Gastrointestinal Diseases, Genetic Risk, and Incident Dementia: A Prospective Cohort Study in 352,463 Middle-Aged Adults
Authors: Yuan Shuai , Dan Lintao , Zhang Yao , Wu Jing , Zhao Jianhui , Chen Jie , Li Xue , Kivipelto Miia , Larsson Susanna C. 
Published: November 2022

AbstractImportanceAlthough gastrointestinal disease affects gut microbiota and their metabolites associated with dementia risk, the associations between gastrointestinal diseases and the risk of incident dementia are not established.ObjectiveTo examine the associations between 14 gastrointestinal diseases and incident dementia.Design, setting, and participantsCohort study. This cohort analysis included 352,463 participants free of baseline dementia. Participants joined the UK Biobank study from 2006 to 2010 and were followed up until 2018 or 2021.ExposuresFourteen baseline gastrointestinal diseases were defined with data from inpatient, primary care, national cancer registries and self-reported data. Polygenic risk score (RPS) and apolipoprotein E (APOE) was constructed by individuals’ genetic data.Main Outcomes and MeasuresPrimary outcome was incident all-cause dementia ascertained via a inpatient, primary care, and national death registries. Secondary outcomes were risk of common subtypes of dementia, including Alzheimer’s disease and vascular dementia as well as early-onset (i.e., with the onset age < 65 years) and late-onset (≥ 65 years) dementia by diagnosis age.ResultsDuring a median follow-up of 12.4 years among 352,463 participants (mean [SD] age, 55.8 [8.1] years; 54.1% were women), 5648 incident dementia cases were diagnosed. Seven gastrointestinal diseases showed significant associations with an increased risk of dementia after controlling covariates and multiple testing. Compared to individuals without gastrointestinal diseases, the risk of dementia increased from 26% (95% confidence interval 13%-41%) for patients with intestinal diverticular disease to 121% (95% confidence interval 57%-211%) for patients with cirrhosis. The associations were different between certain gastrointestinal diseases and dementia by onset age. The associations appeared to be stronger for cirrhosis (P= 0.001), irritable bowel syndrome (P< 0.001), gastritis and duodenitis (P= 0.002), gastroesophageal reflux disease (P< 0.001), and peptic ulcer (P= 0.030) with early-onset dementia. There were no multiplicative interactions for PRS orAPOE(P> 0.05).Conclusions and relevanceThis study found associations of several gastrointestinal diseases with an increased risk of incident dementia, especially early-onset dementia. Our findings imply the great importance of dementia prevention among patients with gastrointestinal diseases.Key PointsQuestionAre the gastrointestinal diseases associated with risk of incident dementia?FindingsThis large-scaled prospective cohort study including 352,463 participants found that seven gastrointestinal diseases were associated with an increased risk of dementia. The associations of cirrhosis, irritable bowel syndrome, gastritis and duodenitis, gastroesophageal reflux disease, and peptic ulcer appeared to be more strongly associated with early-onset dementia compared to late-onset dementia.MeaningSeven gastrointestinal diseases are associated with an increased risk of incident dementia and appeared to be stronger for early-onset dementia compared to late-onset dementia.