Altered medial temporal lobe responses during visuospatial encoding in healthy APOE*4 carriers

Abstract

The apolipoprotein varepsilon4 allele (APOE*4) is a major genetic risk factor for Alzheimer's disease (AD) and has been associated with altered cortical activation as assessed by functional neuroimaging in cognitively normal younger and older carriers. We chose to evaluate medial temporal lobe (MTL) activation during encoding and recognition using a perspective-dependent (route or survey) visuospatial memory task by monitoring the blood-oxygen-level-dependent (BOLD) fMRI response in older, non-demented APOE*4 carriers (APOE*4+) and non-carriers (APOE*4-). During encoding, the APOE*4- group had greater average task-associated BOLD responses in ventral visual pathways, including the MTLs, as compared to the APOE*4+ group. Furthermore, MTL activation was greater during route encoding than survey encoding on average in APOE*4-, but not APOE*4+, subjects. During recognition, both groups performed similarly and no BOLD signal differences were found. Finally, within-group analysis revealed MTL activation during encoding was correlated with recognition performance in APOE*4-, but not APOE*4+ subjects. Reduced task-associated MTL activation that does not correlate with either visuospatial perspective or task performance suggests that MTL dysregulation occurs prior to clinical symptoms of dementia in APOE*4 carriers.

Figure 1

Cortical activation during route and survey encoding contrasted with fixation. (a) APOE*4− subjects displayed robust activation of MTLs, ventral occipital regons areas and prefrontal cortex (not shown) during both route (upper) and survey (lower) encoding. (b) APOE*4+ subjects had less overall task associated activation during encoding which statistically was limited to the fusiform gyrus during route (upper) and survey (lower) encoding. An area of deactivation (blue) in the temporal/parietal regions was evident during survey encoding. Within-group contrasts with z-threshold = 2.7 and p < 0.01 (n=7 per group).

Figure 2

Regions of greater activation in APOE*4− than APOE*4+ subjects during encoding. (a) Regions where APOE*4− subjects had greater BOLD signal during either route or survey encoding include the posterior (left) and anterior (right) MTLs and areas around the occipital-temporal-parietal junction. Between-group contrasts with z-threshold = 2.5 and p < 0.01 (n=14). (b) Average z-scores for individual subjects in the MTLroi during route (filled symbols:●,■) and survey (open symbols: ○, □) encoding. APOE*4− subjects (■, □) and APOE*4+ subjects (●, ○).

Figure 3

Route/survey activation differential in APOE*4− subjects. (a) Regions of greater activation during route than survey encoding in APOE*4− subjects include the MTLs bilaterally, the left frontal and the right parietal cortex. Within-group contrasts with z-threshold = 2.5 and p < 0.01 (n=7). (b) Average route/survey differential z-scores in individual subjects within the MTLroi. APOE*4− subjects (■) and APOE*4+ subjects (○).

Figure 4

Performance correlated activation in the MTLs during encoding. (a) Areas where there is a genotype x performance interaction in the left (p=0.01) and posterior right (p=0.08) MTLs during route encoding. Z-threshold = 2.3. (b) Average z-scores within these areas (combined) during route encoding correlate with performance in APOE*4− but not APOE*4+ subjects. APOE*4− subjects (■) and APOE*4+ subjects (○).