The Pathogen Hypothesis
There’s no doubt that amyloid plaque is associated with AD, but is it the cause? Many researchers think not. Amyloid-β, they theorize, doesn’t cause AD. Rather, it is the consequence of an underlying condition – pathogenic infection – which itself is the cause or one of several causes.
In the March 2016 edition of the Journal of Alzheimer’s, a group of 33 AD researchers published an editorial calling upon the neuroscience community to give greater consideration to the growing body of evidence supporting the “pathogen hypothesis” of AD.[19] Briefly put, this hypothesis says AD has an infectious etiology, meaning an infection, or a combination of infections, triggers a cascade of events which eventually culminates in AD.
The available evidence shows, unequivocally, that AD is strongly associated with certain bacterial and viral infections. In 2015, for example, a team of Australian scientists conducted the first ever meta-analysis addressing the relationship between two types of bacteria – spirochetal and Chlamydophila pneumoniae (Cpn) – and AD. According to their analysis, spirochetal infection is associated with a ten-fold increase in AD occurrence, whereas Cpn infection is associated with a five-fold increase.[20]
Besides these bacteria, the herpes simplex 1 virus (HSV-1) is also strongly associated with AD. HSV-1 is a ubiquitous virus, infecting around two-thirds of the population 50 years or younger and as much as 80% of those 65 or older.[21],[22] The virus can’t usually gain access to the brain, but as we age, for reasons discussed below, brain access becomes increasingly feasible. In fact, studies have shown that a high percentage of elderly people – around 60% – exhibit latent HSV-1 DNA in their brains.[23],[24]
Dr. Ruth Itzhaki and her colleagues at the University of Manchester have been studying the relationship between HSV-1 and AD for the past two decades. According to their research, AD risk increases twelve-fold when the following two conditions are met:[25], [26]
- HSV-1 is present in the brain.
- The patient has a particular genetic variant – APOE4 – which is independently strongly associated with AD.
Infections are associated with AD, but researchers have thus far been unable to demonstrate causation. It’s possible, for example, that those who have AD are more susceptible to infection and thus acquire these infections after AD has already started progressing. Nevertheless, as we’ll see below, some studies show that infection can come first, thereby triggering the disease process.
Normally we think about infections as causing acute sickness. For example, you become infected with a virus and shortly thereafter you experience a sore throat, a runny nose, sneezing, and other symptoms; after about one week, you’re back to normal. Some pathogens, however, are latent, meaning after the initial infection – sometimes many years later – the pathogen emerges from a dormant state, thus causing chronic, long-term damage. Herpes simplex 1 virus (HSV-1) and Chlamydophila pneumoniae are the top two pathogens associated with AD and both of have latent properties.[27], [28]
The Infection-Amyloid Connection
So, if infection and amyloid plaque are both associated with AD, what’s the relationship between them? In 2002, a pair of Australian neurologists, Drs. Stephen Robinson and Glenda Bishop, issued a strong challenge to the amyloid cascade theory. According to their research, the brain might intentionally produce amyloid-β in order to protect itself when infections arise.[29]
It wasn’t until 2016, however, that neurologist Robert Moir and his colleagues demonstrated this conclusively. Just hours after injecting salmonella into the brains of mice, they witnessed the development of amyloid plaque at the injection sites.[30] So what does it mean? Does it mean that amyloid plaque is good or bad? The evidence seems to suggest both. Amyloid plaque protects the brain against infections, but after killing an infection, the plaque remains. When enough plaque accumulates, a cascade of inflammation and other harmful developments ensues.
How Do Pathogens Access the Brain?
If the pathogen hypothesis is correct, pathogens must be able to enter the brain. This could be done in various ways. HSV-1, for example, can infect the cornea and travel to the brain via the trigeminal nerve.[31] The most obvious route to the brain, however, is via the blood brain barrier (BBB). Nevertheless, the BBB is extremely effective at preventing pathogens from entering the brain. So how can they possibly enter?
Some pathogens have developed clever strategies and techniques for bypassing the BBB. According to Dr. Kwang Sik Kim, the Director of Pediatric Infectious Diseases at John Hopkins Children’s Center, “Pathogens can cross the blood–brain barrier transcellularly, paracellularly and/or in infected phagocytes (the so-called Trojan-horse mechanism).”[32]
Patience, it turns out, may be a pathogen’s most effective strategy. As we age, the BBB becomes more permeable, thus making brain access easier. In January 2015, researchers from the University of Southern California, led by Dr. Berislav Zlokovic, pioneered the use of a dynamic contrast-enhanced MRI to measure BBB permeability.
Whereas previously, researchers could only observe BBB damage via postmortem tissue analyses, Zlokovic et al. demonstrated age-dependent BBB breakdown in living subjects. Specifically, they found that aging makes us more prone to leaks within the hippocampus, the area of the brain involved with memory and learning.[33] Other researchers have also shown hippocampus damage to be a critical event in the development of AD.[34]
Conclusions and Prevention Strategies
It’s possible that countless dollars and many years have been wasted chasing an AD cure based on an incorrect understand of AD etiology. Unfortunately, the neuroscience community embraced the amyloid cascade theory for decades while consistently disregarding or outright rejecting competing theories.
The upcoming years will be extremely telling with respect to understanding AD and developing more effective treatment and prevention strategies. Age is the strongest risk factor for AD, but can we take proactive steps to minimize our risk? In other words, is AD also a lifestyle disease, or at least one whose risk can be curbed through healthy living? If the pathogen hypothesis is correct, then adopting a diet and lifestyle that nurtures and strengthens the immune system might indeed decrease one’s AD risk later in life.
It’s also worth noting that type-2 diabetes and obesity are both significant risk factors for AD.[35], [36] Being obese in mid-life, for example, increases one’s risk for AD by 80 percent.[37]
Moreover, some researchers are now referring to AD as “type-3 diabetes,” based on increasing evidence suggesting that AD is a brain-specific form of diabetes, characterized by insulin resistance within the brain.[38], [39], [40]
Does lifestyle influence AD risk? Dr. Jeff Cummings, Director of the Cleveland Clinic’s Lou Ruvo Center for Brain Health, sums it up nicely, “Roughly half of the risk for Alzheimer’s disease is linked to things we can’t control, like age and genetics, but the other half are things that are at least partially in our control – you can reduce your risk with lifestyle modification.”[41] The Paleo Diet, because it reduces type-2 diabetes and obesity risks while strengthening the immune system, is a great way to start.
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