Sex-specific relationship between non-alcoholic fatty liver disease and amyloid-β in cognitively unimpaired individuals

Background: Non-alcoholic fatty liver disease (NAFLD) is known to be associated with a high risk of clinically diagnosed Alzheimer’s disease (AD). Additionally, the prevalence of NAFLD and AD is higher in elderly females than in males. However, a sex-specific association between NAFLD and amyloid-beta (Aβ) deposition remains unclear. Therefore, we investigated the sex-specific relationship between NAFLD and Aβ deposition in a large-sized cohort of cognitively unimpaired (CU) individuals. Methods: We enrolled 673 (410 [60.9%] females and 263 [39.1%] males) CU individuals aged ≥45 years who underwent Aβ positron emission tomography (PET). The presence of NAFLD, assessed using the hepatic steatosis index, and the severity of NAFLD, assessed using the Fibrosis-4 index, were considered predictors. Aβ deposition on PET was considered as an outcome. Results: Females had a higher frequency of NAFLD than males (48 and 23.2%, p < 0.001). Among females, the presence of NAFLD (β = 0.216, p < 0.001) was predictive of increased Aβ deposition, whereas among males, the presence of NAFLD (β = 0.191, p = 0.064) was not associated with Aβ deposition. Among females, the presence of NAFLD with low (β = 0.254, p = 0.039), intermediate (β = 0.201, p = 0.006), and high fibrosis (β = 0.257, p = 0.027) was predictive of increased Aβ deposition. Aβ deposition also increased as the severity of NAFLD increased in females (p for trend = 0.001). Conclusion: We highlight the marked influence of NAFLD and its severity on the risk of Aβ deposition in relation to sex. Furthermore, our findings suggest that sex-specific strategies regarding the management of NAFLD are necessary for the prevention of Aβ deposition.