Disrupted white matter structural networks in healthy older adult APOE ε4 carriers - An international multicenter DTI study.

The ε4 allelic variant of the Apolipoprotein E gene (APOE ε4) is the best-established genetic risk factor for late-onset Alzheimer's disease (AD). White matter (WM) microstructural damages measured with Diffusion Tensor Imaging (DTI) represent an early sign of fiber tract disconnection in AD. We examined the impact of APOE ε4 on WM microstructure in elderly individuals from the multicenter European DTI Study on Dementia. Voxelwise statistical analysis of fractional anisotropy (FA), mean diffusivity, radial and axial diffusivity (MD, radD and axD respectively) was carried out using Tract-Based Spatial Statistics. Seventy-four healthy elderly individuals - 31 APOE ε4 carriers (APOE ε4+) and 43 APOE ε4 non-carriers (APOE ε4-) -were considered for data analysis. All the results were corrected for scanner acquisition protocols, age, gender and for multiple comparisons. APOE ε4+ and APOE ε4- subjects were comparable regarding sociodemographic features and global cognition. A significant reduction of FA and increased radD was found in the APOE ε4+ compared to the APOE ε4- in the cingulum, in the corpus callosum, in the inferior fronto-occipital and in the inferior longitudinal fasciculi, internal and external capsule. APOE ε4+, compared to APOE ε4- showed higher MD in the genu, right internal capsule, superior longitudinal fasciculus and corona radiate. Comparisons stratified by center supported the results obtained on the whole sample. These findings support previous evidence in monocentric studies indicating a modulatory role of APOE ɛ4 allele on WM microstructure in elderly individuals at risk for AD suggesting early vulnerability and/or reduced resilience of WM tracts involved in AD.

Cortical amyloid accumulation is associated with alterations of structural integrity in older people with subjective memory complaints.

We determined the effect of cortical amyloid load using 18F-florbetapir PET on cognitive performance and gray matter structural integrity derived from MRI in 318 cognitively normally performing older people with subjective memory impairment from the INSIGHT-preAD cohort using multivariate partial least squares regression. Amyloid uptake was associated with reduced gray matter structural integrity in hippocampus, entorhinal and cingulate cortex, middle temporal gyrus, prefrontal cortex, and lentiform nucleus (p < 0.01, permutation test). Higher amyloid load was associated with poorer global cognitive performance, delayed recall and attention (p < 0.05), independently of its effects on gray matter connectivity. These findings agree with the assumption of a two-stage effect of amyloid on cognition, (1) an early direct effect in the preclinical stages of Alzheimer's disease and (2) a delayed effect mediated by downstream effects of amyloid accumulation, such as gray matter connectivity decline.