“To be able to reverse memory loss, to allow people in their 70s, 80s, and 90s to live free and independent lives, is a major challenge for brain science.”
- Eric Kandel, Neuroscientist and Noble Laureate
“I am seeking, I am not lost/ I am forgetful, I am not gone.”
- Koenig Coste, Author and Alzheimer’s Disease Advocate
In 1906, Dr. Alois Alzheimer, a clinical psychiatrist and neuroanatomist practicing at a mental asylum in Germany, delivered a paper describing a “peculiar severe disease process of the cerebral cortex” of a 50-year-old woman with progressive dementia. The paper aroused little interest. It was, however, the first description of a disease later named after him and one that would emerge as a major pandemic by the end of the 20th Century—Alzheimer’s disease.
It is estimated that there are approximately 44 million people worldwide living with this disease or a related form of dementia. In the U.S., an estimated 5.5 million Americans have Alzheimer’s disease. Almost all of us know or have known someone close to us afflicted by this disease. We therefore have witnessed the devastating effects that Alzheimer’s has on the patient and also the toll it takes on his/her loved ones who oftentimes are the sole or primary care givers.
Despite a prodigious research effort, the cause of this devastating neurodegenerative disease remains unknown. Two years ago, immunologist and medical-publishing entrepreneur Leslie Norins offered to award one million dollars of his own money to any scientist who could prove that Alzheimer’s disease is caused by a germ. To my knowledge nobody has collected this award. Perhaps, however, that is about to change. In this Germ Gem post I review some new evidence that suggests an infectious agent may be the trigger for Alzheimer’s disease.
What is known about Alzheimer’s disease? The hallmark of Alzheimer’s disease is dementia: the degeneration of cognitive functioning—language, memory, problem solving—and other thinking abilities to such an extent that the loss is severe enough to interfere with a person’s daily life activities. People with Down’s syndrome are at a higher risk of developing the disease as are people who have had a severe head injury. But by far the biggest risk factor for Alzheimer’s is old age as the disease mainly affects people over 65. Moreover, of the one in six people over 80 who have dementia, many have Alzheimer’s disease.
Since first described, much of the research on Alzheimer’s disease has been focused on the neuropathologic features of the disease. Two predominant hypotheses that emerged were that beta-amyloid protein plaques and neurofibrillary tangles composed of tau protein, or neuroinflammation played a pivotal role in the development of Alzheimer’s disease.
Beta-amyloid protein plaques are clusters that form in the spaces between the nerve cells (neurons), whereas neurofibrillary tangles form a knot within brain cells. Both are thought to interfere with the neurotransmitter messages within the brain.
Neurons are considered the major player in determining brain function (cognition or thinking, and movement). But glial cells (outnumbering neurons by about 10 to 1) are also extremely important. These cells which come in various forms—such as, microglia, astrocytes, and oligodendrocytes—surround and support the function and health of neurons. Researchers focused on evidence of neuroinflammation in the brains of Alzheimer’s patients point to activated microglia and astrocytes in this inflammatory process. Studies in our Neuroimmunology Research Laboratory at the University of Minnesota more than two decades ago supported this theory, showing that beta-amyloid protein stimulates microglia to produce inflammatory mediators, that is cytokines, that in turn could be involved in the neurodegeneration that occurs in the brain of Alzheimer’s patients.
The main problem with both of these hypotheses—beta-amyloid protein or neuroinflammation playing a critical role in the development of Alzheimer’s disease—is that numerous studies with agents that remove beta-amyloid protein or that suppress neuroinflammation have shown little or no clinical benefit to patients. That does not, however, rule out the possibility that they are contributory factors in the neuropathogenesis of Alzheimer’s disease.
Pathogens known to cause dementia. In the early 20th century, as many as one-third of the patients in mental hospitals suffered from a ubiquitous, fatal form of a neurodegenerative mental illness termed “general paresis of the insane.” At that time, practitioners attributed the illness to “bad heredity,” “weak character,” or moral turpitude. Then in 1913 a Japanese microbiologist, Hideyo Noguchi, working at the Rockefeller University in New York City, discovered the bacterium that causes syphilis, Treponema pallidum, in cadaver brains obtained from people who had died in mental hospitals. To put it simply, Noguchi found that the cause (etiology) of their medical (mental) disorder was the infection neurosyphilis. When antimicrobial agents against this bacterium were developed subsequently, curative treatment became available. And to this day, penicillin remains the mainstay of treatment of neurosyphilis.
The HIV virus is the most recent microbe to cause a neurodegenerative disease pandemic. In the early years of the HIV/AIDS pandemic, I consulted on a number of patients suffering with what was called “AIDS Dementia Complex” (ADC). At the end stage of this tragic disease, these patients were severally demented and many became mute. But when highly active antiretroviral therapy came along in the mid-1990s, ADC was rarely seen. Again, antimicrobial therapy essentially eradicated a devastating neurodegenerative disease.
Pathogen hypothesis of Alzheimer’s disease. If the hypothesis that Alzheimer’s disease is caused by a microbe is proven, it shouldn’t be all that surprising. In addition to Treponema pallidum and HIV, dozens of viruses, bacteria, parasites, and fungi are “neurotropic,” that is, they have a predilection for the brain. In their pursuit of the cause of Alzheimer’s disease, an increasing number of neuroscience researchers have been testing the hypothesis that the etiology of Alzheimer’s disease is a neurotropic pathogen.
There is now mounting supportive evidence pointing to two neurotropic viruses that may serve as triggers of Alzheimer’s disease. Both are members of the herpesvirus group: herpes simplex virus-1 (HSV-1) and human herpes virus 6A (HHV 6A). Both viruses cause very common infections (more than 90% of people have been infected): in the case of HSV-1 “cold sores,” whereas in the case of HHV-6, acute febrile illness in childhood. And a number of postmortem studies of brains of Alzheimer’s patients have demonstrated a significantly increased expression of both viruses.
Importantly, both HSV-1 and HHV-6A are DNA viruses that share the capacity to latently infect cells. It is postulated that under stressful conditions, this dormant state of viral existence can be reactivated leading to neuroinflammation and neurodegeneration. But the exact mechanisms whereby these viruses cause Alzheimer’s disease are complex and still under investigation. For those interested in a more in-depth review of the evidence supporting that HSV-1 is a culprit, I recommend reading “Corroboration of a Major Role of Herpes Simplex Virus Type 1 in Alzheimer’s Disease” in the October, 2018 issue of Frontiers in Aging Neuroscience. And for a review of the evidence incriminating HHV-6A, I suggest reading the article “Viral Connection to Alzheimer’s: Herpes Virus Implicated in Alzheimer’s Disease,” in the June 2018 Neuroscience News.
For those of you who read the January 13th Germ Gem post “What’s your Psychobiome Telling You?,” you may recall that the human gut microbiome contains an estimated 40 trillion bacteria and 380 trillion viruses, most of which have yet to be named. You may also recall that cells of the immune system are trained in the gastrointestinal tract. Therefore, it should come as no surprise that some researchers have even turned to the gut to look for the cause of Alzheimer’s disease, as was recently described in the October 2, 2020 issue of Journal of Neuroinflammation, “Associations between gut microbiota and Alzheimer’s disease, major depressive disorder, and schizophrenia.” While some interesting associations have been found, the solution to the Alzheimer’s disease pathogen hypothesis puzzle has yet to be solved.
The search, however, continues. In December 2020, the University of Texas at San Antonio closed entries for the Oskar Fischer Prize—a four million dollar prize to be awarded to scientists who review the existing medical literature and come up with a theory on what causes Alzheimer’s disease. The prize is named after Oskar Fischer, a Czech psychiatrist, neuropathologist and rival of Alzheimer, who published a paper in 1907 describing neuritic plaque in 12 cases of senile dementia. Fischer did not receive recognition for his work due to academic competition between the Prague and Munich schools of neuropathology as well the rampant antisemitism that existed in Europe at that time. (Fischer died in Therensienstadt Concentration Camp in 1942). Fischer was, however, the first on record to suggest that chronic infection might be the cause for what we today call Alzheimer’s disease. Moreover, the rediscovery in 2008 of his papers has led to a reexamination of his research and seems to suggest that Fischer was considerably closer than anyone else—either then or now—to discovering the cause of Alzheimer’s disease.
What should you do to prevent Alzheimer’s disease? There is no known cure or treatment for Alzheimer’s disease. Admittedly, I am biased in my enthusiasm for the renaissance of the interest in the “pathogen hypothesis of Alzheimer’s disease.” This is not only because of my background as an infectious diseases specialist and my personal research interest in defense against and damage to the brain by microbes, but also because I am old, that is, at risk.
New research suggests, however, that the flu and pneumococcal pneumonia vaccines may lower the risk of Alzheimer’s. I therefore highly recommend these vaccines for everyone. Moreover, the National Institute of Aging is funding a clinical trial of valcyclovir, an agent active against HSV-1, in patients with Alzheimer’s disease. At this juncture, it is premature to recommend this antiviral.
I am encouraged by a recent Dutch study showing that many centenarians (people who are over 100 years old) don’t have evidence of Alzheimer’s despite high levels of beta-amyloid protein in their brains. The study suggests that lifestyle modifications, such as exercising and a nutritious diet, play a role in “brain healthy” longevity. This may be an old idea, but it’s certainly food for thought.
