APOE ɛ4 exacerbates age-dependent deficits in cortical microstructure
Authors: Mak Elijah , Dounavi Maria-Eleni , Operto Grégory , Ziukelis Elina T , Jones Peter Simon , Low Audrey , Swann Peter , Newton Coco , Muniz Terrera Graciela , Malhotra Paresh , Koychev Ivan , Falcon Carles , Mackay Clare , Lawlor Brian , Naci Lorina , Wells Katie , Ritchie Craig , Ritchie Karen , Su Li , Gispert Juan Domingo , O’Brien John T ,   PREVENT-Dementia and ALFA studies, Bridgeman Katie , Chouliaras Leonidas , Coleman Siobhan , Darwin Hannah , Driscoll David , Dounavi Maria-Elena , Dudas Robert , Gregory Sarah , Koychev Ivan , Lawlor Brian , Low Audrey , Mak Elijah , Mackay Clare , Malhotra Paresh , Manson Jean , Muniz-Terrera Graciela , Naci Lorina , O’Brien T John , Oakley Richard , Raymont Vanessa , Ritchie Craig , Ritchie Karen , Stewart William , Su Li , Swann Peter , Thayanandan Tony , Williams B Guy , Aguilar Ricardo A , Gorriti Annabella B , Serrat Anna B , Cacciaglia Raffaele , Gispert Lidia C , Martinez Alba C , Milan Marta D , Gomez Carmen D , Iglesias Ruth D , Karine Marie E F , Julian Sherezade F , Serra Patricia G , Gispert Juan D , Escalante Armand G , Rivera Oriol G , Penas Laura H , Rodriguez Gema H , Ninou Jordi H , Gamez Laura I , Knezevic Iva , Alvarez Paula M , Diaz Tania M , Gil Carolina M , Palacios Eva , Pascual Maria , Ballester Albina P , Mendez Sandra P , Radoi Irina A , Fernandez Blanca R , Freixedes Laura R , Vila Aleix S , Benavides Gonzalo A Sanchez , Mahnaz Mahnaz S , Harster Lluis S , Prat Anna S , Stankeviciute Laura S , Calvet Marc S , Jaramillo Marc V , Tejedor Natalia V 
Published: February 2024

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.