APOE ε4 gene dose drives a canonical and predictable topography of amyloid deposition
Augusto J. Mendes, Cecilia Boccalini, Federica Ribaldi, Michela Pievani, Débora Peretti, Valentina Garibotto, Andrea Chincarini, Giovanni B. Frisoni,Abstract
INTRODUCTION
Apolipoprotein E ε4 (APOE ε4) carriership is associated with higher amyloid burden in Alzheimer's disease (AD), but whether it constrains the spatial predictability of amyloid deposition at the individual level remains unknown.
METHODS
We analyzed voxel‐wise amyloid positron emission tomography data from 781 amyloid‐positive individuals across two independent cohorts (Alzheimer's Disease Neuroimaging Initiative and Geneva Memory Center), spanning the full clinical continuum. Individual topographic similarity to canonical AD amyloid maps and within‐group spatial homogeneity were assessed via voxel‐wise correlations and linear regression adjusted for age, sex, and global amyloid burden.
RESULTS
APOE ε4 carriers exhibited amyloid distributions more aligned with canonical AD topographies than non‐carriers ( p < 0.001), with a clear gene‐dose effect on within‐group spatial homogeneity: Homozygotes showed the highest inter‐subject consistency, followed by heterozygotes and non‐carriers. Effects were robust across tracers, clinical stages, and cohorts.
DISCUSSION
APOE ε4 gene dose constrains the spatial predictability of amyloid accumulation, informing genotype‐stratified approaches in anti‐amyloid trials.