What do people fear the most about getting old? The answer is Alzheimer’s disease. Indeed, a 2014 poll conducted in the United Kingdom found that two thirds 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 percent 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 major diseases that cannot be treated, prevented or cured. 99.6 percent 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 trials. Despite the thousands of scientists who are conducting research on Alzheimer’s, the Food and Drug Administration hasn’t approved a new Alzheimer’s drug since 2003.

Existing medications have mostly sought to inhibit the protein amyloid beta. For the past few decades, the majority of researchers have agreed that abnormal production of amyloid beta 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 amyloid beta 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 amyloid beta 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 amyloid beta may not be intrinsically pathological. To be clear, excessive levels of amyloid beta certainly contribute to Alzheimer’s, but it would be wrong to characterize amyloid beta 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, amyloid beta 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 percent 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 amyloid beta production in infected cell cultures and furthermore that 90 percent of amyloid beta 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, Eimer and his colleagues demonstrated that amyloid beta 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 amyloid beta fought the virus more effectively than normal rodents.

Eimer’s findings align with the antimicrobial protection hypothesis (APH), which states that amyloid beta 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 amyloid beta 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. Amyloid beta itself is a very old protein, one that may have evolved some 540–630 million years ago, and it is conserved incredibly well across a variety of vertebrates. Thus, it is possible that amyloid beta has been fighting HSV-1 for a very long time.

Tanzi and Moir, the neuroscientists who came up with the APH, point out that many antimicrobial peptides like amyloid beta 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 amyloid beta 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 defends 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 amyloid beta 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 that undergoing treatment for HSV-1 lowered their risk of Alzheimer’s by over 80 percent.

Perhaps if researchers seriously consider the role of pathogens and examine their interactions with amyloid beta 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 three-dimensional 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.