<i>APOE</i> ɛ4 exacerbates age-dependent deficits in cortical microstructure
Elijah Mak, Maria‐Eleni Dounavi, Grégory Operto, Elina T Ziukelis, P. Simon Jones, Audrey Low, Peter Swann, Coco Newton, Graciela Muñiz‐Terrera, Paresh Malhotra, Ivan Koychev, Carles Falcón, Clare E. Mackay, Brian Lawlor, Lorina Naçi, Katie Wells, Craig Ritchie, Karen Ritchie, Li Su, Juan Domingo Gispert, John T. O’Brien, PREVENT-Dementia and ALFA studies, Katie Bridgeman, Leonidas Chouliaras, Siobhan Coleman, Hannah Darwin, David Driscoll, Maria-Elena Dounavi, Robert B. Dudas, Sarah Gregory, Ivan Koychev, Brian Lawlor, Audrey Low, Elijah Mak, Clare E. Mackay, Paresh Malhotra, Jean Manson, Graciela Muñiz‐Terrera, Lorina Naçi, Terence J. O’Brien, Richard T. Oakley, Vanessa Raymont, Craig Ritchie, Karen Ritchie, William Stewart, Li Su, Peter Swann, Tony Thayanandan, B Guy Williams, Ricardo A Aguilar, Annabella B Gorriti, Anna Brugulat Serrat, Raffaele Cacciaglia, Lidia C Gispert, Alba C Martinez, Marta del Campo, Carmen D Gomez, Ruth D Iglesias, Marie E F Karine, Sherezade F Julian, P Serra, Juan Domingo Gispert, Armand González Escalante, Oriol G Rivera, Laura H Penas, Gema H Rodriguez, Jordi H Ninou, Laura I Gamez, Iva Knezevic, Paula M Alvarez, Tania M Diaz, Carolina M Gil, Eva Palacios, María Pascual, A Ballester, Sandra P Mendez, Irina A Radoi, Blanca R Fernandez, Laura Ros Freixedes, Aleix S Vila, Gonzalo A Sanchez Benavides, Mahnaz S Mahnaz, Lluis S Harster, Anna S Prat, Laura Stankeviciute, Marc Suárez Calvet, Marc V Jaramillo, N. Tejedor
Abstract
The apolipoprotein E ɛ4 allele is the primary genetic risk factor for the sporadic type of Alzheimer's disease. However, the mechanisms by which apolipoprotein E ɛ4 are associated with neurodegeneration are still poorly understood. We applied the Neurite Orientation Dispersion Model to characterize the effects of apolipoprotein ɛ4 and its interactions with age and education on cortical microstructure in cognitively normal individuals. Data from 1954 participants were included from the PREVENT-Dementia and ALFA (ALzheimer and FAmilies) studies (mean age = 57, 1197 non-carriers and 757 apolipoprotein E ɛ4 carriers). Structural MRI datasets were processed with FreeSurfer v7.2. The Microstructure Diffusion Toolbox was used to derive Orientation Dispersion Index maps from diffusion MRI datasets. Primary analyses were focused on (i) the main effects of apolipoprotein E ɛ4, and (ii) the interactions of apolipoprotein E ɛ4 with age and education on lobar and vertex-wise Orientation Dispersion Index and implemented using Permutation Analysis of Linear Models. There were apolipoprotein E ɛ4 × age interactions in the temporo-parietal and frontal lobes, indicating steeper age-dependent Orientation Dispersion Index changes in apolipoprotein E ɛ4 carriers. Steeper age-related Orientation Dispersion Index declines were observed among apolipoprotein E ɛ4 carriers with lower years of education. We demonstrated that apolipoprotein E ɛ4 worsened age-related Orientation Dispersion Index decreases in brain regions typically associated with atrophy patterns of Alzheimer's disease. This finding also suggests that apolipoprotein E ɛ4 may hasten the onset age of dementia by accelerating age-dependent reductions in cortical Orientation Dispersion Index.