Resting-state functional dynamics alterations relate to plasma amyloid markers and explain memory impairments in the TgF344-AD model of Alzheimer’s disease

Resting-state (RS) fMRI studies of Alzheimer’s disease’s (AD) impact on brain function commonly use functional connectivity (FC), ignoring short-timescale network dynamics, captured by co-activation patterns (CAPs), shown to accurately classify transgenic rodents from the wild-type (WT). We acquired high temporal resolution RS-fMRI data in the TgF344-AD rat model at pre-plaque and plaque stages and delineated brain functional alterations using FC and CAPs. We also assessed plaque-stage blood amyloid levels and memory performance in the same animals and investigated the statistical relationship between pathological, RS-functional, and behavioral phenotypes. TgF344-AD (TG) rats had elevated blood amyloid levels, committed more working and reference memory errors and showed reduced hippocampal FC with the lateral cortical and default-mode-like network (DMLN) compared to WT at the plaque stage. They showed DMLN and hippocampal hyper- and hypo-activation at pre- and plaque stages respectively in multiple CAPs. While blood amyloid levels were explained better by plaque-stage, than pre-plaque stage, FC values and CAP activations, it was the pre-plaque stage, more than the plaque stage, CAP activations that accurately explained memory impairments. Our findings not only identify early signatures of AD in brain functional dynamics in this translational rat model but demonstrate their relevance for prognosis of memory deficits.