Memory-behavior correlation in pre-onset Alzheimer's reverses following beta amyloid accumulation

Alzheimer’s disease (AD) causes cognitive decline with aging, hypothetically due to the accumulation of beta-amyloid (Aβ) plaques. Animal models are critical in the study of AD, and the 3xTg-AD mouse model is increasingly used due to its initial absence of significant physical or behavioral impairments in youth and progressive Aβ plaque development with age. This mouse model thus provides an opportunity to find early biomarkers for AD through two stages of study. However, while altered structural and functional networks occur across the whole brain in human AD, such whole-brain networks have never been studied changes in 3xTg-AD mice. Using wild-type (WT) and 3xTg-AD mice, aged 22 and 40 weeks (before and after Aβ plaque development), we measured resting state functional magnetic resonance imaging to examine functional connectivity (FC) between brain regions and diffusion tensor imaging to evaluate the structural connectivity (SC) and axonal integrity of brain white matter fiber bundles. At 22 weeks, 3xTg-AD mice unexpectedly had higher SC and FC, and there was positive correlation between behavioral performance and functional connectivity density. By 40 weeks, SC and FC was lower in AD mice (similar to human AD patients), but the behavior-functional correlation was negative. Thus, our novel methods identified a shift in 3xTg-AD mice between two abnormal states, with the latter state resembling human AD patients. Such a shift could be an early biomarker in human patients, or, if it is not present, that the 3xTg-AD mouse model only becomes relevant after this shift occurs.