Distinct patterns of brain activity in young carriers of the APOE-epsilon4 allele

Abstract

The APOE epsilon4 allele is a risk factor for late-life pathological changes that is also associated with anatomical and functional brain changes in middle-aged and elderly healthy subjects. We investigated structural and functional effects of the APOE polymorphism in 18 young healthy APOE epsilon4-carriers and 18 matched noncarriers (age range: 20-35 years). Brain activity was studied both at rest and during an encoding memory paradigm using blood oxygen level-dependent fMRI. Resting fMRI revealed increased "default mode network" (involving retrosplenial, medial temporal, and medial-prefrontal cortical areas) coactivation in epsilon4-carriers relative to noncarriers. The encoding task produced greater hippocampal activation in epsilon4-carriers relative to noncarriers. Neither result could be explained by differences in memory performance, brain morphology, or resting cerebral blood flow. The APOE epsilon4 allele modulates brain function decades before any clinical or neurophysiological expression of neurodegenerative processes.

Fig. 1.

Results of analysis of resting fMRI. (A) Spatial map representing the DMN for all 36 subjects. Regions belonging to this network include prefrontal, anterior and posterior cingulate, lateral parietal, and inferior/middle temporal gyri; cerebellar areas; and thalamic nuclei and extending to MTL regions. (B) DMN comparison between the 2 groups revealed increased coactivation in retrosplenial, medial-prefrontal, and MTL (head of the hippocampus and amygdala) regions of the DMN in APOE ε4-carriers relative to noncarriers. Red-to-yellow colors define increases in coactivation. R, right hemisphere; L, left hemisphere.

Fig. 2.

fMRI results for the novel vs. familiar contrast in the encoding task. (A) Mean activation for the novel vs. familiar contrast for all 36 subjects. Activation was found bilaterally in primary and secondary visual cortices as well as in regions involved in memory processes: hippocampus, temporal fusiform cortex, parahippocampal gyrus. (B) Regions of significantly increased BOLD for ε4-carriers relative to noncarriers. Activation in the right hippocampus and cerebellum was greater in the APOE ε4-carriers than in the noncarriers (P < 0.05, corrected for multiple comparisons). Red-to-yellow colors define increases in brain activation. R, right hemisphere; L, left hemisphere.