Disentangling the association between genetics and functional connectivity in Mild Cognitive Impairment

Despite the increasing effort being devoted to the investigation of the link between imaging endophenotypes (IDPs) and genetic determinants (GDs) in Mild Cognitive Impairment (MCI) and Alzheimer’s disease (AD), many issues remain open and deserve investigation. Among these, the role of functional connectivity (FC) is still blurred. This paper aims at shading some light on the topic relying on the ADNI repository (177 patients, out of which 82 MCI and 95 controls). The within/between-network connectivities were derived from individual FC matrices and used as IDPs. Conversely, the GDs consisted of two Polygenic Risk Scores (PRS) that have recently been proven to play a role in AD. A Partial Least Squares (PLS) model equipped with LASSO regularization was finally fitted to the data for associating IDPs and GDs. In the first component, all FC coefficients had the same sign, and were correlated with PRS2. Connectivities involving the dorsal attention (DAN) and frontoparietal control (CON) networks reached the highest weights, while within/between-network FC for the limbic (LIM) were less represented. Overall, the within-network FC values were less pronounced compared to the between-network ones. In the second component, most of the FC features had zero weights. Visual (VIS) and somatomotory (SMN) showed a correlated trend, while being anti-correlated with LIM, CON and default mode network as well as with PRS1. Our findings suggest that the two PRSs correlated with a possible pattern of aberrant within/between-network FC changes occurring in RSNs devoted to higher cognitive functions and more vulnerable in this pathology.