Nonlinear changes in delayed functional network topology in Alzheimer's disease: relationship with amyloid and tau pathology.

BACKGROUND: Alzheimer's disease is a neurodegenerative disorder associated with the abnormal deposition of pathological processes, such as amyloid-ß and tau, which produces nonlinear changes in the functional connectivity patterns between different brain regions across the Alzheimer's disease continuum. However, the mechanisms underlying these nonlinear changes remain largely unknown. Here, we address this question using a novel method based on temporal or delayed correlations and calculate new whole-brain functional networks to tackle these mechanisms. METHODS: To assess our method, we evaluated 166 individuals from the ADNI database, including amyloid-beta negative and positive cognitively normal subjects, patients with mild cognitive impairment, and patients with Alzheimer's disease dementia. We used the clustering coefficient and the global efficiency to measure the functional network topology and assessed their relationship with amyloid and tau pathology measured by positron emission tomography, as well as cognitive performance using tests measuring memory, executive function, attention, and global cognition. RESULTS: Our study found nonlinear changes in the global efficiency, but not in the clustering coefficient, showing that the nonlinear changes in functional connectivity are due to an altered ability of brain regions to communicate with each other through direct paths. These changes in global efficiency were most prominent in early disease stages. However, later stages of Alzheimer's disease were associated with widespread network disruptions characterized by changes in both network measures. The temporal delays required for the detection of these changes varied across the Alzheimer's disease continuum, with shorter delays necessary to detect changes in early stages and longer delays necessary to detect changes in late stages. Both global efficiency and clustering coefficient showed quadratic associations with pathological amyloid and tau burden as well as cognitive decline. CONCLUSIONS: This study suggests that global efficiency is a more sensitive indicator of network changes in Alzheimer's disease when compared to clustering coefficient. Both network properties were associated with pathology and cognitive performance, demonstrating their relevance in clinical settings. Our findings provide an insight into the mechanisms underlying nonlinear changes in functional network organization in Alzheimer's disease, suggesting that it is the lack of direct connections that drives these functional changes.