Female 3xTg-AD mice demonstrate hyperexcitability phenotype of Alzheimer’s disease in structure-function and function-behavior relationships

Alzheimer's disease (AD) causes cognitive decline with aging, hypothetically due to the accumulation of beta-amyloid (A<i>β</i>) plaques. The 3xTg-AD mouse model is increasingly used due to its initial absence of significant physical or behavioral impairments in youth and progressive A<i>β</i> plaque development with age. This mouse model thus provides an opportunity for comparison with human AD through two stages of study. Using wild-type (WT) and 3xTg-AD mice, aged 22 and 40 weeks (before and after the large increase in A<i>β</i> plaques), we measured functional connectivity (FC) and structural connectivity (SC) between brain regions. At 22 weeks, 3xTg-AD mice unexpectedly had higher SC and FC, and there was positive correlation between behavioral performance and FC 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 methods identified a shift in 3xTg-AD mice between two abnormal states relative to WT, moving from a hyperconnected to a hypoconnected state. Such a shift matches the hyperexcitability phenotype of AD observed in human patients, and thus suggests that 3xTg-AD mice can model the multistage etiology of AD of that phenotype.