4. CRS and AD—How Close Are They?
Researchers have investigated the correlation between dementia and CRS. A recent retrospective study following patients from 2006 to 2019 found that in patients with CRS, the risk of dementia was also increased 
. This study followed patients with mild cognitive impairment with or without CRS for the study period, which found that patients with mild cognitive impairment and CRS were more likely to develop dementia than those with mild cognitive impairment but without CRS 
. Similarly, a case-control Taiwanese study included 8768 dementia patients and confirmed significantly higher odds of CRS in the dementia population 
. The authors suggested that CRS is associated with other comorbidities, such as stroke and vasculopathy, leading to an increased risk of vascular dementia. In addition, several other studies have also found a correlation between CRS and cognitive impairment 
Some studies, however, failed to find a correlation between AD and CRS 
. This may be due to the variation in how CRS was diagnosed. In some cases, CRS was self-diagnosed, and even with clinical examination, it is hard to differentiate between CRS and rhinitis. Thus, computed tomography (CT) scans are needed to confirm the diagnosis, which is not routinely performed in every patient 
. Another reason why studies failed to find a correlation between CRS and dementia is that dementia is a disease manifested in old age, and CRS symptoms can be improved with aging due to the alterations in the immune system. For example, Holmes et al. showed that the burden of CRS is higher in patients under 39 years of age than elderly patients 
. Another study found that in CRS patients, the nasal epithelial barrier function is worsened with aging 
. This reduced inflammatory burden of CRS in the aging population may make it harder to be recognised by the patients themselves, and subsequently identified and diagnosed by the clinicians.
Even with impaired epithelial integrity in elderly patients, a bacterial infection in the sinuses cannot spread to the brain because of the blood-brain barrier; however, the inflammation can spread through the olfactory bulb and the olfactory neural system to reach the brain where the blood-brain barrier is lacking. Chronic inflammation is present in both CRS and AD, which may bridge CRS and the risk of neurodegeneration causing dementia 
. It is well known that increased brain inflammation causes cognitive decline even before the onset of AD neuropathology, i.e., Aβ aggregation and tau hyperphosphorylation 
. Inflammatory cytokines from active microglia and astrocytes impair cortical function and reduce hippocampal volume, which leads to memory and learning impairments 
. Moreover, human brains with Aβ aggregations have microglial activation and increased pro-inflammatory cytokine production; increased circulating levels of inflammatory proteins, such as C-reactive protein, are also correlated with the presence of dementia 
. During the early stages of AD, microglia and astrocytes are activated and able to clear Aβ, but the chronic activation of those cells has detrimental effects due to the secretion of inflammatory mediators tumour necrosis factor-α (TNF-α) and interleukin (IL)-6 
. These inflammatory mediators play crucial roles in the neurodegenerative process due to less Aβ clearance and increased accumulation. Interestingly, the role of inflammation in AD has been supported by a human study showing that AD risk was lowered by anti-inflammatory medications 
In CRS, the immune system is dysregulated, which may be the driving force for inflammation. The innate immune system is suppressed with decreased immunoglobulin J chain, antileukoproteinase, tertiary lymphoid structure and surfactant protein-A 
. On the other hand, immune cells, such as eosinophils and basophils, are increased in patients with CRS 
. Activation of these inflammatory cells leads to the recruitment of more cells, the polarisation of Th2 cells, and the production of inflammatory cytokines, such as IL-13, IL-5 and IL-4 
. Moreover, inflammation disrupts nasal epithelial cell regeneration through the inhibition of neural progenitor cell proliferation, which may aggravate CRS 
. Such inflammatory response due to CRS can further affect the development of AD (Figure 2
). A meta-analysis shows that dementia is associated with increased circulating inflammatory mediators, e.g., IL-6, IL-12, IL-18, TNF-α, IL-1β and transforming growth factor-β (TGF-β) 
. IL-1β, IL-6, TNF-α and TGF-β are also elevated in the mucosa of patients with CRS 
. However, it is unclear if increased cytokines in the nasal cavity can directly affect neural integrity in the central nervous system that leads to neurodegeneration.
Figure 2. The route showing how inflammation caused by nasal bacterial dysbiosis and Aβ deposition in the olfactory nerve in CRS spread to other parts of the central nervous system, through the olfactory bulb to the piriform cortex, amygdala, entorhinal cortex and hippocampus.