Multivariate white matter differences links to cognition in individuals with family history of Alzheimer’s disease and APOE4 genetic risk

Abstract

AbstractBackgroundGrowing evidence suggests Alzheimer’s disease (AD) develops from a complex cascade of events that vary between individuals. Multivariate approaches have the potential to capture the complexity and heterogeneity of pathologies underlying AD in a more holistic manner compared to univariate approaches.MethodThe MRI data of 105 older adults with a family history of AD from the PREVENT‐AD dataset were analysed. Forty six of these individuals had the APOE4‐3 genotype (greater risk of developing AD), while 59 subjects had the APOE3‐3 genotype (normal risk). Diffusion‐weighted imaging and multi‐echo magnetization transfer, proton density and T1‐weighted data were used to compute several WM metrics (Fig1 b‐c). We computed the voxel‐wise Mahalanobis distance (D2) in WM between APOE4‐3 individuals and a reference group (APOE3‐3) (Fig1). D2 is a multivariate measure that combines several MRI metrics, accounting for their covariance, and yielding a score indicative of the degree of abnormality at each WM voxel (Fig2). Associations between WM D2 and cognitive performance were then investigated (Fig3). Independent component analysis (ICA) was performed on spatial dimensions and linear regression analyses were conducted between D2 in ICA components and scores on items of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). We then extracted the contribution of each MRI feature to D2 in the regions where significant associations were found.ResultA significant negative association (R = ‐0.36, p = 0.014) was found between D2 in a component corresponding to the splenium of the corpus callosum (CC) and scores on RBANS‐immediate memory (Fig3), indicating a link between a greater degree of WM abnormality and poorer performance. Proton density (MPM_PD) and longitudinal relaxation rate (MPM_R1), potentially indicative of WM loss, contributed most to D2 in this region.ConclusionOur findings suggest that microstructural alterations in the posterior part of the CC may play a role in memory deficit in older adults who are at greater risk of developing AD. This is in line with other studies that showed a link between CC degeneration and memory impairments in early AD stages.1 1. Qiu et al. (2016). Inter‐hemispheric dysconnectivity in AD and aMCI. Sci.Rep.