# Sex differences in diffusion-weighted imaging outcomes in autosomal dominant Alzheimer’s disease

## TL;DR

The study finds sex-specific patterns in white matter changes in early-onset Alzheimer's disease, with females showing preserved brain connections and slower decline with tau buildup.

## Contribution

The study reveals novel sex-specific differences in white matter microstructure and their relation to Alzheimer's pathology in a genetic model of the disease.

## Key findings

- Females showed higher fibre cross-section in specific white matter tracts like the anterior thalamic radiation and corpus callosum.
- Males exhibited stronger structure–function coupling in tracts like the cingulum and corticospinal tract.
- Sex moderated the relationship between pathology and white matter integrity, with females showing slower deterioration with increasing tau burden.

## Abstract

Alzheimer's disease is characterized by amyloid-β and tau protein accumulation. Growing evidence suggests that white matter degeneration contributes to disease progression. Despite Alzheimer's disease being more prevalent in women, understanding of sex differences in white matter microstructure across the Alzheimer's disease continuum remains limited. This study investigated sex-specific patterns of white matter integrity in individuals genetically predisposed to autosomal dominant Alzheimer's disease. We analysed 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 autosomal dominant Alzheimer's disease. Participants underwent diffusion-weighted imaging, amyloid and tau positron emission tomography and cognitive assessment. Using fixel-based analysis, we examined fibre density, fibre-bundle cross-section and combined fibre 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 fibre 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 autosomal dominant Alzheimer's disease, with females showing preserved fibre 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 Alzheimer's disease and suggest the potential utility of considering sex differences in the development of personalized interventions and clinical trials for persons with Alzheimer's disease.

Giudicessi et al. report that females with inherited early-onset Alzheimer's disease carrying the presenilin-1 mutation show preserved connections between brain regions and slower decline as tau protein accumulates, whereas males show stronger dependence on these connections to support memory. These patterns suggest complementary sex-specific protective mechanisms in Alzheimer's disease.

Graphical Abstract