequently, impairment in memory, visuospatial, language, and attention as well as atrophy in the temporal lobe, thalamus, and mid-cingulate cortex were detectable in A beta+ mild cognitive impairment (MCI) subjects. In MCI and dementia A beta+ subjects, epsilon 4 carriers had more severe atrophy of the medial temporal lobe and memory impairment but higher EF/PS compared to non-carriers. Conclusions: EF/PS decline and right parietal atrophy might act as non-invasive screening tests for abnormal amyloid deposition in cognitively normal elderly. APOE modulation on subsequent trajectories in cognition and atrophy should be taken into account when analyzing disease progression.