The findings of this study suggest that certain oral bacteria may play an important role in cognitive decline and the risk of dementia. While some appear to be associated with a protective effect, others may contribute to the progression of the disease.
Aging is a natural process of life, but in some people it is accompanied by a decline in cognitive ability. In more advanced cases, this decline can progress to a condition called Mild Cognitive Impairment (MCI), a condition that affects about 15% of older adults and increases the risk of developing neurodegenerative diseases, such as Alzheimer's.
It is estimated that approximately 10% of people with Mild Cognitive Impairment progress to dementia each year. Given this worrying scenario, scientists are seeking to understand the factors that contribute to cognitive decline and how we can prevent it.
Recent research suggests that oral health may be directly linked to brain function.
Periodontal diseases, such as periodontitis, have been linked to poorer cognitive function, and studies have shown that tooth loss may be linked to poorer performance on memory and cognition tests. But how might oral health affect the brain?
One explanation is the action of harmful bacteria present in the mouth, such as Porphyromonas gingivalis, Treponema denticola and Prevotella intermedia.
These bacteria can increase inflammation levels in the body, creating a more favorable environment for the development of neurodegenerative diseases.
In patients with Alzheimer's, high levels of these bacteria have been found in the mouth and a lower bacterial diversity compared to healthy people.
Scientists believe that there are two main ways in which oral bacteria can affect brain function:
Direct Route – When there is damage to the mouth (such as wounds or inflammation), these bacteria can enter the bloodstream and reach the brain, crossing the protective barrier that normally prevents the entry of dangerous substances. As this barrier becomes more permeable in people with Alzheimer's, the bacteria can settle in the brain and contribute to the progression of the disease.
Indirect Route – Oral bacteria can cause chronic inflammation in the body. This inflammation can affect the brain indirectly, hindering communication between neurons and increasing the risk of cognitive decline.
Another important factor in the relationship between the mouth and the brain is nitric oxide (NO), a molecule essential for several functions in the body, including blood circulation, communication between neurons and defense against microorganisms.
The human body can produce nitric oxide in two ways. The first occurs within cells, through an enzyme called NO synthase (NOS).
The second occurs thanks to bacteria present in the mouth, which transform nitrates from food into nitric oxide. This second route is especially important for the brain, as nitric oxide helps in the formation of memory and brain plasticity (the brain's ability to adapt and learn).
As we age, the production of NO decreases, which can impair cognition and increase the risk of Alzheimer's. Studies show that patients with the disease have reduced levels of this molecule in their blood and brain.
In addition to oral health, genetics can also play an important role in the risk of cognitive decline. One of the main genetic factors associated with Alzheimer's is the APOE4 gene, which is linked to the weakening of the blood-brain barrier (the brain's natural protection against harmful substances).
People who have this gene also have a higher risk of developing cardiovascular and muscular diseases, all conditions marked by nitric oxide deficiency.
Scientists at the University of Exeter, UK, have hypothesized that there may be an interaction between the APOE4 gene, nitric oxide levels and the oral microbiome in the progression of cognitive decline.
However, it is still unclear whether changes in oral bacteria can be detected in healthy older adults before dementia is diagnosed.
To investigate these connections, the researchers analyzed oral health, nitric oxide biomarkers and cognitive function in two groups: 60 older adults with Mild Cognitive Impairment and 60 healthy older adults.
In addition, within the Mild Cognitive Impairment group, they compared the oral microbiomes between carriers and non-carriers of the APOE4 gene.
The results showed that some oral bacteria were associated with better cognitive performance. For example: Neisseria bacteria were linked to better executive function and attention in older adults with Mild Cognitive Impairment and better working memory in healthy older adults.
The bacteria Haemophilus and Haemophilus parainfluenzae, which coexist with Neisseria, were also associated with better executive function in the Mild Cognitive Impairment group.
Haemophilus parainfluenzae bacteria. Source: Manitoba Health and Fine Art America.
On the other hand, some bacteria were linked to an increased risk of cognitive decline. The bacterium Porphyromonas was identified as a marker for Mild Cognitive Impairment.
Finally, the bacterium Prevotella intermedia was associated with the APOE4 gene, suggesting that its presence may increase the genetic risk of developing dementia.
Scanning electron micrographs showing surface structures of Prevotella intermedia 17 (A), OD1-16 (B), and ATCC 25611 (C) and Porphyromonas gingivalis ATCC 33277 (D), 381 (E), and W83 (F) strains grown on blood agar plates. Image: Yamanaka et al. DOI: 10.1186/1471-2334-11-228. CC BY 4.0
Interestingly, there were no significant differences in nitric oxide levels between the groups, indicating that other factors may be influencing this relationship.
The findings of this study suggest that certain oral bacteria may play an important role in cognitive decline and dementia risk. While some appear to be associated with a protective effect, others may contribute to disease progression.
Based on these findings, the researchers propose that interventions that increase the presence of Neisseria and Haemophilus bacteria and reduce Prevotella bacteria may help slow cognitive decline. In the future, strategies such as oral probiotics or dietary changes could be explored as potential preventive measures to protect the brain against aging and neurodegenerative diseases.
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Oral microbiome and nitric oxide biomarkers in older people with mild cognitive impairment and APOE4 genotype
Joanna E L’Heureux, Anne Corbett, Clive Ballard, David Vauzour, Byron Creese, Paul G Winyard, Andrew M Jones, Anni Vanhatalo Author Notes
PNAS Nexus, Volume 4, Issue 1, January 2025, pgae543
Abstract:
Apolipoprotein E4 (APOE4) genotype and nitric oxide (NO) deficiency are risk factors for age-associated cognitive decline. The oral microbiome plays a critical role in maintaining NO bioavailability during aging. The aim of this study was to assess interactions between the oral microbiome, NO biomarkers, and cognitive function in 60 participants with mild cognitive impairment (MCI) and 60 healthy controls using weighted gene co-occurrence network analysis and to compare the oral microbiomes between APOE4 carriers and noncarriers in a subgroup of 35 MCI participants. Within the MCI group, a high relative abundance of Neisseria was associated with better indices of cognition relating to executive function (Switching Stroop, rs = 0.33, P = 0.03) and visual attention (Trail Making, rs = −0.30, P = 0.05), and in the healthy group, Neisseria correlated with working memory (Digit Span, rs = 0.26, P = 0.04). High abundances of Haemophilus (rs = 0.38, P = 0.01) and Haemophilus parainfluenzae (rs = 0.32, P = 0.03), that co-occurred with Neisseria correlated with better scores on executive function (Switching Stroop) in the MCI group. There were no differences in oral nitrate (P = 0.48) or nitrite concentrations (P = 0.84) between the MCI and healthy groups. Linear discriminant analysis Effect Size identified Porphyromonas as a predictor for MCI and Prevotella intermedia as a predictor of APOE4-carrier status. The principal findings of this study were that a greater prevalence of oral P. intermedia is linked to elevated genetic risk for dementia (APOE4 genotype) in individuals with MCI prior to dementia diagnosis and that interventions that promote the oral Neisseria–Haemophilus and suppress Prevotella-dominated modules have potential for delaying cognitive decline.
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