Association between thiopurine medication exposure and Alzheimer's disease among a cohort of patients with inflammatory bowel disease

Abstract

IntroductionRas-related C3 botulinum toxin substrate 1 (Rac1), a member of the Rho-GTPase family of proteins, could be an Alzheimer's disease (AD) triggering co-factor due to its effect on both amyloid precursor protein (APP) and tau. Thiopurine medications, such as azathioprine and mercaptopurine, are immunosuppressants that suppress Rac1 activation. We hypothesize that due to their ability to suppress Rac1, thiopurines are associated with a lower risk of AD.MethodsTo explore the relationship between thiopurines and incident AD diagnosis, we conducted a national retrospective cohort study among U.S. Veterans with inflammatory bowel disease (IBD), including Crohn's disease (CD) or ulcerative colitis (UC), as well as a non-IBD control. We created propensity score-matched cohorts and estimated the hazard ratio via the time-dependent Cox proportional hazards model.ResultsThe study sample size was 66,312 patients and consisted of 24,057 IBD patients (4354 thiopurine exposed and 19,703 unexposed) and 42,255 patients without IBD or thiopurine exposure. Patients exposed to thiopurines have the lowest rate of AD, and our results demonstrate for each additional year of thiopurine exposure risk of AD is reduced by 8.3%% (adjusted HR = 0.917; 95% CI = [0.851–0.989]).DiscussionOur results support the preclinical findings implicating Rac1 in the AD disease process. A national cohort study demonstrated that Rac1 is associated with the AD process consistent with the preclinical evidence. Further exploration and evaluation of Rac1 inhibition are needed.

The Risk of Developing Alzheimer’s Disease and Parkinson’s Disease in Patients with Inflammatory Bowel Disease: A Meta-Analysis

“…Another 59 reports out of 67 were excluded from the analysis because they did not contain data on the association between IBD and AD or IBD and neurodegenerative diseases, including AD and PD, or they did not provide data on a control group, or because of article type (they were comments, case-reports, reviews, meta-analyses). Finally, 8 articles were included in this meta-analysis [30][31][32][33][34][35][36][37].…”

“…Microbiota is able to influence the activation of peripheral immune cells and cytokine profile, which affect systemic and CNS inflammation and injury [8,9,16,40]. As demonstrated by Park et al and Sutton et al, there was a lower risk of developing AD or PD in IBD patients who were under anti-inflammatory or immunomodulatory treatment [33,34].…”

Small GTPases of the Ras and Rho Families Switch on/off Signaling Pathways in Neurodegenerative Diseases

“…The advantage of this treatment would be that ibuprofen is already available for use in humans, so it would be able to skip some steps of clinical trials. Furthermore, thiopurine, an active substance for inflammatory bowel disease that suppress Rac1 activation, resulted in a lower rate of AD in U.S. veterans with inflammatory bowel disease, and for each additional year of thiopurine exposure, the risk of AD is reduced by 8.3% [ 118 ]. The association between Rac1 and the AD neurodegeneration process opens up the possibility that Rac1 might be triggering early neurodegenerative responses at the onset of AD.…”

Inflammatory bowel disease and risk of dementia: An updated meta-analysis

“…A total of 672 records were identified by database search. After the reviewing of titles and abstracts, 17 articles were retained for full-text reading, and finally, nine studies met the review criteria, including seven cohort studies ( Sutton et al, 2019 ; Bernstein et al, 2021 ; Kim et al, 2021 ; Sun et al, 2021 ; Zhang et al, 2021 ; Zingel et al, 2021 ; Sand et al, 2022 ), one cross-sectional study ( Bähler et al, 2017 ), and one case-control study ( Zhou et al’s, 2020 ; Figure 1 ). The detailed exclusion list is provided in Supplementary Table 2 .…”