Brain-wide functional connectome analysis of 40,000 individuals reveals brain networks that show aging effects in...

The functional connectome changes with aging. We systematically evaluated aging-related alterations in the functional connectome using a whole-brain connectome network analysis in 39,675 participants in UK Biobank project. We used adaptive dense network discovery tools to identify networks directly associated with aging from resting-state functional magnetic resonance imaging (fMRI) data. We replicated our findings in 499 participants from the Lifespan Human Connectome Project in Aging study. The results consistently revealed two motor-related subnetworks (both with permutation test p-values <0.001) that showed a decline in resting-state functional connectivity (rsFC) with increasing age. The first network primarily comprises sensorimotor and dorsal/ventral attention regions from precentral gyrus, postcentral gyrus, superior temporal gyrus, and insular gyrus, while the second network is exclusively composed of basal ganglia regions, namely the caudate, putamen, and globus pallidus. Path analysis indicates that white matter fractional anisotropy mediates 19.6% (p < 0.001, 95% CI [7.6% 36.0%]) and 11.5% (p < 0.001, 95% CI [6.3% 17.0%]) of the age-related decrease in both networks, respectively. The total volume of white matter hyperintensity mediates 32.1% (p < 0.001, 95% CI [16.8% 53.0%]) of the aging-related effect on rsFC in the first subnetwork.