Abstract P501: Midlife and Late-Life Non-Alcoholic Fatty Liver Disease and Incident Dementia: The Atherosclerosis Risk in Communities (ARIC) Study

Introduction: Associations of nonalcoholic fatty liver disease (NAFLD) with dementia are controversial. The full spectrum of NAFLD from simple steatosis to fibrosis has been less investigated. Hypothesis: The severity of NAFLD, especially with the stage of liver fibrosis, is associated with dementia. Methods: The associations between midlife (1990-92, N=9283, mean age 57, female 55%) and late-life (2011-13, N=5138, mean age 75, female 58%) NAFLD and all cause dementia were quantified by Cox regression. NAFLD was characterized using the fatty liver index and liver fibrosis assessment model (FIB-4). Dementia was adjudicated and ascertained through Dec. 31, 2019 from neuropsychological assessments, annual participant or informant contact, and medical record surveillance. We used Cox models with adjustment for demographics, APOE ε4, alcohol, and kidney function. Additional adjustments were made for metabolic factors to explore the independent contribution of NAFLD to dementia. Results: During a median follow-up of 24.5 years after midlife NAFLD assessment, 1854 participants developed dementia. During a median of 6.3 years in late-life, there were 893 dementia cases. A graded increase in dementia risk across the spectrum of NAFLD was observed at midlife (p-trend <0.001), but not at older age ( Figure ). In fact, NAFLD in late-life tended to be protective against dementia. After adjusting for the metabolic factors, the associations remained statistically significant in some categories. Conclusions: Remodeling of hepatic architecture and dysregulation in hepatocellular function in NAFLD at midlife plausibly induce peripheral promoters of neurodegeneration and may expose a large segment of the population to increased risk of dementia. The inverse association of NAFLD with dementia at late-life requires further investigation, possibly reflecting the depletion of susceptibles, the reversibility of NAFLD due to weight loss, and the lack of accuracy in identifying NAFLD using clinical prediction models at older age.