Risk of Neurodegenerative Diseases in Patients with Inflammatory Bowel Disease: A Nationwide Population-based Cohort Study

Abstract

Background and Aims Although recent studies have reported that inflammatory bowel disease (IBD) is associated with the development of neurodegenerative diseases via chronic intestinal inflammation and the gut-brain axis, there is insufficient evidence supporting this notion. The aim of this study was to determine the risk of neurodegenerative diseases including Parkinson’s disease (PD) and Alzheimer’s disease (AD) in patients with IBD. Methods Using the National Health Insurance Service data for the entire Korean population, we identified patients with IBD and controls from 2009 to 2011 and followed them up until 2017. We selected the controls in a 1:4 ratio based on age and sex for comparison with cases. Results Of 24,830 IBD patients and 99,320 non-IBD controls, 98 IBD patients and 256 controls developed PD, while 644 IBD patients and 2,303 controls developed AD. The overall neurodegenerative disease risk was higher in IBD patients [PD: adjusted hazard ratio (HR), 1.56; 95% confidence interval (CI), 1.24-1.97; AD: adjusted HR, 1.14; 95% CI, 1.05-1.25). Younger IBD patients aged 40-65 years had a higher risk of PD compared to controls (adjusted HR, 2.34; 1.63-3.35)]. In contrast, patients aged ≥65 years had an increased risk of AD compared to controls (adjusted HR, 1.14; 1.04-1.25). In a nested case-control study of the IBD cohort, patients aged ≥65 years and the female sex were risk factors for AD, while living in an urban area was protective against AD. Conclusions The risk of neurodegenerative diseases was higher in IBD patients than in the non-IBD population.

Mechanistic Insights Into Gut Microbiome Dysbiosis-Mediated Neuroimmune Dysregulation and Protein Misfolding and Clearance in the Pathogenesis of Chronic Neurodegenerative Disorders

“…Commonalities also exist between IBD incidence and increased risk of AD. A recent Korean cohort study identified that IBD patients ≥65 years suffer an increased risk of AD compared to controls (Kim et al, 2021). These findings further supported a Taiwanese cohort study suggesting the overall incidence of AD dementia is significantly elevated among patients with IBD (Zhang et al, 2021).…”

“…Emerging studies suggest that the enteric microbiome -neuroimmune system interaction could contribute to a novel etiopathogenesis of neurodegenerative disorders. Of the GI-associated conditions commonly associated with an increased risk of neurodegenerative disease, IBS (Liu et al, 2021) and IBD are the most relevant; however, this section will focus on IBD (Kim et al, 2021). The genetic and pathophysiological overlap between IBD and neurodegenerative diseases converges on shared mechanisms, representing early therapy targets.…”

“…Recent epidemiological evidence suggests that an increased incidence of IBD is associated with a 20-90% higher risk of PD (Lee et al, 2021a). Furthermore, younger IBD patients aged 40-65 years are at greater risk of developing PD (Kim et al, 2021); however, individuals already with PD are not at risk of developing IBD (Lee et al, 2021a). If chronic gut inflammation can trigger the onset of PD, perhaps early intervention strategies could prevent or slow the downstream pathology.…”

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

“…At the stage of reviewing this paper, another report from the observational study was published, providing further evidence that the incidence of such neurodegenerative diseases as AD and PD is higher in IBD patients than in the non-IBD population. This study also reveals that among IBD patients, female sex is a risk factor, while living in an urban area is protective for AD development [55]. However, due to the probability of repetition of any participant between the previously published study by Park et al [33] assessing the Korean population in 2010-2013 and the newly published study by Kim et al [55] assessing the Korean population in the period from 2009 to 2011 we decided not to include the article by Kim et al in the statistical analysis to avoid the probability of double counting the data, and instead to present the results obtained by the authors descriptively [24].…”

Enteric glia adopt an activated pro-inflammatory state in response to human and bacterial amyloids

“…Recently, the gut-brain connection has gained attention since it might represent a more accessible and faster route for diagnosing and modulating sporadic neurodegenerative disorders like Alzheimer’s disease (AD) 1 . This was fueled by epidemiologic correlation between Inflammatory Bowel Disease (IBD, i.e., recurrent GI inflammation) and dementia risk 2,3 , by parallel neuropathological manifestations in the brain and ENS of mouse models with a mutated Amyloid Precursor Protein (APP) 4,5 , and by experimental transfer of injected amyloids from the GI tract towards the brain in mice 6 .…”