Altered brain white matter integrity in healthy carriers of the APOE ε4 allele

Background: Previous research has shown that polymorphisms of apolipoprotein E (APOE) represent genetic risk factors for dementia and for cognitive impairment in the elderly. The neural mechanisms by which these genetic variations influence behavioral performance or clinical severity are not well understood. Methods: The authors used diffusion tensor imaging to investigate ultrastructural properties in brain white matter to detect pathologic processes that modify tissue integrity. Sixty participants were included in the study of which 30 were homozygous for the APOE ε3 allele, 10 were homozygous for the APOE ε4 allele, and 20 had the APOE ε34 allele combination. All individuals were non-demented, and the groups were matched on demographic variables and cognitive performance. Results: The results showed a decline in fractional anisotropy, a marker for white matter integrity, in the posterior corpus callosum of ε4 carriers compared to non-carriers. Additional sites of altered white matter integrity included the medial temporal lobe. Conclusions: Although the mechanism underlying vulnerability of white matter tracts in APOE ε4 carriers is still unknown, these findings suggest that increased genetic risk for developing Alzheimer disease is associated with changes in microscopic white matter integrity well before the onset of dementia.