Dementia is a common neurodegenerative disease among older adults and includes different sub-phenotypes, such as Alzheimer’s disease (AD), vascular dementia (VD), and frontotemporal dementia. AD and VD account for 60% ~ 80 and 15% ~ 20% of all dementia cases (Wolters and Arfan Ikram, 2019; Erkkinen et al., 2018; Raz et al., 2016). According to the World Health Organization (WHO) reports in 2023, the number of people living with dementia worldwide had reached 55 million, with nearly 10 million new cases appearing annually. Dementia causes approximately 1.3 trillion US dollars in economic losses to the global economy each year (Dementia, 2025). In addition, as a non-communicable chronic disease (NCD), it is essential to investigate the potential risk factors and implement corresponding measures to prevent and control it. Some studies have found that various factors could increase the risk of dementia, such as aging (Jin et al., 2024), less activity (Raichlen et al., 2023), education (Lövdén et al., 2020), social participation (Sommerlad et al., 2023), and smoking status (Livingston et al., 2024; Durazzo et al., 2014). Furthermore, other NCDs could also increase the risk of dementia, for example, hypertension (Barnes and Yaffe, 2011), diabetes (Biessels and Despa, 2018), and obesity (Tang et al., 2021).

Chronic rhinosinusitis (CRS) is a disease with a high recurrence rate (Hamilos, 2011; Xie et al., 2023). Patients with CRS typically experience insomnia, facial pain/pressure, anosmia, and persistent (often ≥12 weeks) inflammation of the nasal or sinus mucosa (Hamilos, 2011). A mechanistic study revealed that nasal cavity inflammation could propagate through the olfactory bulb and olfactory neural system, potentially serving as a link between CRS and dementia (Harrass et al., 2021). Several studies’ results have shown that inflammation status may be associated with the risk of dementia (Zhang et al., 2022; Luo et al., 2022; Patani et al., 2023). In addition, some cross-sectional studies have shown that CRS might be a risk factor for AD or cognitive dysfunction (Jung et al., 2021; Chung et al., 2015). However, the results of a longitudinal study and a nested case–control study showed that CRS was not associated with dementia or the subtypes of dementia, such as AD and Parkinson’s disease (Wee et al., 2020). Therefore, the association between CRS and the risk of dementia warrants further attention.

Given the inconsistency of the above research results, the lack of research exploring the mediating role of inflammation in CRS and dementia, and the lack of large-scale cohort studies in this field, we conducted this cohort study to evaluate the association between CRS and the risk of dementia using the UK Biobank (UKB) and explore whether inflammatory factors mediate the association between CRS and dementia. Investigating the association among CRS, dementia, and inflammation can help understand the relationship between different organs of the body and disease processes.

We conducted this cohort study to explore the association between CRS and dementia. The results of the Cox regression model showed that CRS was significantly associated with a higher risk of AD but not associated with the risk of all-cause dementia and VD. In addition, we found that this relationship between CRS and Alzheimer’s disease could be mediated by the SII, with a mediation proportion of 0.0042. In the stratified analysis, the male participants, participants with hypertension, former smokers, participants with less than a college education, and participants with a medium PRS-AD were more susceptible to AD. The male participants and participants with hypertension were more susceptible to all-cause dementia. According to our results, CRS might be a risk factor for dementia, and inflammation caused by CRS may mediate the relationship between CRS and AD.

Previous cross-sectional studies (Jung et al., 2021; Chung et al., 2015) have reported that CRS is positively associated with dementia, which is consistent with our findings. However, our results differ from those of a previous longitudinal study (Son et al., 2024), which showed that CRS was not associated with dementia and its subtypes. Compared to this longitudinal study, our cohort was larger, had a longer follow-up period of up to 12 years, and included a broader age range. In addition, the UK Biobank primarily included participants of European ancestry, which differs from the Korean participants of Asian ancestry in terms of genetic background and body composition. In summary, compared to previous studies, our study involved a larger population, a longer follow-up period, and the use of mediation analysis to investigate the association between CRS and dementia.

The association between CRS and dementia differed in the sex subgroup analysis. Apart from the ICD-10 classification criteria, CRS can be divided into three main types: CRS with nasal polyps, CRS without nasal polyps, and allergic fungal rhinosinusitis. Among these three types, CRS with nasal polyps is considered the most severe and is more difficult to treat or control due to the high likelihood of polyp recurrence (Mullol et al., 2022). In addition, a study reported that CRS with nasal polyps has a higher prevalence in male individuals (Ramkumar et al., 2023). Overall, due to the recurrence of nasal polyps, the difficulty in treating CRS with nasal polyps, and its higher prevalence in male individuals, the association between CRS and dementia may be more easily observed in male individuals. Participants with lower education levels may be associated with lower socioeconomic status (Lai et al., 2023) or may have limited time for treatment, which may make them more prone to developing dementia.

Although the etiology of CRS and dementia is not yet fully understood, several hypotheses regarding the mechanisms of dementia have been proposed, such as the hyperphosphorylated tau protein and amyloid-β hypothesis (Ashrafian et al., 2021; Zhang et al., 2021), the oxidative stress hypothesis (Bai et al., 2022), and the inflammation hypothesis (Guerrero et al., 2021; Irwin and Vitiello, 2019). The CRS may increase the risk of Alzheimer’s disease through chronic inflammation. The blood–brain barrier could be disrupted in the progression of neurodegenerative diseases, which might make the brain susceptible to inflammation status (Sweeney et al., 2018). The sinuses are close to the brain in physical distance, and there are several kinds of opportunistic pathogens in the sinuses, which can potentially cause neuroinflammation and aggregate CRS when the body’s conditions allow (Lal et al., 2017). Neuroinflammation could affect different kinds of microglia and ultimately facilitate the progression of Alzheimer’s disease (Kwon and Koh, 2020; Leng and Edison, 2021). In addition, neutrophils may play a significant role and proliferate during CRS (Delemarre et al., 2021). Neutrophils could produce platelet-activating factors to aggregate and increase the level of platelets (Gill et al., 2015), which could increase the level of the SII. However, according to a review in 2023 (Xie et al., 2023), inflammation caused by CRS can be divided into three types, all characterized by abnormal levels of special cell cytokines. As an important type of white blood cell with the largest quantity, neutrophils may cause a cascade effect of inflammation, leading to a significant increase in cell cytokines (Megha et al., 2021). Therefore, the SII may not be the main path from CRS to dementia, and cell cytokines may play a key role, which means that the effect of cell cytokines should be explored carefully in future studies.

Apart from inflammation, other symptoms caused by CRS, such as loss of smell and infections, have also been associated with dementia. A cohort study showed that olfactory dysfunction may be a risk factor for amnestic mild cognitive impairment and AD (Roberts et al., 2016). According to previous studies, inflammation caused by CRS with nasal polyposis could contribute to olfactory dysfunction and cause the volume of the olfactory bulb to decrease (Huang et al., 2024; Shehata et al., 2018). On the other hand, CRS could cause upper respiratory infections (Volpe et al., 2023), which may, in turn, induce the appearance of inflammation and ultimately contribute to olfactory dysfunction (Shehata et al., 2018). In the brain, the entorhinal cortex is close to the olfactory system and plays a significant role in attention, conditioning, event processing, and spatial cognition (Coutureau and Di Scala, 2009), etc. In the preclinical stage of AD, specific dysfunction of the entorhinal cortex can be observed (Igarashi, 2023). This impairment might lead to hyperactivation of adjacent brain areas (such as the hippocampus and olfactory bulb), potentially resulting in hippocampus and olfactory bulb degeneration (Dan et al., 2021). In addition, reduced oxygen uptake due to nasal congestion caused by CRS may contribute to dementia (Li et al., 2018; Liu et al., 2023).

Overall, the underlying mechanism of this relationship needs further exploration. From a public health perspective, understanding this relationship could help control dementia better. From a clinical perspective, understanding this relationship could help prevent AD by reducing or eliminating inflammation status caused by CRS. In life, people should take CRS seriously and seek active treatment as soon as they are diagnosed. According to the mediation analysis results, inflammation status only accounts for a small portion of the risk from CRS to AD. Therefore, exploring the underlying relationship between CRS and dementia and identifying other mediation factors through clinical approaches is important for treating patients with CRS. In addition, investigating the relationship between CRS and dementia can help us more comprehensively understand the risks associated with CRS and motivate healthcare workers to find better ways to treat patients with CRS.

Our study has several strengths. First, it was a prospective study, which provided a fixed sequence of time from exposure to outcome. Therefore, it could offer more reliable evidence compared to cross-sectional studies. Second, compared to previous studies, we conducted a cohort study with a longer follow-up period and a larger population, and we performed three sensitivity analyses to evaluate the robustness of our results. Third, we were the first to investigate the effect of inflammation status caused by CRS on the development of dementia through mediation analysis, which provided evidence for the role of inflammation in the process of dementia. Fourth, we initially investigated the mediation role of the inflammation index in the association between CRS and AD, providing new insights into the underlying mechanisms of CRS.

However, our study also has some limitations. First, the majority of participants in the UKB were White people of European ancestry, which may limit the generalizability of our results. Second, the inflammation mediation analysis was limited to blood cell counts and derived ratios, without including subsets of inflammatory cells or cytokines produced by inflammatory cells. Third, reverse causation cannot be completely ruled out because cohort studies cannot avoid reverse causation. Fourth, due to information unavailability, we could not classify CRS into CRS with nasal polyps and CRS without nasal polyps. Since different types of CRS might have different effects on AD, we could only explore the overall effect of CRS on AD, and this might increase the gap between data research and clinical applications. Fifth, because we excluded more than 1,30,000 participants, the statistical power may be decreased and the interpretation of the results requires caution. Sixth, the mediation proportion was very small, suggesting that its actual impact may be limited. Therefore, the mechanism linking CRS and dementia requires further investigation. Finally, although our analysis was adjusted for several confounding factors, there were still some potential confounders that we could not take into consideration, such as the use of anti-inflammatory medications.

CRS may be associated with a higher risk of AD, and the association is mediated, in a very small part, by the SII. Our findings may provide some clues for research into the cause of AD.