Inflammatory bowel disease (IBD), which comprises ulcerative colitis (UC) and Crohn disease (CD), is associated with a proinflammatory state within the intestinal mucosa. This inflammation can lead to various symptoms including diarrhea, abdominal pain, and gastrointestinal (GI) bleeding. Numerous treatments are available to inhibit inflammation via different pharmacologic mechanisms.

Treatment goals include the induction and maintenance of remission, which has several important definitions to note, especially when evaluating a patient for potential sequelae of IBD. Clinical remission is typically defined as lack of symptoms, although this does not always correlate with endoscopic (mucosal healing), histologic (no microscopic changes on biopsies), or biomarker (C-reactive protein, fecal calprotectin) remission.1 Deep remission is sometimes referred to as achieving clinical, biomarker, and mucosal healing.2

The pathophysiology underlying IBD is complex and not completely understood; however, it most likely includes at least some form of dysregulation of the body’s immune system and gut microbiome.1 There is growing evidence that similar mechanisms may also play a part in other non-GI conditions, including anxiety, depression, Parkinson disease, and dementia.1 Specifically within dementia, a proinflammatory state may lead to increased levels of oxidative stress and subsequent misfolding of neurogenic proteins along with thromboembolic events predisposing to further vascular damage.1 Alterations in the gut microbiome may also lead to changes in bacterial metabolism and dysregulation of the immune system, predisposing to pathophysiologic conditions that may contribute to dementia.1 Certain flora within the gut microbiome may be able to synthesize certain neurotransmitters that could be implicated in dementia.1 These excess neurotransmitters may have an easier path to the central nervous symbol (CNS) via intestinal mucosa, with increased permeability in a patient with IBD.  


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There is currently a paucity of data evaluating the association between IBD and dementia. Therefore, a group led by Zhang et al recently conducted a retrospective, population-based, longitudinal study evaluating the risk for dementia in patients with IBD.1 They conducted this study using a national database from Taiwan, which identified 1742 patients aged 45 years and older with IBD and compared them with 17,420 matched participants without IBD (control).

The overall incidence of dementia was found to be significantly increased in the IBD group compared with the control group (5.5% vs 1.4%; P < .001). Patients with IBD were diagnosed with dementia approximately 7 years earlier than participants without IBD (mean age 76.24±8.22 vs 83.45±6.32 years). The increased risk encompassed all subtypes of dementia evaluated, including Alzheimer dementia (1.9% vs 0.2%; P < .001) and vascular (0.7% vs 0.2%; P < .001) dementia. This increased incidence translated to a hazard ratio (HR) of developing dementia within the IBD group of 2.54 (95% CI, 1.91-3.37). Within subtypes of dementia, the HR was highest for Alzheimer dementia in the presence of IBD (HR 6.19; 95% CI, 3.31-11.57).  There were no statistically significant differences in risk for dementia between patients with UC and CD as well as men vs women.

The authors used medication type to stratify patients into mild or moderate to severe groups, although they did not provide details regarding this classification system. It was unclear which medications would place a patient into the mild vs moderate to severe group. Patients with mild disease had an adjusted hazard ratio (aHR) of 2.7 (95% CI, 1.94-3.76) compared with an aHR of 2.07 (95% CI, 1.04-4.11) for patients in the moderate to severe group. 

The authors concluded that patients with IBD are at increased risk of developing dementia, as well as developing it at a younger age, when compared with participants without IBD. Although this risk could be attributed to multiple factors, the underlying proinflammatory state observed in IBD most likely is the primary explanation. The type of medication taken for IBD also appears to play a significant role, and future studies should aim to further clarify the mechanisms as well as outcomes with specific medication classes. When evaluating these medication classes, it will be important to research the impact on both the GI tract as well as directly on the CNS. Depending on the medication itself, its own pharmacologic properties may preclude distribution into the CNS. In addition, as medications continue to improve for IBD, this may lead to increased life expectancy for patients and therefore increased dementia “risk” over time.

As mentioned earlier, the varying definitions of remission may also play a role in the risk for dementia. The impact of different types of remission on dementia risk should be carefully evaluated in the future. If patients with deep remission are shown to have less significant risk for dementia compared with other groups, it may alter a physician’s treatment algorithm.  How these types of remission influence certain nutritional factors such as vitamin B12 and folate levels is also important to consider, as this may contribute to a patient’s mental status.

This study also only included patients from Taiwan; therefore the results may not be directly applicable to patients in the United States and elsewhere. A study evaluating patients with IBD in Switzerland found no statistically significant differences in rates of dementia when compared with matched control participants.3 Similarly, this study did not include a detailed analysis of how a patient’s medications potentially contributed to or protected against dementia. For example, tumor necrosis factor (TNF)-α inhibitors are frequently used to treat IBD and have mixed data in the literature regarding the risk for dementia directly related to the medication itself. Some studies have even proposed that TNF-α inhibitors may slow cognitive decline, although most of this research is in the preclinical stage.4

A recent retrospective, case-control study conducted using a US database found that TNF-α inhibitors were associated with lower risk for Alzheimer dementia, albeit in patients with psoriasis and rheumatoid arthritis.5 The authors found an increased risk of developing Alzheimer disease in patients with multiple types of inflammatory conditions, including IBD (adjusted odds ratio [aOR] 2.46 [95% CI, 2.33-2.59]), UC (aOR 1.82 [95% CI, 1.74-1.91]), and CD (aOR 2.33 [95% CI, 2.22-2.43]), all of which were statistically significant. In patients with rheumatoid arthritis and psoriasis, the use of TNF-α inhibitors (including etanercept, adalimumab, and infliximab) was associated with decreased risks of developing Alzheimer disease. The data presented did not include any specific information on TNF-α inhibitor use in IBD and risk for dementia. The authors noted that their findings in rheumatoid arthritis were especially interesting, as etanercept and adalimumab do not cross the blood brain barrier significantly, which would indicate most of their benefits are based on reduced amounts of systemic inflammation vs direct action on the CNS.

References

1. Zhang B, Wang HE, Bai YM, et al. Inflammatory bowel disease is associated with higher dementia risk: a nationwide longitudinal study. Gut. 2021;70(1):85-91. doi:10.1136/gutjnl-2020-320789

2. Zallot C, Peyrin-Biroulet L.  Deep remission in inflammatory bowel disease: looking beyond symptoms. Curr Gastroenterol Rep. 2013;15(3):315. doi:10.1007/s11894-013-0315-7

3. Bähler C, Schoepfer AM, Vavricka SR, Brüngger B, Reich O. Chronic comorbidities associated with inflammatory bowel disease: prevalence and impact on healthcare costs in Switzerland. Eur J Gastroenterol Hepatol. 2017;29(8):916-925. doi:10.1097/MEG.0000000000000891

4. Decourt B, Lahiri DK, Sabbagh MN. Targeting tumor necrosis factor alpha for Alzheimer’s disease. Curr Alzheimer Res. 2017;14(4):412-425. doi:10.2174/1567205013666160930110551

5. Zhou M, Xu R, Kaelber DC, Gurney ME. Tumor necrosis factor (TNF) blocking agents are associated with lower risk of Alzheimer’s disease in patients with rheumatoid arthritis and psoriasis. PLoS One. 2020;15(3):e0229819. doi:10.1371/journal.pone.0229819