Kenneth Shinozuka and Dhruva Gupta
This article was recently published under the title “Could Alzheimer’s Be a Reaction to Infection?” in the op-ed blog of Scientific American.
Header image taken from here.
What do people fear the most about getting old? The answer is Alzheimer’s disease. Indeed, a 2014 poll conducted in the UK found that 2/3 of people over the age of 50 were worried about developing dementia, which primarily manifests in the form of Alzheimer’s disease, while just 10% were concerned about getting cancer.
They fear the disease for good reason: in some places, Alzheimer’s is the leading cause of death, and the number of Alzheimer’s patients is expected to triple by 2050. However, it is also one of the few prevalent diseases that cannot be treated, prevented, or cured. 99.6% of Alzheimer’s drugs developed between 2002 and 2012 failed in clinical trials, and since then, multiple treatments that appeared to be promising delivered disappointing results in FDA trials. Despite the thousands of scientists who are conducting research on Alzheimer’s, the FDA hasn’t approved a new Alzheimer’s drug since 2003.
These drugs have mostly sought to inhibit the protein amyloid beta (Aβ). For the past few decades, the majority of researchers have agreed that abnormal production of Aβ triggers the neurodegeneration that occurs in Alzheimer’s. However, the repeated failure of the drugs would appear to suggest that the so-called “amyloid beta hypothesis” may not be entirely correct. Staunch believers in the hypothesis assert that the drugs either were flawed or were not administered to patients at the right time; aggregates of Aβ known as plaques can form in the brain decades before people begin to exhibit symptoms of Alzheimer’s. Time will tell whether this claim holds ground, as initiatives like the A4 study test drugs that lower Aβ production on elderly people who are at risk of Alzheimer’s but haven’t yet developed the symptoms. In the meantime, it’s worth at least entertaining the possibility that Aβ may not be intrinsically pathological. To be clear, excessive levels of Aβ certainly do contribute to Alzheimer’s, but it would be wrong to characterize Aβ as a protein whose sole function in the brain is to cause disease.
Furthermore, this view is not merely speculative. According to recent hypotheses that have firm empirical support, Aβ may, in fact, be a tool that the brain uses in order to fight the underlying cause of Alzheimer’s: infections by pathogens, such as viruses, bacteria, and fungi. Many different pathogens have been linked to Alzheimer’s; one that has been studied quite extensively is Herpes Simplex Virus Type-1 (HSV-1). In part because it is orally transmitted, this virus is very ubiquitous, present in over 67% of people around the world who are under age 50. The immediate effects of HSV-1 are mostly harmless: the majority of those who are infected display cold sores, and some never even exhibit any symptoms. But in 1997, a team of scientists led by Ruth Itzhaki at the University of Manchester found that HSV-1 infection in people who have the APOE ε4 gene, which is, on its own, associated with Alzheimer’s, have a much higher risk of developing the condition. More recently, Itzhaki and her colleagues have shown that HSV-1 causes a dramatic increase in Aβ production in infected cell cultures and furthermore that 90% of Aβ plaques contain the viral DNA of HSV-1. A large share of the research that has been conducted thus far has established a correlation between HSV-1 and Alzheimer’s but not a causal relationship. However, in the past few years, William Eimer, who is conducting research in the labs of Rudolph Tanzi and Robert Moir at Harvard Medical School, has sought out the causal mechanisms by which HSV-1 triggers the telltale signs of Alzheimer’s. In particular, they demonstrated that Aβ binds to the surface of HSV-1 and forms fibrils in order to entrap the virus before it adheres to cells in the brain. In Eimer’s research, mice that expressed higher concentrations of Aβ fought the virus more effectively than normal rodents.
Eimer’s findings align with the antimicrobial protection hypothesis (APH), which states that Aβ actually serves a positive role when it is produced at normal concentrations: it protects the brain from pathogenic infections. The APH stemmed from the discovery that Aβ is very similar to an antimicrobial peptide known as LL-37, which is part of an ancient immune system found in many different biological organisms. Aβ itself is a very old protein, one that may have evolved over 540-630 million years ago, and it is conserved incredibly well across a variety of vertebrates. Thus, it is possible that Aβ has been fighting HSV-1 for a very long time.
Rudolph Tanzi and Robert Moir, the neuroscientists who came up with the APH, point out that many anti-microbial peptides like Aβ modulate several immune pathways, thereby influencing the brain’s response to pathogenic infections. (For instance, these peptides may regulate cell death processes.) When these pathways become chronically over-activated, the brain undergoes inflammation, which Tanzi and other researchers consider to be the most important stage in the progression of Alzheimer’s. Indeed, inflammation might trigger the pervasive cell death that occurs in the brains of late-stage Alzheimer’s patients. Ironically, the activity of Aβ ends up damaging the brain because it is seeking to mitigate the harms of infection, not to exacerbate them.
The APH is still highly controversial. John Hardy, a molecular biologist at the University College London who buys into the mainstream amyloid beta hypothesis, believes that plaques would be more widely distributed in the brains of Alzheimer’s patients if the disease were actually caused by pathogens. Additionally, he says, a small but substantial percentage of Alzheimer’s patients inherit the disease genetically, so pathogenic infections cannot be entirely responsible for the disease. Even Moir acknowledges that we still don’t know for certain whether pathogens are a cause or a consequence of Alzheimer’s. The disease makes the brain more susceptible to infection by weakening the blood-brain barrier, so infection may actually occur after a patient has already gotten Alzheimer’s.
Ultimately, the APH will gain more support if drugs that suppress infection are shown to treat or prevent Alzheimer’s. In fact, there is already promising evidence that suggests that these drugs could be effective. In 2011, Itzhaki and her colleagues showed that the anti-herpes drug acyclovir reduces levels of Aβ in cell cultures that were infected with HSV-1. Last year, a study involving over 34,000 Taiwanese patients found that people who were infected with HSV-1 were 2.56 times more likely to get dementia, but undergoing treatment for HSV-1 lowered their risk of Alzheimer’s by over 80%.
Perhaps if researchers seriously consider the role of pathogens and examine their interactions with Aβ as well as the role of blood brain barrier more carefully, then we will finally be able to overcome our current impasse in finding a cure. In Tanzi’s lab at Harvard Medical School, we are actively pursuing these avenues, developing cutting-edge technology for evaluating pathophysiological mechanisms involved in a 3-D cell culture model (more aptly known as ‘Alzheimer’s-in-a-Dish’). Only through these types of innovative approaches will we be able to accelerate the development of novel therapeutic approaches in the quest to treat and ultimately eradicate this enigmatic disease.