Dynamic Connectivity Alteration Facilitates Cognitive Decline in Alzheimer's Disease Spectrum

Introduction: It is unknown the alterations in the dynamic networks of the brain and the underlying molecular pathological mechanism of Alzheimer's disease (AD) spectrum. Here, we aim to explore the association between alterations in the dynamic brain networks' trajectory and cognitive decline in the AD spectrum. Methods: One hundred sixty subjects were recruited from the ADNI database, including 49 early mild cognitive impairment, 28 late mild cognitive impairment, 24 AD patients, and 59 cognitively normal. All participants completed the resting-state functional magnetic resonance imaging scan and neuropsychological tests. We integrated a new method combining large-scale network analysis and canonical correlation analysis to explore the dynamic spatiotemporal patterns within- and between resting-state networks (RSNs) and their significance in the AD spectrum. Results: All RSNs represented an increase in connectivity within networks by enhancing inner cohesive ability, while 7 out of 10 RSNs were characterized by a decrease in connectivity between networks, which indicated a weakened connector among networks from the early stage to dementia. This dichotomous mode presenting large-scale dynamic network abnormality was significantly correlated with the levels of molecular biomarkers of AD, and cognitive performance, as well as with the accumulating effects of 10 identified AD-related genetic risk factors. Discussion: These findings deepen our understanding of the associated mechanism underlying large-scale network disruption, linking known molecular biomarkers and phenotypic variations in the AD spectrum.