Impairment of the locus coeruleus‐transentorhinal cortex pathway in persons at risk of Alzheimer’s disease

Abstract

AbstractBackgroundRecent studies reported microstructural alterations in the locus coeruleus ‐ transentorhinal cortex (LC‐TEC) pathway in patients with Alzheimer’s disease (AD) but data in subjects at risk of AD (i.e., cognitively intact APOEe4 carriers) are missing. In this study, we apply in‐vivo diffusion weighted images (DWI) to study the effect of APOEe4 on the LC‐TEC pathway in cognitively unimpaired subjects.MethodForty‐five participants (14 APOEe4 carriers: age = 68±7 years, 45% females, MMSE score = 29±0.9; 31 non‐carriers: age = 68±6 years, 57% females, MMSE score = 30±0.6) underwent multimodal 3T MRI and multidomain neuropsychological exams. DWI were corrected for distortions with topup and eddy tools (part of FMRIB’s Software Library – FSL). Microstructural measures as fractional anisotropy (FA), mean (MD), axial (AxD), and radial (RD) diffusivities maps were estimated using the FMRIB’s Diffusion Toolbox (part of FSL) after the exclusion of cerebrospinal fluid voxels. Microstructural integrity of LC‐TEC was assessed using a thresholded probabilistic atlas non‐linearly warped on native maps with FNIRT (part of FSL). A Bonferroni multivariate generalized linear model, corrected for age and sex, was conducted to compare the diffusivity indexes between APOEe4 carriers and non‐carriers. Association with memory functioning (immediate and delayed recall) was also tested using Spearman’s rank correlations test.ResultAPOEe4 carriers and non‐carriers were comparable for cognitive performance (p>.246). Compared to non‐carriers, APOEe4 carriers showed lower FA (p = 0.048) and higher RD (p = 0.036) in the left LC‐TEC. In APOEe4 carriers, left RD negatively correlated with both immediate (rho = ‐0.808, p<0.001) and delayed (rho = ‐0.673, p = 0.025) memory recall.ConclusionMicrostructural alterations of the LC‐TEC pathway are detectable in subjects at‐risk for AD and correlate with lower memory performance. These preliminary results support the view that LC‐TEC impairment may play a role in AD pathophysiology since its early stages.