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Researchers explore link between infection and Alzheimer’s disease
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In a recent editorial, researchers called for more focus and funding to explore the link between infection and Alzheimer’s disease — a relationship they believe is being neglected, and one that they say is often dismissed as “controversial” in the mainstream research community.
Infectious Disease News asked Rudolph E. Tanzi, PhD, professor of neurology at Harvard Medical School and vice-chair of neurology research at Massachusetts General Hospital, and Steven T. DeKosky, MD, professor of Alzheimer’s research and deputy director of the McKnight Brain Institute at the University of Florida, what is controversial about the hypothesis that infection is the root cause of Alzheimer’s disease.
They are saying that infection is the root of the disease and inflammation, which could be interpreted to cast beta-amyloid deposits aside as byproducts. That is where we are a little bit in disagreement. We believe amyloid is still the root cause, but infection is one way to get there. Given how rare the mutations are that get you amyloid, infection may be the main route of seeding amyloid that then triggers the rest of the disease.
Any hypothesis that is not mainstream is controversial. It is just the way science is. The authors who signed the editorial all have their own favorite microbe that they think causes the disease. One says herpes, one says chlamydia, etc. We are nondenominational about that; we are agnostic. We are doing something called the Brain Microbiome Project where we are sequencing RNA in Alzheimer’s brains and control brains and asking what foreign microbial RNAs are there — especially which ones attract to plaques — because in our model, the plaque is trapped in the microbes to protect the brain. In this same model, the microbes also trigger the deposition of the beta-amyloid as part of the brain’s defense mechanisms.
To say infection is the root cause of Alzheimer’s is controversial because there are just too much data that say you can get Alzheimer’s without an infection — as a result of certain gene mutations, for example. Some proponents of the infectious disease hypothesis also claim that beta-amyloid is not the root cause. The better answer is that amyloid is still triggering the disease early on; the genetics and brain imaging show that. But infection is one root to get amyloid seeded and deposited in the brain. It may turn out — but we do not know yet — that infection may be the main route for doing that. We know there are gene mutations that get you amyloid no matter what, but most Alzheimer’s patients do not carry those mutations.
I am a big proponent of the role of infection in the disease, but I think it is causing Alzheimer’s through the amyloid pathway. In other words, the amyloid is being triggered by the infection, depositing, and then causing the rest of the pathology, including inflammation and tangles. Of course, infection could also lead to some inflammation, so it can contribute there as well.
- Reference:
- Itzhaki RF, et al. J Alzheimers Dis. 2016;doi:10.3233/JAD-160152.
Disclosure: Tanzi reports no relevant financial disclosures.
Most of the data in the studies are either in vitro studies (in cell culture), sometimes in mice; or associations of the presence of a marker, such as an antibody for HSV, in people who have Alzheimer’s disease. These data are the ones that in my view help make their case. However, beta-amyloid goes up in a lot of injuries — cell injuries, trauma, etc. — at least temporarily. So, when considering the cell culture studies, if the design involves an infection and they find that beta-amyloid is elevated, and if you suppress the infection and it lowers the effect of beta-amyloid — that does not make infection a “cause” of Alzheimer’s disease.
I think it is interesting biology, but I do not believe it immediately moves us to the idea that these various infections relate directly to Alzheimer’s disease. We have a great deal of evidence that Alzheimer’s disease has genetic causes. Certainly, infection is not necessary for the occurrence of Alzheimer’s disease in people with Down syndrome; we know why it happens. In all people with autosomal-dominant Alzheimer’s disease, due to a mutation, we know why it happens. At best, you could show an association with late-onset Alzheimer’s disease and a higher presence of a marker of an infection, but I do not know if anyone has ever shown a direct relationship between an infection — for example, chlamydia — and Alzheimer’s disease.
The associations do not prove causation. I do not know if study of the relationship of infection and Alzheimer’s disease has been neglected as much as there are limited ways to address the issue. Experiments on chlamydia increasing the likelihood or possibility of Alzheimer’s disease, for example, would mean following a group of people who had been infected with chlamydia, with matched controls, to see which group ended up with a greater incidence of Alzheimer’s disease. These are difficult studies to do.
Finally, we know there is a significant inflammatory component of Alzheimer’s disease, that there are neural inflammatory changes in the brain. It is not unreasonable that if there is infection or inflammation that these might either hasten the emergence of or show as an association with Alzheimer’s disease, and it is possible that some of these infectious routes that people are talking about come from this mechanism. We know, at least in retrospect from epidemiological studies, that people who take anti-inflammatory agents like nonsteroidal anti-inflammatory drugs have a lower prevalence of Alzheimer’s disease later in life than those who do not take them, but that does not make infections the cause of Alzheimer’s disease. And I think that part of the issue — going from the studies that have been done to saying that it is causative — of why it is referred to as controversial, and certainly unproven, by most of the world of science. Having said that, there are a lot of distinguished scientists on the editorial. I think their problem will be proving that infections are the cause of, as opposed to associated with, Alzheimer’s disease, which is much more difficult.
Disclosure: DeKosky reports no relevant financial disclosures.