Unraveling sex differences in Alzheimer's disease and related endophenotypes with brain proteomes

Sex differences exist in Alzheimer's disease (AD), but the underlying mechanisms remain unclear.

We examined brain proteomes profiled from the dorsolateral prefrontal cortex of 770 donors (66.2% female).

Proteome-wide differential expression analysis in males and females jointly identified many significant proteins for AD dementia (n = 1228), amyloid beta (n = 1183), tangles (n = 1309), and global cognitive trajectory (n = 2325) at a false discovery rate of <0.05. Sex-stratified analyses also identified many proteins associated with AD or its endophenotypes. Finally, we found 10 proteins with significant sex-by-trait interactions, including one in AD clinical diagnosis (MARCKS), seven in cognitive trajectories (TOGARAM1, PLCD3, SLC22A5, MTFR1L, DCUN1D5, S100A12, and TRIM46), and two in cerebral pathologies (PANK4 and SOS1).

The 10 proteins with sex interaction in AD cover a range of functions likely relevant for AD pathogenesis, including estrogen response, inflammation, and mitochondrial biology, and their specific roles in AD ought to be studied. Future work should test their potential as sex-specific AD biomarkers.

At the phenotypic level, we found sex differences in baseline cognitive performance, cognitive trajectories, and AD hallmark pathologies. Proteome-wide differential expression analyses identified many brain proteins associated with AD and its endophenotypes in either sex alone or when considered together. We found 10 brain proteins with significant sex interactions in AD and its endophenotypes, which could be investigated as potential sex-specific biomarkers of AD.