Interaction of APOE, cerebral blood flow, and cortical thickness in the entorhinal cortex predicts memory decline

Abstract

The ε4 allele of the apolipoprotein E (APOE) gene, a risk factor for cognitive decline, is associated with alterations in medial temporal lobe (MTL) structure and function, yet little research has been dedicated to understanding how these alterations might interact to negatively impact cognition. To bridge this gap, the present study employed linear regression models to determine the extent to which APOE genotype (ε4+, ε4-) modifies interactive effects of baseline arterial spin labeling MRI-measured cerebral blood flow (CBF) and FreeSurfer-derived cortical thickness/volume (CT/Vo) in two MTL regions of interest (entorhinal cortex, hippocampus) on memory change in 98 older adults who were cognitively normal at baseline. Baseline entorhinal CBF was positively associated with memory change, but only among ε4 carriers with lower entorhinal CT. Similarly, baseline entorhinal CT was positively associated with memory change, but only among ε4 carriers with lower entorhinal CBF. Findings suggest that APOE ε4 carriers may experience concomitant alterations in neurovascular function and morphology in the MTL that interact to negatively affect cognition prior to the onset of overt clinical symptoms. Results also suggest the presence of distinct multimodal neural signatures in the entorhinal cortex that may signal relative risk for cognitive decline among this group, perhaps reflecting different stages of cerebrovascular compensation (early effective vs. later ineffective).

Keywords: APOE ε4; Aging; Cerebral blood flow; Cognitive decline; Cortical thickness.

Fig. 1a.. Effects of entorhinal CT, CBF, and APOE on memory change.

Three-way interaction plot with simple slopes (mean ±1SD) showing that the relationship between baseline entorhinal CBF and memory change differs significantly by APOE genotype and CT, such that lower baseline entorhinal CBF is associated with greater memory decline, but only among ε4 carriers with lower baseline entorhinal CT, with higher CT appearing relatively protective against future cognitive decline. Note: EC= Entorhinal cortex; APOE= Apolipoprotein E gene; CBF= Cerebral blood flow; CT= Cortical thickness; std= Z-score standardization; SD= standard deviation; t= t-statistic; p= p-value; **Simple slope significance at p<0.01; simple slope significance at p<0.001

Fig. 1b.. Effects of entorhinal CT, CBF, and APOE on memory change.

Three-way interaction plot with simple slopes (mean ±1SD) showing that the relationship between baseline entorhinal CT and memory change differs significantly by APOE genotype and CBF, such that lower baseline entorhinal CT is associated with greater memory decline, but only among ε4 carriers with average or lower baseline entorhinal CBF, with higher CBF appearing protective against future cognitive decline. Note: EC= Entorhinal cortex; APOE= Apolipoprotein E gene; CBF= Cerebral blood flow; CT= Cortical thickness; std= Z-score standardization; SD= standard deviation; t= t-statistic; p= p-value; **Simple slope significance at p<0.01

Fig. 1c.. Effects of entorhinal CT, CBF, and APOE on memory change.

Johnson-Neyman plots showing the intervals (depicted in blue) for which the interaction of EC CBF and CT on memory change is statically significant for ε4 carriers and non-carriers. Lower baseline entorhinal CBF is associated with greater memory decline, but only among ε4 carriers with lower (≤ 0.01SD) baseline entorhinal CT. Similarly, lower baseline CT is associated with greater cognitive decline, but only among ε4 carriers with lower (≤ 0.63SD) baseline entorhinal CBF. These findings suggest that, among ε4 carriers, the combination of lower CT and lower CBF in the entorhinal cortex is associated with future cognitive decline, whereas having higher levels of at least one of these brain measures (CBF or CT) at baseline is relatively protective against future cognitive decline. Note: EC= Entorhinal cortex; APOE= Apolipoprotein E gene; CBF= Cerebral blood flow; CT= Cortical thickness; std= Z-score standardization; n.s.= not significant

Fig. 2.. Differential effects of CBF, CT, and APOE on baseline memory and memory change.

Three-way interaction plots with simple slopes (mean ±1SD) showing that the combination of higher CBF and lower CT among ε4 carriers is associated with worse memory performance at baseline, but with greater memory stability over time. In contrast, the combination of lower CBF and lower CT at baseline among ε4 carriers is associated with greater memory decline over time. These differential findings suggest that compensatory increases in CBF at baseline among ε4 carriers with lower cortical reserve (although associated with worse baseline memory) are supportive of memory function over time, whereas relative reductions in CBF among this same group are associated with memory decline, likely reflecting an absence or breakdown of cerebrovascular compensatory mechanisms. Note: EC= Entorhinal cortex; APOE= Apolipoprotein E gene; CBF= Cerebral blood flow; CT= Cortical thickness; std= Z-score standardization; SD= standard deviation; t= t-statistic; p= p-value; n.s.= not significant; +Denotes marginal simple slope significance at p<0.10; **Denotes simple slope significance at p<0.01