Abstract Alzheimer's disease (AD) is characterized by amyloid-β and tau protein accumulation. Growing evidence suggests that white matter degeneration contributes to disease progression. Despite AD being more prevalent in women, understanding of sex differences in white matter microstructure across the AD continuum remains limited. This study investigated sex-specific patterns of white matter integrity in individuals genetically predisposed to autosomal dominant Alzheimer's disease (ADAD). We analyzed data from 63 individuals (30 Presenilin-1 Glutamic Acid to Alanine at codon 280 (PSEN1 E280A) mutation carriers, 33 non-carriers) from a Colombian kindred with early-onset ADAD. Participants underwent diffusion-weighted imaging, amyloid and tau positron emission tomography, and cognitive assessment. Using fixel-based analysis, we examined fiber density, fiber-bundle cross-section, and combined fiber density and cross-section across major white matter tracts. Linear regression models assessed sex differences in white matter microstructure and examined how sex moderated relations between pathological burden, white matter integrity, and cognitive performance. Females showed trends towards higher fiber cross-section than males in the anterior thalamic radiation (β=0.057, p=0.004), forceps minor of the corpus callosum (β=0.047, p=0.012), and inferior fronto-occipital fasciculus (β=0.030, p=0.015), but lower values in the cingulum (cingulate gyrus portion) (β=-0.07, p=0.031). Sex appeared to moderate the association between pathology and white matter in multiple tracts. However, these findings did not survive correction for multiple comparisons and should be interpreted as exploratory. In the right temporal superior longitudinal fasciculus, females showed relatively preserved integrity compared to males as tau burden increased (β=0.23, p=0.016), while males exhibited greater amyloid-β-associated disruption than females in the uncinate fasciculus (β=-0.14, p=0.05). Sex also moderated relations between white matter integrity and cognition, with males showing stronger structure-function coupling than females in tracts such as the cingulum (hippocampus portion), forceps major, and corticospinal tract. Our findings revealed significant sex-specific patterns of white matter microstructural alterations in ADAD, with females showing preserved fiber cross-section in key tracts and slower rates of white matter deterioration with increasing tau pathology in memory-related circuits, whereas males demonstrated advantages in structure-function coupling. These data highlight the importance of considering sex differences in understanding white matter alterations in AD and suggest the potential utility of considering sex differences in the development of personalized interventions and clinical trials for persons with AD.
Giudicessi et al. (Tue,) studied this question.