Voxel-wise insights into early Alzheimer’s disease pathology progression: the association with APOE and memory decline

Abstract

Longitudinal investigation of the Apolipoprotein E (APOE) genotype’s impact on Alzheimer’s disease (AD) biomarker progression, focusing on amyloid beta (Aβ) accumulation and gray matter (GM) atrophy, integrating cognitive decline and baseline levels. Longitudinal florbetapir-PET and T1-weighted MRI data from 100 cognitively normal (CN) and mild cognitive impaired (MCI) participants both with considerable global Aβ accumulation (“high Aβ accumulators”) were analyzed using a voxel-wise approach. Associations of APOE genotype and memory decline with Aβ accumulation and GM atrophy were examined separately for each neuroimaging modality, controlling for baseline Aβ levels and diagnosis. Alternatively, the effect of baseline diagnosis, while controlling for memory decline, was investigated. A multimodal analysis evaluated interactions between genotype, memory decline, and GM atrophy on Aβ accumulation. High Aβ accumulators displayed extensive Aβ pathology predominantly in the medial orbito-frontal cortex, cingulate cortex, and precuneus, along with GM atrophy in temporal, occipital, orbito-frontal, and parietal areas. ɛ4 carriers with memory decline exhibited greater Aβ accumulation and GM atrophy in selective regions compared to non-carriers with memory decline, while no genotype difference was observed in individuals without decline. No interaction effect was observed for MCI diagnosis. Regional associations between the two biomarkers were similarly dependent on genotype and memory decline. ɛ4 carriers exhibiting memory decline present an accelerated neurobiological pattern at predementia stages, supporting early ɛ4 carrier monitoring and interventions in this at-risk group. Importantly, memory decline might be more informative than MCI regarding AD pathology progression emphasizing the importance of repeated cognitive assessments.