Apolipoprotein E (APOE) ε4 moderates the relationship between c-reactive protein, cognitive functioning, and white matter integrity.

Elevated serum C-reactive protein (CRP) and possessing an APOE e4 allele are two of the most prominent risk factors for cognitive and neurological dysfunction in older adults, but little is known about the unique or cumulative effects of these risk factors in young-to-middle aged adults. To further characterize these potential relationships, measures of cognition and microstructural white matter integrity were examined using data from a sample of 329 post-9/11 war veterans that was collected as part of a comprehensive evaluation that included assessment of neuropsychological functioning, MRI scanning, psychiatric diagnoses, health screening, markers of inflammation, and APOE genotypes. Hierarchical linear regression analyses revealed the CRP and APOE e4 interaction was associated with global cognition (β = -.888), executive functioning (β = -.804), and global fractional anisotropy (β = -.652); such that elevated CRP was associated with worse cognition and white matter integrity in APOE e4 carriers. Diffusion tensor imaging (DTI) was used to determine if CRP x APOE e4 presence was associated with regionally specific fractional anisotropy in white matter tracts. Tract-Based Spatial Statistics revealed CRP x APOE e4 presence was associated with fractional anisotropy in the corpus callosum, right superior longitudinal fasciculus, right posterior corona radiata, as well as the bilateral anterior and superior corona radiatas. This suggests that APOE e4 carriers may be uniquely vulnerable to the potentially negative impact of elevated systematic inflammation to cognition and microstructural white matter integrity.