Linking genetics to MRI-DTI: HFE polymorphism delays Alzheimer's disease white matter degeneration in APOE4 carriers

Background While APOE4 mutation impacts normal myelination through disruptions of iron and lipid homeostasis, the HFE (homeostatic iron regulatory gene) polymorphism directly participates in white matter (WM) myelination and neuroinflammations processes via modulating iron homeostasis. Objective This study investigated effects of HFE polymorphism in APOE4 gene carriers in the context of WM degeneration and neuroinflammation in Alzheimer's disease (AD). Methods WM degeneration in AD subjects of APOE4 carriers with and without HFE H63D polymorphism was evaluated and compared with age- and sex-matched cognitive normal (CN) groups using diffusion tensor imaging (DTI) data from the Alzheimer's Disease Neuroimaging Initiative database. Results DTI radial and mean diffusivity demonstrated an extensive and precipitous age-related WM degeneration in all the AD groups compared to the CN cohorts. This AD-related WM degeneration, however, was significantly attenuated with HFE H63D polymorphism than that of wildtype along with reduced cognitive decline in the AD group. To link the observed protective effect of HFE H63D polymorphism to WM degeneration and cognitive decline in AD, a mediation model was developed and verified using structure equation modeling. This protective effect of HFE H63D polymorphism on WM is also associated with higher cerebrospinal fluid sTREM2 level. Conclusions This is the first genetic-to-imaging study linking HFE polymorphism to WM degeneration and consequentially to cognitive declines in AD. Our data provide original information on the role of iron homeostasis specifically in WM degeneration, which suggests that manipulating iron homeostasis could be incorporated into the overall AD prevention and intervention strategies.