Editors' Note: Association of Nonalcoholic Fatty Liver Disease and Fibrosis With Incident Dementia and Cognition: The Rotterdam Study

Dr. Xiao et al. investigated the association of nonalcoholic fatty liver disease (NAFLD) and fibrosis with incident dementia and cognition among participants in the Rotterdam Study, a prospective cohort study that included 3,975 patients with available fatty liver index (FLI), 4,577 patients with abdominal ultrasound, and 3,300 patients with liver stiffness assessments. NAFLD was defined as FLI ≥60 or steatosis on ultrasound and fibrosis as liver stiffness ≥8.0 kPa. Over 5 or more years of follow-up, NAFLD and liver fibrosis were not associated with an increased risk of incident dementia, and NAFLD was not associated with impaired cognitive function. Of interesting, NAFLD diagnosis was associated with a significantly decreased risk of incident dementia in the first 5 years of follow-up after FLI assessment. In response, Dr. Gupta notes the current lack of a biological model for linking NAFLD to protection from dementia, seeks evidence for weight loss–induced NAFLD regression, and wonders what phenomena might be occurring in these patients before vs after 5 years of follow-up to explain the study observations. Responding to these comments, the authors note that weight loss is the hallmark of NAFLD regressions, citing studies where regressions occurred even with slight weight reductions. They also note the interesting observation in several dementia cohorts (including theirs) of weight loss occurring in the years before dementia onset. By excluding the initial years of follow-up to address confounding by these intertwined mechanisms of weight loss and dementia, they note that the apparent beneficial effect of NAFLD disappeared. They posit that the presence of NAFLD may simply reflect the absence of weight loss rather than any true protective effect against dementia, but note the need for further studies to clarify these questions. This correspondence highlights the challenges of disentangling the complex interplay between weight loss and the natural history of NAFLD and dementia.