This review will be investigating how poor dental hygiene can be a risk factor for Alzheimer’s disease (AD). AD is a progressive brain disorder that results in a decline in cognitive functions such as thinking, memory and behaviour (Holmer et al., 2018). It is the most common type of dementia (Gaur & Agnihotri, 2015) and is categorised into 3 main stages: mild, moderate and severe. A hallmark for the disease is brain inflammation (Rogers, 2008) and the presence of beta amyloid plaques in the brain and neurofibrillary tangles made up by hyperphosphorylated tau proteins. These plaques are sticky aggregates of amyloid precursor protein (APP) that can be neurotoxic. The plaques and tangles can cause a disruption in the supply of nutrients to brain cells resulting in neuron cell death and a decline in cognitive function which can lead to AD (Rogers et al., 1988).
The development of AD can be caused by many factors such as age, genes and environmental factors (Liu et al., 2019). One of the possible risk factors can be poor dental hygiene. This article is going to discuss research looking into the relation between these two factors and how one might cause the other. Alzheimer’s is most common in elderly patients (Rogers, 2008) and there can be bacterial, fungal and viral causes. This review will be focussing on the elderly population and looking into the bacterial causes of AD.
Beta amyloid plaques and Neurofibrillary tangles in Alzheimer’s Disease
The beta amyloid plaques in the brain are thought to trigger neurodegeneration which can cause Alzheimer’s and so it could be assumed that there would be more plaques in the brain of an AD sufferer. This is supported by (Kamer et al., 2009). These beta amyloid aggregates and neurofibrillary tangles would specifically be found in certain areas of the brain that are affected by AD and this is supported by a study that shows that they were found in areas such as the limbic system and the frontal neocortex (Rogers, 2008) which are responsible for cognitive skills such as memory, judgement and problem solving (Kunst et al., 2019). These are the skills that can be known to deteriorate during progression of Alzheimer’s so the presence of the aggregates and tangles here suggests they could play a part in the pathogenesis of the disease.
These plaques and tangles cause neuroinflammation by forming beta-pleated aggregates that are surrounded by microglia cells. These cells can be activated by the presence of beta amyloid plaques and neurofibrillary tangles as a CNS response to prevent neurodegeneration. As a result, the microglia cells can release inflammatory mediators and when activated and cause neuroinflammation.
Bacteria found in the brain can trigger these microglia cells so that they become activated. Overstimulation of microglia cells can cause harmful neuroinflammation and neurodegeneration through the release of cytokines and neurotoxic substances such as free radicals which cause neuron cell death (Olsen & Singhrao, 2015).
Oral microbiota dysbiosis in AD
Poor dental hygiene can result in caries and periodontal disease which can cause dysbiosis of the oral microbiota. Periodontal disease can result in, gram-negative, anaerobic bacteria such as Porphyromonas gingivalis and Treponema denticola (also known as keystone pathogens), dominating under the low bioavailability. This decreases the overall species richness and diversity of the oral microbiota (Harding et al., 2017). This is supported by a study that analysed the saliva samples of AD patients and found that the bacterial populations had a lower species diversity and richness in patients with AD than in non-AD patients. Another study that reflects this used the sequencing of 16s rRNA and also found that those with AD had a lower diversity of microbiota. This further supports the idea that the constituents of the oral microbiota can cause or affect the development of Alzheimer’s (Liu et al., 2019). Both of these studies are very recent and there is not much data backing up the findings so further experiments could have different results. More evidence would be needed to draw a strong association between constituents of the oral microbiota and the progression of AD.
This dysbiotic flora can over-activate the inflammatory response and cause periodontal tissue destruction leading to the release of many inflammatory mediators and an increase in the number of harmful bacteria in the oral tissues. The inflammatory mediators and bacteria can travel to the brain after entering the blood stream through bacteraemia. Methods of bacteraemia can be through daily actions such as brushing your teeth and chewing (Allen, 2010). The inflammation and dysbiosis positively reinforce each other as inflammatory tissue breakdown products are used as nutrients by the dysbiotic microbiota, which will result in neuroinflammation and neurodegeneration. Figure 1 shows the effect of oral bacteria in the brain on neuronal cells.
The presence of poor dental hygiene associated bacteria in the brain of AD patients is a factor supporting the theory that there is an association between poor dental hygiene and AD development. A very recent study found certain periodontal bacteria such as Trepenoma denticola in brain tissue of patients with Alzheimer’s (Riviere et al., 2002). This can suggest oral bacteria can travel to the brain and trigger the neuroinflammation although the extent to which these bacteria effect the severity of the disease is still being looked into. It can be suggested that particularly spirochete bacteria such as Trepenoma denitcola can cause Alzheimer’s as spirochetes were found in 14/16 of the brains of patients with AD using varying techniques (Riviere et al., 2002) (Miklossy, 2011) and it was found that they produced beta amyloid plaques in the brain which is a hallmark for AD (Miklossy et al., 2006).
Association between peripheral inflammation and AD
Neuroinflammation can be caused by proinflammatory mediators travelling from an area of peripheral infection to the brain. (Kempuraj et al., 2020). Poor dental hygiene can lead to a build-up of plaque which can cause gum disease and periodontitis – a form of peripheral infection (Marchini et al., 2019). Periodontitis is an oral infection that can produce inflammatory mediators, virulence factors and result in an increase in harmful bacteria that can travel to the brain through the bloodstream. Peripheral infections can increase the permeability of the blood brain barrier and so it is easier for these pathogens and mediators to reach the brain. The bacteria can result in activation of microglia cells which can release neurotoxic substances such as free radicals that cause neuron cell death (Riviere et al., 2002). The microglia cells can also cause the formation of beta amyloid plaques and tau protein hyperphosphorylation in the brain which causes neurodegeneration and activates further microglia cells.
Oral bacteria and the brain
Bacteria can also enter the brain through parts of the vascular system not involving the BBB such as the choroid plexus. In the brain, microglia cells can use their CD14 receptors and Toll-like receptors (TLRs) to recognise LPS (Lipopolysaccharide) of the bacteria (Lacroix et al., 1998). When bacteria enter the bloodstream, the innate immune system is activated by the recognition of PRR (pattern recognition receptors) and TLRs (toll like receptors) (Dunn et al., 2005). The TLRs release cytokines into the bloodstream which can cause the release of secondary mediators that can cause neurodegeneration in the brain (Holmes et al., 2003). Furthermore, periodontitis can precede other health conditions such as atherosclerosis and other inflammatory disease in the systemic system (Pischon et al., 2007). This can result in further inflammatory mediators in the bloodstream that can travel to the brain and contribute towards further neuroinflammation.
Immune responses to oral bacteria in the brain
Antibodies related to bacteria involved in periodontal disease such as Porphyromonas gingivalis are found in patients who suffer from AD and can be evidence towards the link between the disease and poor dental hygiene. Kamer et al. (2009) found that those with AD had a higher level of specific antibodies against certain periodontal pathogens. This study only involved 34 subjects which is a relatively small sample size and is not be representative of the whole population. Furthermore, all of the subjects were selected from New York University and so the results can only be representative of that area. Furthermore, the level of antibodies found may vary based on the different severities of AD and so these results would not reflect that. However, from the data that was found, we can assume that bacterial populations that become more common in the oral microbiota of a patient with poor dental hygiene could travel to the brain and cause neurodegeneration. The release of antibodies against these bacteria is a defence mechanism to try and kill the bacteria hence we can look at these specific antibodies to tell us that pathogenic oral bacteria is present in the brain.
The complement pathway may also cause an increase in the severity of AD and can be activated by poor dental hygiene. C1q is a protein which acts as a component of the complement activation pathway. It can be found in patients who suffer from AD. It is thought that C1q may have a role in Alzheimer’s as the complement pathway is known to increase inflammation (Fonesca et al., 2004). In a study, mice with and without C1q were observed and it was found that both the mice had beta amyloid plaques present however, in the mice without C1q, there were less microglia cells accumulated around the plaques than in the mouse with C1q. This can suggest that the presence of C1q allows the complement cascade to be activated in the brain of an AD patient and that this can contribute towards the neurodegeneration in the disease. This study is quite old but is supported by a more recent study by Hajjshengallis G et al. (2019) which is very popular and found that there can be hyperactivity of the complement cascade during periodontitis which can result in inflammatory mediators being released that can travel to the brain and cause neuroinflammation . Since one of the main causes of periodontitis is poor dental health, we can draw the assumption that poor dental health can result in activation of the complement cascade which can go onto increase the rate of progression of Alzheimer’s (Hajishengallis, 2015). In support of this, (Emery et al., 2017) found that complement can be activated by oral bacteria.
Inverse effect of AD on poor dental hygiene
Poor dental hygiene could be a risk factor for Alzheimer’s, but the progressive cognitive decline may also result in a deterioration of dental hygiene which can create a cycle in which both get progressively worse. In the severe stage of AD, the patient will most likely be reliant on their caregiver to manage their oral hygiene. A caregiver will also be responsible of taking care of them in other ways due to their loss of functionality and so oral hygiene may not be a priority and therefore, may suffer (Marchini et al., 2019).This can further have a detrimental effect on both your oral health and the severity of neurodegeneration. A study that shows that oral health care in some institutions is not seen as good is (Yoon et al., 2018). However, this study was conducted in Canada and cannot be representative of care homes everywhere, the results may vary country to country.
There is a strong association between poor dental hygiene and the development of AD as there have been studies that have found periodontal related oral bacteria in the brain of Alzheimer’s patients and linked this to activation of microglia cells and the complement system, hyperphosphorylation of tau proteins and accumulation of beta amyloid plaques; all of which can cause neuron cell death. Furthermore, patient’s with later stages of Alzheimer’s have decreased functionality and so their dental hygiene suffers even more which can cause the Alzheimer’s to the progress further. However, there is still a lack of research with regards to this topic and although we can predict a strong association between the two factors, there is further scientific research needed to strengthen the currently existing evidence.