Apolipoprotein E (APOE) genotype has dissociable effects on memory and attentional-executive network function in Alzheimer's disease

Abstract

The epsilon4 allele of the apolipoprotein E (APOE) gene is the major genetic risk factor for Alzheimer's disease (AD), but limited work has suggested that APOE genotype may modulate disease phenotype. Carriers of the epsilon4 allele have been reported to have greater medial temporal lobe (MTL) pathology and poorer memory than noncarriers. Less attention has focused on whether there are domains of cognition and neuroanatomical regions more affected in noncarriers. Further, a major potential confound of prior in vivo studies is the possibility of different rates of clinical misdiagnosis for carriers vs. noncarriers. We compared phenotypic differences in cognition and topography of regional cortical atrophy of epsilon4 carriers (n = 67) vs. noncarriers (n = 24) with mild AD from the Alzheimer's Disease Neuroimaging Initiative, restricted to those with a cerebrospinal fluid (CSF) molecular profile consistent with AD. Between-group comparisons were made for psychometric tests and morphometric measures of cortical thickness and hippocampal volume. Carriers displayed significantly greater impairment on measures of memory retention, whereas noncarriers were more impaired on tests of working memory, executive control, and lexical access. Consistent with this cognitive dissociation, carriers exhibited greater MTL atrophy, whereas noncarriers had greater frontoparietal atrophy. Performance deficits in particular cognitive domains were associated with disproportionate regional brain atrophy within nodes of cortical networks thought to subserve these cognitive processes. These convergent cognitive and neuroanatomic findings in individuals with a CSF molecular profile consistent with AD support the hypothesis that APOE genotype modulates the clinical phenotype of AD through influence on specific large-scale brain networks.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Cognitive profile differences of APOE carriers versus noncarriers. Between-group comparison of psychometric performance on (A) memory and (B) nonmemory measures, presented as ADNI control-referenced z scores (Trails A/B and BNT were natural log and square root transformed, respectively). Error bars represent ±SEM; #, P = 0.06, *, P < 0.05, **, P < 0.01 for ANCOVA models.

Fig. 2.

Atrophy pattern profile differences of APOE carriers versus noncarriers. Between-group comparison of morphometric values for specific ROIs, including (B) MTL ROIs (rostral medial temporal cortex and hippocampus) and (C) isocortical ROIs (angular gyrus and superior frontal gyrus). Error bars represent ±SEM. Cortical surface inset illustrates localization of ROIs (A); #, P = 0.07, *, P < 0.05 for ANCOVA models.

Fig. 3.

Exploratory analysis across the entire cerebral cortex of regions in which mild AD ε4 carriers demonstrated thinner cortex than noncarriers (blue) and in which noncarriers demonstrated thinner cortex than carriers (red-yellow). Map is thresholded at P < 0.1 to illustrate relatively subtle effects. Bar graphs illustrate group differences in (A) superior frontal gyrus, (B) angular gyrus, and (D) MTL defined on these maps. The precentral gyrus (C) is included as a control region to illustrate similarities between groups. Error bars represent ±SEM.