The association between genetic variations and morphology-based brain networks changes in Alzheimer's disease

Alzheimer's disease (AD) is a highly heritable disease. The morphological changes of cortical cortex (such as, cortical thickness and surface area) in AD always accompany by the change of the functional connectivity to other brain regions and influence the short- and long-range brain network connections, causing functional deficits of AD. In this study, the first hypothesis is that genetic variations might affect morphology-based brain networks, leading to functional deficits; the second hypothesis is that protein-protein interaction (PPI) between the candidate proteins and known interacting proteins to AD might exist and influence AD. 600 470 variants and structural magnetic resonance imaging scans from 175 AD patients and 214 healthy controls were obtained from the Alzheimer's Disease Neuroimaging Initiative-1 database. A co-sparse reduced-rank regression model was fit to study the relationship between non-synonymous mutations and morphology-based brain networks. After that, PPIs between selected genes and BACE1, an enzyme that was known to be related to AD, are explored by using molecular dynamics (MD) simulation and co-immunoprecipitation (Co-IP) experiments. Eight genes affecting morphology-based brain networks were identified. The results of MD simulation showed that the PPI between TGM4 and BACE1 was the strongest among them and its interaction was verified by Co-IP. Hence, gene variations influence morphology-based brain networks in AD, leading to functional deficits. This finding, validated by MD simulation and Co-IP, suggests that the effect is robust.