Genetic basis of anatomical asymmetry and aberrant dynamic functional networks in Alzheimer's disease

Genetic associations with macroscopic brain networks can provide insights into healthy and aberrant cortical connectivity in disease. However, associations specific to dynamic functional connectivity in Alzheimer's disease are still largely unexplored. Understanding the association between gene expression in the brain and functional networks may provide useful information about the molecular processes underlying variations in impaired brain function. Given the potential of dynamic functional connectivity to uncover brain states associated with Alzheimer's disease, it is interesting to ask: How does gene expression associated with Alzheimer's disease map onto the dynamic functional brain connectivity? If genetic variants associated with neurodegenerative processes involved in Alzheimer's disease are to be correlated with brain function, it is essential to generate such a map. Here, we investigate how the relation between gene expression in the brain and dynamic functional connectivity arises from nodal interactions, quantified by their role in network centrality (i.e. the drivers of the metastability), and the principal component of genetic co-expression across the brain. Our analyses include genetic variations associated with Alzheimer's disease and also genetic variants expressed within the cholinergic brain pathways. Our findings show that contrasts in metastability of functional networks between Alzheimer's and healthy individuals can in part be explained by the two combinations of genetic co-variations in the brain with the confidence interval between 72% and 92%. The highly central nodes, driving the brain aberrant metastable dynamics in Alzheimer's disease, highly correlate with the magnitude of variations from two combinations of genes expressed in the brain. These nodes include mainly the white matter, parietal and occipital brain regions, each of which (or their combinations) are involved in impaired cognitive function in Alzheimer's disease. In addition, our results provide evidence of the role of genetic associations across brain regions in asymmetric changes in ageing. We validated our findings on the same cohort using alternative brain parcellation methods. This work demonstrates how genetic variations underpin aberrant dynamic functional connectivity in Alzheimer's disease. How do genetic variations associated with Alzheimer's disease and the cholinergic pathway contribute to functional network involvement in the disease? In this study, Rubido et al., are first to report the genetic basis of anatomical asymmetry in healthy brains and its relationship with aberrant dynamic functional connectivity in Alzheimer's disease. Graphical Abstract