Association of laxatives use with incident dementia and modifying effect of genetic susceptibility: a population-based cohort study with propensity score matching

Jiangtao Feng, Nan Zheng, Xutong Fan, Shu Li, Yuhan Jiang, Xianfu Yi, Hongxi Yang

Constipation was associated with incidence of dementia and cognitive decline. Laxatives are the mainstay of constipation management and are commonly used among older populations for both treatment and prevention of constipation. However, the association between use of laxatives and incident dementia, and whether laxatives use may modify the effect of genetic predisposition on dementia remains unclear. We applied 1:3 propensity score matching to balance the baseline characteristics of the laxative users versus non-users and to reduce potential confounders using multi-variates adjusted Cox hazards regression models. We categorized genetic risk into three groups (low, middle, and high) through a genetic risk score of common genetic variants. Information on laxatives use was assessed at baseline and categories into four varieties, including bulk forming laxatives, softeners and emollients, osmotic laxatives, and stimulant laxatives. Of 486,994 participants, there were 14,422 laxatives users in UK Biobank. After propensity score matching, participants with use of laxatives (n = 14,422) and matched non-laxative (n = 43,266) exposed individuals were enrolled. Over follow-up to 15 years, there were 1377 participants developed dementia (539 for Alzheimer's disease, and 343 for vascular dementia). The use of laxatives had greater risk of dementia (HR, 1.72; 95% CI:1.54-1.92), Alzheimer's disease (HR, 1.36; 95% CI: 1.13-1.63), and vascular dementia (HR, 1.53; 95% CI: 1.23-1.92). Compared to non-laxative exposed participants, those with use of softeners and emollients drugs, stimulant laxatives, and osmotic laxatives were associated with 96% (HR, 1.96; 95 CI: 1.23-3.12; P = 0.005), 80% (HR, 1.80; 95% CI: 1.37-2.37; P < 0.001), and 107% (HR, 2.07; 95% CI: 1.47-2.92; P < 0.001) higher risk of developed incident dementia, respectively. In joint effect analysis, compared to participants with low/middle genetic susceptibility and non-laxatives use, the HR (95% CIs) of dementia was 4.10 (3.49-4.81) for those with high genetic susceptibility plus use of laxatives. There was an additive interaction between laxatives use and genetic susceptibility on dementia (RERI: 0.736, 95% CI: 0.127 to 1.246; AP: 0.180, 95% CI: 0.047 to 0.312). Use of laxatives was associated with higher risk of dementia and modify the effect of genetic susceptibility on dementia. Our findings suggested that attention should be paid to the relationship between laxatives use and dementia, especially in people at high genetic susceptibility.