Molecular links between inflammatory bowel disease and Alzheimer’s disease through immune signaling and inflammatory pathways

Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), has been increasingly associated with the progression of neurodegenerative disorders, particularly Alzheimer's disease (AD). Emerging data from population-based meta-analyses and <i>in vivo</i> experimental models demonstrate that systemic inflammation associated with IBD exacerbates disruption of the gut-brain axis (GBA). This disruption promotes the deposition of amyloid-β (Aβ) plaques, and cognitive decline. Together, these effects contribute to the progression of AD. Chronic colitis, a hallmark of IBD, accelerates Aβ pathology and induces cognitive impairment in transgenic mouse models, providing direct evidence of the detrimental effects of gut inflammation on neurodegeneration. Although numerous clinical and meta-analytical studies have examined the prevalence of AD in IBD patients, the molecular mechanisms underlying this association remain inadequately understood. In particular, the roles of immune regulation and GBA interactions require further investigation. This review aims to critically compile current evidence that elucidates the shared pathophysiological mechanisms underlying this association, such as chronic systemic inflammation, gut dysbiosis, and dysregulated immune responses. Although anti-inflammatory therapies, probiotics, and modulation of the gut microbiota have the potential to reduce the risk of AD and slow its progression, age-related gut inflammation and dysbiosis can aggravate AD pathology. This underscores the necessity for treatments that specifically target IBD-associated inflammation to limit AD progression. In addition, this review also meticulously examines how immune signaling and regulatory pathways in IBD, such as triggering receptor expression <i>via</i> myeloid cell receptor activation; NLRP3 inflammasome-driven inflammation; disrupted interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) signaling; and elevated C-reactive protein levels, contribute to increased amyloidogenesis. This paper proposes a comprehensive framework for therapeutic strategies targeting IBD-related inflammation and elucidates their potential to attenuate the progression of AD.