Sex Moderates the Association Between Age and Myelin Water Fraction in the Cingulum and Fornix among Older Adults Without Dementia:A Preliminary Study

Abstract

AbstractBackgroundCognitive decline in normal aging and Alzheimer’s disease (AD) has been associated with changes in cerebral white matter tracts. Although women are at higher risk of developing AD, studies investigating the effect of sex on white matter integrity have been mixed. Decreased white matter integrity in limbic pathways including the fornix and cingulum have been reported in AD although underlying mechanisms and potential sex differences remain understudied. We explored sex as a moderator of the effect of age on myelin water fraction (MWF), a measure of myelin content, in older adults.MethodFifty‐two older adults without dementia (mean age = 72; 61% female) underwent neuropsychological evaluation and 3T MRI at two research sites. Multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) quantified MWF in three a priori regions of interest including the fornix, cingulum in the hippocampal formation (CGH), and cingulum in the cingulate gyrus (CGC). The California Verbal Learning Test‐Second Edition assessed learning and long‐delay free recall. Separate multiple linear regressions assessed for (1) interactions between age and sex on regional MWF and (2) associations of regional MWF and memory. All models adjusted for APOE e4 allele frequency, vascular risk, and site; the second analysis additionally adjusted for age and sex.Result(1) There was a significant ageXsex interaction for CGC MWF (p = 0.006) and fornix MWF (p = 0.016) (see Figure) but not CGH MWF (p = 0.443). Specifically, for both interactions, in women but not men, as age increased, MWF decreased. (2) Fornix MWF was associated with memory (p = 0.002), but MWF of the two cingulum regions were not (p>0.05). Results did not change when adjusting for hippocampal volume.ConclusionResults suggest that the relationship between age and myelin content of limbic fiber pathways depends on sex, with women but not men showing age‐related decreases. Additionally, and consistent with previous studies, we observed an association between fornix MWF and learning and memory. Understanding sex differences in MWF may facilitate earlier detection of AD risk for women. Longitudinal study with larger samples is needed to further clarify the role sex plays in limbic system myelin integrity and potentially inform interventions.