Could a Common Eye Bacteria Be Linked to Alzheimer’s?

Bacteria found in the eye may offer new clues about inflammation, cognitive decline, and the progression of Alzheimer’s disease.

Dr. Maya Koronyo-Hamaoui, a professor of neurosurgery, neurology and biomedical sciences at Cedars-Sinai Health Sciences University, has found that Chlamydia pneumoniae, a common respiratory bacterium, may be linked to Alzheimer’s disease-related changes in the brain and retina. Her work, focusing on Alzheimer’s disease, neuroinflammation and retinal imaging, seeks to improve how neurodegenerative diseases are detected, monitored, and treated.

During this conversation with Being Patient’s Mark Niu, Koronyo-Hamaoui explained how her team found evidence of Chlamydia pneumoniae in eye and brain tissue, with higher bacterial burden associated with more severe Alzheimer’s disease. She also discussed how the retina may serve as a noninvasive window into brain health, why chronic inflammation may play a role in disease progression, and why future research is needed to understand whether infection may contribute to Alzheimer’s risk in some people.

Being Patient: What is Chlamydia pneumoniae and how common is exposure to this bacterium?

Dr. Maya Koronyo-Hamaoui: Chlamydia pneumoniae is a common type of bacteria that infects the lung and airways. It spreads similarly to cold and flu through coughing, sneezing, and close contact and can cause sinus infection, bronchitis, or pneumonia. 

Many people are exposed to it during their lifetime. There is an estimate of about 50 to 70 percent seropositivity, meaning people have been exposed throughout their life to this bacteria, and because it presents as atypical pneumonia, it can go undiagnosed or untreated. 

The important point I would add here is that routine exposure does not mean that someone will definitely develop Alzheimer’s disease. Our study asks a more specific question: whether, in some people, persistent infection and related inflammation contributes to Alzheimer’s biology or progression.

Being Patient: How did you even begin to get onto this concept that what’s in your eye can be impacting Alzheimer’s?

Koronyo-Hamaoui: It’s a combination of two questions. How we think of the eye is one thing, and how we come upon bacteria in the eye is another additional layer of investigation. 

Early on, about two decades ago, we were asking ourselves whether we can monitor response to therapy in a way that would be non-invasive and whether we can use the eye as a part of the brain — as an extension of the brain — to monitor changes in the brain, since the brain is shielded by bone and the eye is not encapsulated by the skull or by bone. Can we see the changes of Alzheimer’s disease in the eye? 

Our team is actually pioneering a lot of these investigations into the eye, in preclinical animal models but also in clinical patients, both in vivo and in autopsy tissue, where we see the changes of Alzheimer’s disease in the retina. By changes, I mean the hallmarks — Alzheimer’s is obviously a very complex disease, it’s a multifactorial disease. We see changes in amyloid and tau pathology, which are the way that we diagnose Alzheimer’s disease, but we also see changes in inflammation. We see changes to blood vessels, we see changes in synapses, the connectivity between the neurons in the retina, and they reflect the changes in the brain. So far, we’ve seen many of these changes in Alzheimer’s disease through the retina. 

The idea is to use the eye — the back of the eye, this tissue that is connected directly with the brain — as a surrogate, as a window into brain disorders, to diagnose it early, to help with assessing progression and tracking the disease. The idea of the eye came from the need for a noninvasive, feasible way to monitor the disease. 

In terms of the bacteria, this started very early on, where scientists noticed that there are infectious elements within plaques in patients that died with Alzheimer’s disease. However, the prevalent hypothesis thought to be causing Alzheimer’s disease is the accumulation of abnormal amyloid — those sticky proteins that are toxic to nerve cells. Under the scope, we have seen in recent years structures that reminded us of bacteria, and these were associated with this amyloid toxic plaque. We thought about looking at bacteria, and then we collaborated with Timothy Crother, another investigator here, to look specifically at Chlamydia pneumoniae. But it doesn’t mean that other bacteria or even viruses cannot also cause the same elements of inflammation and persistent infection. 

Another reason we looked at Chlamydia pneumoniae specifically is that there were a lot of GWAS studies — genome-wide association studies in humans — and a lot of studies showed that the bacterium is present in the amyloid plaque of these patients. This particular bacterium was shown to be infiltrating the brain and can stay persistent in the brain, but it was never shown in the human retina.

“The idea is to use the eye… as a surrogate, as a window into brain disorders, to diagnose it early, to help with assessing progression and tracking the disease.”

Being Patient: What’s the data on what you found? What is the relationship between the amyloid and the Chlamydia pneumoniae?

Koronyo-Hamaoui: What we found first is evidence of Chlamydia pneumoniae and its inclusions within cells, meaning that it infects cells within the retina — the back of the eye, connected with the brain. We see that the burden of this bacteria, the amount of these inclusions of Chlamydia pneumoniae, is higher in patients with AD dementia. This is true also for the retina and the brain. 

This is the first study that looked at mild cognitively impaired patients who died and were confirmed after death in autopsy to have mild cognitive impairment due to Alzheimer’s disease. We couldn’t find statistically significantly elevated bacteria, but we did find that they carry this bacterium. Also, some patients who died with normal cognition had some traces of this bacterium. But in Alzheimer’s disease patients, there was marked elevation — very statistically significant elevation — about a two- to three-fold increase in the amount of bacterium. 

What we found is that there was an association between the amount of bacteria in the retina and in the brain and the severity of the disease, meaning if the patient died in earlier stages, there were lower numbers of bacteria in the retina and in the brain. If the patient died in a more advanced stage of the disease, where there was more amyloid, more tau, more spread of the tau throughout the brain and the retina, that patient had elevated levels of the bacterium. 

More importantly, what we found is that the presence of the bacterium was associated with a low-grade inflammatory response — what we call the NLRP3 inflammasome. It was very important to find that this was an active element, and it was elevated even in the mild cognitively impaired stage, meaning some people were very susceptible to persistent infection. They already had elevated levels of this inflammation, and this inflammation is causing the release of cytokines that are highly toxic to nerve cells and are known to be implicated in Alzheimer’s disease progression and biology. This is the main idea.

Beyond what we found in humans — which was a strong association — we looked at about 104 individuals: approximately 37 individuals with normal cognition who died with no cognitive impairment, 16 individuals who died with mild cognitive impairment due to AD, and about 51 patients with Alzheimer’s disease dementia at different stages. Beyond the strong association and the presence of the bacteria, which was confirmed through multiple methodologies — genetic, protein level, proteomics — our study really set the stage and proved that the bacterium is really there because we used genetic and protein level, and multiple layers of methodology to show that the bacterium is there. 

We also conducted mechanistic studies in animal models. These are genetically modified models of Alzheimer’s disease that develop Alzheimer’s-like pathology and cognitive decline. What we saw is that even a single infection with Chlamydia pneumoniae through the nasal route appeared in the brain and caused exacerbation or worsening of Alzheimer’s disease pathology. There was more amyloid in the brain, there was more astrogliosis and microgliosis, and the individual mice exposed to this bacterium performed worse on cognition and vision tests. Their function was reduced dramatically. 

Another line of evidence was in cell cultures, where we infected cells — cell lines and primary hippocampal cell cultures — and analyzed them. After the infection, there were elevated levels of the type of amyloid beta that is highly neurotoxic — the A-beta 42 type. There was elevation along with elevated levels of inflammasome activation and signs of cell damage or cytotoxicity. 

Our conclusion was that Alzheimer’s disease can be worsened or amplified by infection. In some individuals with an elevated level of this persistent infection in the brain, there would also be inflammation in the brain, and they would show a more progressed disease phenotype.

Being Patient: Can you correlate higher levels of the bacterium to a greater degree or a more advanced stage of Alzheimer’s — compared to somebody with MCI, maybe having less, compared to somebody in a late stage of Alzheimer’s?

Koronyo-Hamaoui: Correct, that’s exactly it. What we find is that having a higher burden of this bacterium in the retina — which also correlates with a higher level of bacterium in the brain — is associated with a more severe degree of Alzheimer’s disease, meaning these individuals died with more severe functional impairment and more severe dementia. 

Another thing I want to add is that individuals who carried the APOE4 allele had higher levels of the bacterium as well. APOE4 is the most common gene associated with late-onset Alzheimer’s disease, or sporadic cases of Alzheimer’s disease, and is the strongest genetic risk factor. In those individuals who carried either one allele or two alleles, they had higher levels of the bacterium.

Being Patient: How is the bacterium getting in there in the first place? And can you get rid of it? Do some people clear it with their body’s immune response, or how does one lessen the bacterium?

Koronyo-Hamaoui: We do not know yet exactly the route in humans. We have some animal model studies, and we think that Chlamydia pneumoniae can enter the central nervous system through the olfactory or the trigeminal nerves, traveling from the nasal cavity directly into the brain. 

Possible routes also include spread through the blood. Chlamydia pneumoniae infects immune cells and nerve-associated pathways, or it moves across vulnerable barriers of the brain. While Chlamydia pneumoniae is primarily a respiratory pathogen that infects the sinuses and lungs, it can infect the nose and sinus passages, so it offers direct access to the brain and then the retina as well. 

As mentioned, Chlamydia lives and grows inside other cells, including immune cells that can penetrate the brain and the retina. It can enter the central nervous system via what we call a Trojan horse type of situation — it goes in, infects other cells, releases bacterium particles, and then infects other cells. 

To your question about whether some people can manage the bacterium better than others: we believe there is enough evidence to suggest that there is. In our cohort, and in other studies, we find individuals with much lower burden than others. There is a wide distribution in the amount of bacterium in the brain and in the retina, meaning some individuals have a genetic background or structural markup that allows them to be more resistant to the bacterium — they can recognize it better and clear it more effectively. Therefore, the bacterium does not persist as much or at higher levels in their brains and retinas and does not cause the detrimental chronic inflammation that we see linked with its presence.

Being Patient: Can some sort of treatment address that? Do doctors look for that specific bacterium? What kind of medicine exists today to treat this and stop it beforehand?

Koronyo-Hamaoui: There are specific antibiotics. Routinely, people would not be checked for Chlamydia pneumoniae. If there is some element of suspicion or concern, people would undergo blood tests — that is the routine test to check whether there is an active infection. 

In the active acute phase, there is definitely good reasoning to use a specific type or combination of antibiotics targeting Chlamydia pneumoniae. These are not every type of antibiotic, so if a person is misdiagnosed for another infection or a different type of bacterium, that individual will not be treated right. In the acute phase, it is definitely important to treat individuals with the correct antibiotics that target Chlamydia pneumoniae.

There is a Taiwanese study published — I believe in 2021 — a large-scale study involving nearly 7,000 individuals who were Chlamydia pneumoniae positive and were treated with macrolides or the correct antibiotics. They had much lower risk of developing Alzheimer’s disease than others. It was a longitudinal study, and when they looked at the outcomes of these individuals, they had much lower rates of Alzheimer’s and dementia. That is very strong support for this idea. 

However, once the acute infection is cleared, what we believe is sustained in the brain are what we call inclusions or inclusion bodies of this bacterium, which have already triggered an inflammatory response — the NLRP3 inflammasome. It’s a kind of danger sensing immune pathway with several molecules that indicate its activation state. In this study, we showed for the first time that the Chlamydia pneumoniae inclusions are tightly associated with activation of the NLRP3 inflammasome. One of the outcomes of this inflammasome is pro-inflammatory cytokines, which can harm immune cells and nerve cells and their connectivity, and can cause neurodegeneration. 

We believe that this chronic, persistent infection — because of the bacterial load — is what causes the outcomes we see and the cognitive decline. 

“What we find is that having a higher burden of this bacterium in the retina… is associated with a more severe degree of Alzheimer’s disease, meaning these individuals died with more severe functional impairment and more severe dementia.”

Being Patient: Does ocular or oral hygiene help? 

Koronyo-Hamaoui: Again, the important thing is to say that not everybody that bears infection will develop Alzheimer’s disease.

But the oral hygiene was spot on because there is actually a type of bacteria that is called J gingivitis, and it was also associated with higher risk for Alzheimer’s disease. So there are a few types, like herpes virus, shown to be elevating risk for Alzheimer’s disease. There are types of infections that we believe can sustain for a prolonged time, and individuals who are more aged, and more vulnerable individuals that have maybe the genetic markup of vulnerability susceptibility, they would have a higher load of this infection and then inflammation — that is harmful inflammation that is caused or triggered by this infection. And this will cause them to progress into maybe from mild impairment to dementia state in Alzheimer’s disease and maybe in other types of dementia, which needs to be shown. 

But back to your question of treatment, at this stage, rather than treating with antibiotics, targeting or attenuating the inflammasome may be the approach, and there is a lot of emerging interest in the scientific community in targeting NLRP3 inflammasome in Alzheimer’s disease.

Being Patient: In simplest terms, what is the next step for your research? Where is it leading, and what is the fundamental question or mystery that you still need to solve?

Koronyo-Hamaoui: There are so many mysteries, but I think the next step in humans is definitely to show this in longitudinal studies — to try to detect this bacterium and see whether it is a causative or amplifying factor in longitudinal patient studies. That means checking serum positivity, antibody presence and levels in the blood, maybe checking inflammation through the retina to see whether people who have signs of infection-triggered inflammation have a higher risk of developing Alzheimer’s disease and may need targeted reduction of their inflammatory state. 

We really think that using the eye as a surrogate — looking at cellular, molecular, inflammatory, and blood vessel changes — will be very important as a window to see the disease, monitor it early, and do so non-invasively. In combination with looking at signs of past bacterium infection, this may indicate that an individual has a higher risk and may need closer monitoring.