Liver Integrity Over the Adult Lifespan and Risk of Alzheimer’s Disease and Related Dementias

We quantified the associations of liver integrity, measured as nonalcoholic fatty liver disease (NAFLD) and aminotransferase levels, with incident dementia in the Atherosclerosis Risk in Communities Study. Further, we investigated associations of NAFLD with plasma and cerebral magnetic resonance imaging (MRI) biomarkers of Alzheimer’s disease (AD) and vascular neuropathology.The study population included 9,283 participants with NAFLD assessment and 11,703 with aminotransferases measured in midlife (1990-92, mean age 57), and 5,138 with NAFLD assessment and 5,115 with aminotransferases measured in late-life (2011-13, mean age 75). Additionally, a subpopulation (N=1,706) underwent brain MRI measurements at up to two different visits, in 2011-13 and 2016-19; and plasma biomarkers of neuropathology were measured up to three times in 1993-95, 2011-13, and 2016-19. Cox regression models were used to estimate hazard ratios for incident dementia ascertained through 2019. Weighted multivariate linear regression was performed for cross-temporal associations between midlife NAFLD and change in plasma and brain MRI biomarkers of neuropathology. The primary models adjusted for demographics, Apolipoprotein E, alcohol use, and kidney function.Midlife low, intermediate, and high risk liver fibrosis vs. no NAFLD was associated with a 1.44, 1.39, and 2.03-fold increased dementia risk, respectively. Late-life low alanine aminotransferase was associated with a 1.98-fold higher dementia risk. Midlife NAFLD vs. no NAFLD was associated with greater late-life white matter hyperintensity volume (difference per standard deviation [SD], 0.19 [0.06, 0.31]) and faster late-life increase over 5 years (difference in annual change, 0.28SD [0.05, 0.51]). Midlife NAFLD vs. no NAFLD was also associated with AD biomarkers in midlife (lower amyloid-β42:40, -0.21SD [-0.39, -0.04], measured in 1993-95) and late-life (lower amyloid-β42:40, -0.13SD [-0.23, -0.03], and smaller cortical thickness specific to AD, -0.16SD [-0.28, -0.05], measured in 2011-13). Neurofilament light was lower in individuals with midlife NAFLD, but increased faster from midlife to late-life.Our findings highlight the increased risk of dementia, and the presence of AD and accumulating vascular pathology, in individuals with high-prevalent liver disease. These findings reveal potential pathways linking liver function to dementia and underscore the need for greater attention to the role of liver health in promoting brain health.