APOE-ε4 selectively modulates posteromedial cortex activity during scene perception and short-term memory in young healthy adults

Abstract

Apolipoprotein E (APOE) ε4 is a major genetic risk factor for Alzheimer’s disease (AD), yet the mechanisms by which APOE-ε4 influences early-life brain function, and hence, in turn, risk for later-life AD, are poorly understood. Here, we report a novel, and selective, pattern of functional brain activity alteration in healthy young adult human APOE-ε4 carriers. Our findings suggest that APOE-ε4 may influence vulnerability to poorer later life cognitive health via its effect on posteromedial cortex (PMC), a hub region within a brain network involved in spatial processing, and necessary for episodic memory. In two neuroimaging tasks, APOE-ε4 carriers showed an inability to effectively modulate PMC during scene, but not face and object, working memory and perception. This striking pattern overlaps both functionally and topographically, with the earliest cognitive deficits seen in clinical AD, as well as reported alterations in the default network in amyloid-positive individuals at increased risk of AD.

Functional brain network centrality is related to APOE genotype in cognitively normal elderly

“…Our results are partly concordant with recent findings that APOE‐ε4 carriers show different brain activity during scene perception (Shine, Hodgetts, Postans, Lawrence, & Graham, 2015), and anatomically match previously reported cases of AD‐related visuoperceptual deficits (Chan et al., 2015) and studies of posterior cortical atrophy (Crutch et al., 2012; Migliaccio et al., 2012). …”

Neurochemical correlates of scene processing in the precuneus/posterior cingulate cortex: A multimodal fMRI and 1H‐MRS study

“…(d) the yellow/orange regions show the whole brain fMRI results, displaying significant clusters for the contrast of scenes > faces + objects ( n = 35 participants, Z > 3.1, p < 0.05). The blue region shows the location of the a priori PCu/PCC ROI (from Shine et al, ), which overlaps with the PCu/PCC fMRI cluster. (e) BOLD percent signal change extracted from the a priori PCu/PCC ROI for the contrast scenes >faces + objects.…”

“…Trial start times, relative to scan onset, were obtained from each participant's E‐prime output file. As in previous studies, only correct trials were included in the GLMs (Hodgetts et al, ; Shine et al, ). A parameter estimate image was created for each category relative to the size baseline condition (i.e., scenes > size, faces > size and objects > size), and for the planned contrast of scenes relative to the other main stimulus categories (scenes > faces + objects).…”

“…The BOLD percent signal change in the PCu/PCC ROI for each contrast of scenes, faces and objects relative to size, and for scenes > faces + objects was extracted using the Featquery tool in FSL. The ROI chosen to sample PCu/PCC was a binarized mask of scene‐related activity taken from Shine et al (), which used the same fMRI paradigm, but in a different sample of individuals (peak voxel x = 16, y = −46, z = 30 in MNI co‐ordinates, cluster size 273 voxels; see Figure d). A Neurosynth (Yarkoni, Poldrack, Nichols, Van Essen, & Wager, ) meta‐analysis (http://neurosynth.org/; Database status 507,891 activations reported in 14,371 studies; 1,335 terms), revealed that the top three associations with meta‐analysis maps for the peak voxel were with the terms “autobiographical” ( z ‐score = 5.66); “default network” ( z = 4.98); and “precuneus” ( z = 4.9), confirming its location within the posteromedial network.…”

“…One avenue that remains substantially unexplored is the neuro‐biochemical factors underpinning PCu/PCC activity during complex scene cognition. Given the importance of this core brain hub in healthy brain function, as well as in disease (e.g., activity alterations in Alzheimer's disease and psychiatric disorders such as schizophrenia (Leech & Sharp, ) and in genetic risk of Alzheimer's disease (Shine, Hodgetts, Postans, Lawrence, & Graham, )), improved understanding of the biochemical mechanisms underpinning the PCu/PCC fMRI response could provide useful insight into the physiological basis of its activity, which could in turn provide insight into factors underpinning activity alterations in disease and disease risk (Duncan, Wiebking, Munoz‐Torres, & Northoff, ).…”