Sex differences in histopathological markers of cerebral amyloid angiopathy and related hemorrhage

Background: Men with cerebral amyloid angiopathy (CAA) may have an earlier onset of intracerebral hemorrhage, and a more hemorrhagic disease course compared to women. In this cohort study we investigated sex differences in histopathological markers associated with amyloid-β burden and hemorrhage in cognitively impaired individuals and patients with CAA, using neuropathological data from two autopsy databases. Methods: First, we investigated presence of parenchymal (Thal score) and vascular amyloid-β (CAA severity score) in cognitively impaired individuals from the National Alzheimer’s Coordinating Center (NACC) neuropathology database. Next, we examined sex differences in hemorrhagic ex vivo MRI-markers and local cortical iron burden, and the interaction of sex on factors associated with cortical iron burden (CAA percentage area and vessel remodelling) in patients with pathologically confirmed clinical CAA from the Massachusetts General Hospital (MGH) CAA neuropathology database. Results: In 6120 individuals from the NACC database (45% women, mean age 80y), the presence of parenchymal amyloid-β (OR [95%CI]=0.68 [0.53-0.88]) but not vascular amyloid-β was less in men compared to women. In 19 patients with definite CAA from the MGH CAA database (35% women, mean age 75y), a lower microbleed count (p<0.001), but a higher proportion of cortical superficial siderosis and a higher local cortical iron burden was found in men (p<0.001) compared to women. CAA percentage area was comparable in men and women (p=0.732). Exploratory analyses demonstrated a possible stronger negative relation between cortical CAA percentage area and cortical iron density in men compared to women (p=0.03). Conclusion: Previously observed sex differences in hemorrhage onset and progression in CAA patients are likely not due to differences in global CAA severity between men and women. Other factors, such as vascular remodelling, may contribute, but future studies are necessary to replicate our findings in larger datasets and to further investigate the underlying mechanisms behind these complex sex differences.