Multimodal Imaging in Rat Model Recapitulates Alzheimer's Disease Biomarkers Abnormalities

Imaging biomarkers are frequently proposed as endpoints for clinical trials targeting brain amyloidosis in Alzheimer's disease (AD); however, the specific impact of amyloid-beta (A beta) aggregation on biomarker abnormalities remains elusive in AD. Using the McGill-R-Thy1-APP transgenic rat as a model of selective A beta pathology, we characterized the longitudinal progression of abnormalities in biomarkers commonly used in AD research. Middle-aged (9-11 months) transgenic animals (both male and female) displayed mild spatial memory impairments and disrupted cingulate network connectivity measured by resting-state fMRI, even in the absence of hypometabolism (measured with PET [F-18]FDG) or detectable fibrillary amyloidosis (measured with PET [F-18]NAV4694). At more advanced ages (16-19 months), cognitive deficits progressed in conjunction with resting connectivity abnormalities; furthermore, hypometabolism, A beta plaque accumulation, reduction of CSF A beta(1-42) concentrations, and hippocampal atrophy (structural MRI) were detectable at this stage. The present results emphasize the early impact of A beta on brain connectivity and support a framework in which persistent A beta aggregation itself is sufficient to impose memory circuits dysfunction, which propagates to adjacent brain networks at later stages.