Rethinking the Most Common Causes of Death

Laird Harrison

Disclosures

February 27, 2019

Could our whole theory about the most common causes of death be wrong?

Over the past few decades, the focus of public health has shifted from infectious diseases to lifestyle. Now that we have tamed such scourges as tuberculosis, pneumonia, and cholera, the story goes, we need to focus on exercise and diet. With a bit more self-discipline, we could avoid heart disease, cancer, diabetes, and perhaps even Alzheimer disease.

But what if those killers turn out to be like the old ones—caused, at least in part, by pathogens? It's not a new idea, and it remains outside the mainstream. But proponents argue that recent findings merit much more attention than they have received.

"The evidence is accumulating steadily that these conditions are linked to infection, and yet government agencies, such as the US National Institutes of Health, award almost no funding [to research this topic]," says Richard Lathe, PhD, DSc, an honorary professor of biology at the University of Edinburgh, Scotland.

All three diseases become more common with age, and someone with one of these diseases has an increased risk for the others.

If borne out, the pathogen paradigm could lead to new treatments, perhaps revolutionizing the way the most common diseases are managed. And it could help to explain why seemingly unrelated diseases appear more similar as their causes are investigated.

Alzheimer disease, diabetes, and atherosclerosis all notably involve the buildup of apparently deleterious proteins. Inflammation plays a role in all of them. Insulin resistance figures in both type 2 diabetes and Alzheimer disease. All three diseases become more common with age, and someone with one of these diseases has an increased risk for the others.

The idea that germs might cause senile dementia dates back at least to 1907.[1] But the notion of pathogens as an important factor in Alzheimer disease, type 2 diabetes, cancer, peptic ulcers, or atherosclerosis took a backseat to other apparently more convincing theories—until startling exceptions started cropping up.

In 1989, Michael Bishop and Harold Varmus received the Nobel Prize for the discovery that some retroviruses can cause cancer. In 2005, Barry Marshall and Robin Warren were awarded the same prize for their finding that a bacterium causes gastritis and peptic ulceration. And in 2008, it went to Harald zur Hausen for the discovery that human papillomaviruses can cause cervical cancer.

Could a similar event be in store for Alzheimer disease, diabetes, and atherosclerosis?

The Emerging Link Between Viruses and Alzheimer Disease

For Alzheimer disease particularly, the evidence is tantalizing. Researchers of this disease have long focused on the formation of amyloid plaques and tau tangles. Without quite knowing why these molecules were created, they concentrated on eliminating them. But experimental treatments don't seem to ameliorate the dementia that is the primary symptom of the disease.

"I believe the amyloid theory is more or less on the way out, that amyloid is a by-product," says Jørgen Rungby, MD, PhD, a professor of endocrinology and the University of Copenhagen, Denmark, who is investigating the relationship of Alzheimer disease to type 2 diabetes.

But a by-product of what, exactly? Ruth F. Itzhaki, PhD, thinks she knows. A professor emeritus of neuroscience and experimental psychology at the University of Manchester, United Kingdom, Itzhaki noted back in 1997 that 60% of people with Alzheimer disease had both herpes simplex virus type 1 (HSV1) in their brains and the apolipoprotein E gene (APOE-ε4).[2]

Although the virus is present in the brains of most of people older than 70 years, those who developed Alzheimer disease usually also have the gene. She and others postulated that the gene weakens resistance to the virus. Researchers have found that the gene's carriers are also more vulnerable to cold sores and genital ulcers caused by herpes viruses.[3] After an initial infection, the virus may remain dormant until the immune system further weakens with age.

Other researchers found viral DNA in amyloid plaques and tau protein in cell cultures infected with HSV1, leading them to conclude that these proteins serve as a defense mechanism against the virus.[3] In one study, amyloid beta reduced the growth of Escherichia coli by up to 200-fold in vitro, and was also active against Candida albicans.[4]

"First the antimicrobial proteins cause destruction of the membrane, effectively killing the pathogen," says Lathe. "Then there is increasing evidence that the aggregation by these proteins causes agglutination; the microbe becomes trapped in these insoluble matrices."

Will This Open Up New Treatment Opportunities?

If Alzheimer disease is caused by a virus, then suppressing the virus should help, a theory that is supported by some emerging evidence. In Taiwan, where data on infections are carefully maintained, researchers found that HSV-infected patients treated with antiherpes agents had a 5.8% risk of developing senile dementia, whereas HSV-infected patients who were not treated had a 28.3% risk for senile dementia. (The researchers focused on senile dementia because not all the patients had been definitively diagnosed with Alzheimer disease.)[5]

The finding is enough to convince Lathe of clinical implications. "If you have a patient with overt herpes simplex, don't wait for it to go away, but if you can possibly do so, intervene with aggressive antiviral medication," he says. "It's a very good idea, because that patient may not get Alzheimer disease later on."

The approach has not been tested in a prospective trial, however, nor have antivirals been studied as a treatment for patients who have already developed dementia. One possibility is that they keep the virus from reaching the brain, but can't undo the damage once the virus is there.[3]

Extending the Viral Link to Other Conditions 

Similar, though less dramatic, findings have associated viral infections with schizophrenia,[6] epilepsy,[3] Parkinson disease,[7] and depression.[8] Lathe is working on the theory that prions are antimicrobial as well.

Lathe also believes that similar mechanisms may explain atherosclerosis, which, like Alzheimer disease, is associated with vascular occlusion and decreased cerebral blood flow. The same allelic variants in genes, including APOE, increase the risk for both diseases, and also hyperlipidemia. Moreover, atherosclerotic lesions contain amyloid beta.[9]

Scrutinizing the biochemistry of the two conditions, Lathe theorizes that infection leads to inflammation, including the production of 25-hydroxycholesterol to defend against viruses. The resulting cascade ends in "intracellular accumulation of cholesteryl esters and lipid droplets, vascular occlusion, and overt disease."[9]

For type 1 diabetes, the theories of infection are less controversial. Although no one knows exactly what sets off the process, most researchers believe that a pathogen triggers an immune response that somehow goes awry, turning into an autoimmune attack on the pancreas.

Genetic predisposition is key, but the prevalence varies among genetically similar populations, and even among identical twins. Sudden onset of type 1 diabetes has been reported in conjunction with mumps, parainfluenza, human herpesvirus, and enteroviruses, among other pathogens.[10]

"The protein deposited in diabetes, called amylin, is also an antimicrobial protein," Lathe says.

Evidence in Type 2 Diabetes

Could such infections play a role in type 2 diabetes as well? The increase in prevalence has so closely paralleled the introduction of the Western lifestyle and the rise of obesity that questions about infection have not gained much traction. Still, some researchers believe in a role for infection here as well.

For example, they note that periodontitis is a common risk factor for several chronic inflammatory disorders, including atherosclerosis, stroke, diabetes, and Alzheimer disease.[11]

Infections with Helicobacter pylori and Borrelia are also associated with diabetes. And amyloid beta and amylin deposits, similar to those found in Alzheimer disease, are present in more than 95% of patients with type 2 diabetes. These findings have prompted speculation that a common process unfolds in these diseases, once again entailing an immune response in which amyloid beta and amylin act as antimicrobials but are either unable to completely contain the infections or themselves do damage to healthy tissue.[11]

"If you're an antimicrobial protein produced by a human, you have a tough time to be 100% toxic to microbes and 0% toxic to human cells," says Lathe. "There will always be a little bit of toxicity."

Remaining Questions

Lathe acknowledges that many details need to be worked out, and some evidence is contrary. To cite just one example, knocking out the APOE gene delays Alzheimer disease but accelerates atherosclerosis in a mouse model of that disease.[9]

But perhaps the biggest problem is that no microbe has been definitively proven to cause any of these diseases. Apart from herpes simplex in Alzheimer disease, researchers haven't even found a prime suspect. So many experts remain skeptical.

"We do know that there is inflammation involved in these diseases," says Rungby. "But whether that inflammation is caused by a virus or bacterium is, to my mind, very unlikely." If it were, the pathogens would have been identified by now, he argues.

He does see connections between the diseases, though he doesn't necessarily condone the classification of Alzheimer diabetes as "type 3 diabetes." Both conditions involve insulin resistance and poor glucose metabolism, he points out.

Rungby worked on a study of the type 2 diabetes medication liraglutide in Alzheimer disease. Glucose metabolism improved in the patients' brains.[12] Although the study was not big enough to detect cognitive effects, a larger trial is under way.

A variety of other diabetes drugs have been tried in Alzheimer disease. Insulin administered intranasally had promising results.[13]

The exploration of atherosclerosis drugs for Alzheimer disease and vice versa has not proceeded as far. But trials in mice suggest that both acyl-CoA cholesterol acyltransferase inhibitors and acetylcholinesterase inhibitors might work in both diseases. The findings suggest numerous possibilities for trying treatments for one disease out in another.[9]

Do such findings relieve us of the injunction to eat, exercise, and sleep better? No such luck, says Lathe. Antimicrobials in plants—curcumin and resveratrol are only two of hundreds of possible examples—may attack the microbes behind diabetes, atherosclerosis, and Alzheimer disease, so it's still worthwhile eating lots of fruits and vegetables, Lathe says. And exercise boosts the immune system.

For the time being, a healthy lifestyle remains the best defense against the biggest killers of the 21st century.

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