Sex modulates the apolipoprotein E ε4 effect on white matter and cortical functional connectivity in individuals with amnestic mild cognitive impairment

Recent studies from the Alzheimer's Disease Neuroimaging Initiative show that, in the USA, 75% of patients with Alzheimer's disease are female. To date, there have rarely been any attempts to analyze data by sex or gender, which limits the potential for discovering the effects of sex or gender on disease. Little evidence is available regarding the effect of gender and apolipoprotein E (APOE) ε4 on white matter (WM) connection from the functional perspective due to the lack of appropriate techniques for detecting blood-oxygen-level-dependent signals in WM.We took advantage of a new framework known as functional tensor imaging to investigate the effect of sex and APOEε4 on WM cortical functional connectivity throughout the brain.In a group of female patients with amnestic mild cognitive impairment, we found a significantly reduced functional connectivity in the left posterior limb of the internal capsule, left superior fronto-occipital fasciculus, bilateral temporopolar area and right somatosensory association cortex in APOEε4 carriers in contrast to non-carriers. We also found a significant APOEε4 by sex interaction effect on the right somatosensory association cortex, left temporopolar area and left superior temporal gyrus. The clinical Montreal Cognitive Assessment score was significantly negatively associated with the right somatosensory association cortex with APOEε4 by sex interaction in males.These results indicate that increased APOE-related risk in women may be associated with decreased activity in both gray matter and WM in patients with amnestic mild cognitive impairment compared with men. The finding suggests accounting for sex differences in neuroimaging biomarkers, diagnostics and treatment strategy.