Neural flexibility is higher in Alzheimer's disease and predicts Alzheimer's disease transition

Background Neural flexibility (NF), a measure of dynamic functional connectivity, was associated with psychiatric diseases but has not yet been studied in Alzheimer's disease (AD). Objective We aim to evaluate whether AD is associated with alterations in NF and probe its predictive utility for AD conversion. Method The study included 862 older adults (461 cognitively normal (CN), 294 mild cognitive impairment (MCI), 107 AD) with valid resting-state fMRI data from the Alzheimer's Disease Neuroimaging Initiative. We defined the NF of a node as the number of times that a node changed its community assignment across the sliding windows, normalized by the total number of possible changes. We computed global NF and 12 functional network-specific NFs, then performed linear mixed models on NFs separately to explore the differences in these measures between our three groups. Finally, we evaluated the predictive utility of NF on dementia transition using survival analysis. Results NF is significantly higher in AD than CN on global NF (beta = 0.002, 95% CI 0.001 to 0.004), and NF in six networks, and NF is significantly higher in MCI than CN in the visual network. Among n = 617 non-demented participants at baseline, n = 53 (8.6%) participants converted to dementia during the follow-up visits. Higher NF in the visual network was positively associated with AD transition (HR = 1.323, 95%CI 1.002 to 1.747, p = 0.049, per 1 SD in NF), controlling for age, gender, and education. Conclusions We found that NF during rest was higher in AD patients and predicted dementia transition. Thus, NF may be a valuable biomarker of AD; however, more validation and mechanistic studies need to be performed.