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.

Keywords: APOE; Aging; Alzheimer’s disease; Amyloid; Atrophy; Biomarker; Cognitive decline; Memory; Neuroimaging.

Fig. 1

Amyloid beta (Aβ) accumulation dependent on APOE genotype and memory decline. a Aβ accumulation pattern in participants with signs of memory decline comparing ɛ4 carriers and non-carriers. Statistical threshold was set to p_unc < 0.001 and a k > 100 voxels cluster extent. Color range displays T-values from 1 (red) to 5 (yellow) showing all regions that were significant at a threshold of p_unc < 0.05 and a k > 100 voxels cluster extent. b Visualization of the interaction of APOE genotype and signs of memory decline (memory decline = 1) on region-of-interest (ROI)-based mean intensities of annual Aβ change rates in pre- and post-central areas, and the superior frontal gyrus

Fig. 2

Gray matter (GM) atrophy dependent on APOE genotype and memory decline. a Gray matter (GM) atrophy pattern over time in participants with memory decline comparing ɛ4 carriers to non-carriers. Statistical threshold was set to p_unc < 0.001 and a k > 100 voxels cluster extent. Color range displays T-values from 1 (red) to 5 (yellow) showing all regions that were significant at a threshold of p_unc < 0.05 and a k > 100 voxels cluster extent. b Visualization of the interaction of APOE genotype and signs of memory decline (memory decline = 1) on region-of-interest (ROI)-based mean intensities of annual GM change rates in occipital areas

Fig. 3

Multimodal association of amyloid beta (Aβ) accumulation and gray matter (GM) atrophy. Scatterplot of the association between Aβ annual change and gray matter (GM) change for the region-of-interests (ROIs) based on the significant areas surrounding the precentral gyrus and the fusiform/occipital cortex extracted from the voxel-wise analysis of the three-way interaction of GM atrophy, APOE genotype, and memory decline on Aβ accumulation. Both scatterplots visualize that more GM atrophy is related to higher Aβ accumulation