Microbial Infection and Alzheimer’s Disease

By Jeremy Taylor

What really kicks off Alzheimer’s disease in the first place? What are the founder mechanisms? The accepted wisdom of the vast majority of the medical research profession is sure it is the pathological build up of beta-amyloid protein between neurons and phosphorylated tau protein within them. These have been the outward signs of the pathology of Alzheimer’s ever since the eponymous researcher first noticed them in diseased brains at the start of the twentieth century and those observations have been bolstered over the years by the discovery of a number of genes controlling the pathway by which beta-amyloid is formed which have been shown, in a very deterministic fashion, to predispose to Alzheimer’s disease in those individuals with the familial form of the disorder. Down Syndrome individuals, for instance, where trisomy results in 3 copies of the gene for amyloid precursor protein, are particularly prone to early-onset of the disease.
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Yet slowly, over the last thirty years, it has become more commonly accepted that neuro-inflammation – specifically the production of inflammatory cytokines inside the brain together with the pathological role of primed microglia, precedes build up of amyloid and the presentation of cognitive decline. Even in Down Syndrome, inflammation precedes build up of amyloid. But what causes the brain’s innate immune system to switch to an inflammatory setting? Several researchers, including Clive Holmes and Hugh Perry in Southampton, UK, and Angela Kamer in New York, have pointed out that signals of inflammation in the periphery can communicate with the brain and set off corresponding inflammatory regimes there. These signals could be generated by any number of inflammatory illnesses we tend to increasingly suffer from as we age, including heart disease, cancer, atherosclerosis and diabetes. In fact, Holmes and Kamer have very recently added periodontal gum disease to that list – there seem to be direct links between the inflammation of gum disease and an acceleration and gravity of cognitive decline in Alzheimer’s patients.
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However, a number of scientists have controversially gone one step further, by suggesting that a number of infectious agents can get into the brain and produce the initial damage to neurons that begins the pathology of Alzheimer’s disease. The idea is not new – Paul Ewald suggested a role for microorganisms over twenty years ago. But the idea is still seen as highly controversial, if not laughable, by the bulk of the Alzheimer’s research  community. But, as I pointed out in a chapter on Alzheimer’s disease in Body by Darwin, if you follow a clear line of biological reasoning it is difficult to escape the conclusion that these researchers may have a point worth some research dollars. There are simply too many reports of viruses and other microbes being found in the brains of elderly people, and disproportionately in the brains of those who have died of Alzheimer’s disease.

Because of a general lack of funding, these “infection origin” theorists have historically been a disparate bunch – scattered across the Western hemisphere hanging on for dear life in their laboratories. But, late last year, one of them, Brian Balin, called a conference to discuss the evidence for microbial aetiology of Alzheimer’s disease and in a forthcoming edition of the Journal of Alzheimer’s Disease, 33 of them are co-authors of an editorial titled Microbes and Alzheimer’s Disease. They include Ruth Itzhaki and Melvyn Ball, who have looked at the virus HSV1, Sue Griffin, one of the pioneers of the inflammation hypothesis, Angela Kamer, who has linked a number of oral cavity microbes to Alzheimer’s disease progression, and George Perry, an acknowledged medical historian of Alzheimer’s disease research.
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In a nutshell, these researchers argue that a wide variety of microorganisms, including HSV1, Chlamydia pneumoniae, and spirochetes can reach the brain and nestle there for decades in latent form, waking up when stress, or reduced immune surveillance in aging individuals, allows them to reactivate. As they  multiply they cause widespread synaptic dysfunction, leading to neuronal loss, and the induction of beta-amyloid, which, being a potent anti-microbial, is the first line of innate immune defence. This would make beta-amyloid secondary to the posited infectious prime cause. Critics argue that the infection hypothesis still falls well short of establishing cause and effect. Much of the case is built around indirect evidence, such as the presence of these

HSV1 – culprit or bystander?

microorganisms in autopsied brains, or evidence of viral DNA or polysaccharide molecules specific to a certain species of bacterium, found in brain tissue. And even though Ruth Itzhaki and others have  demonstrated that individuals with a combination of HSV1 infection and carriage of  the APOE epsilon 4 gene variant, which we know increases the chance of contracting Alzheimer’s, have a far greater risk of succumbing to the disease than those carrying one or other factor alone, it doesn’t prove conclusively that they are causally linked. And, of course, the obvious way to test the hypothesis – deliberately introducing one of these infectious agents into healthy individuals and watching the results, is out of the question.

Nevertheless, it is good to see so many of these heretics “under one roof” because alternative hypotheses for Alzheimer’s disease are desperately needed. As this editorial points out, there have been 413 trials of therapy to restrict the production of beta-amyloid in the brain, over the last ten years, and none of them have achieved any success. The request of these co-authors, given the billions of dollars spent propping up the amyloid hypothesis, for a small sum of money to be made available for a trial using the common (and relatively cheap) anti-viral drug acyclovir, seems reasonable, to say the least.

For a popular account of this controversial argument see this article in Scientific American.  Versions of the forthcoming editorial in IOS Press are here and here.