Are some cases of Alzheimer's disease caused by infection?

What causes Alzheimer's disease? "I've spent most of my professional life trying to answer that question," says neuroscientist Rudolph Tanzi, director of the McCance Center for Brain Health at Harvard-affiliated Massachusetts General Hospital. It's an important question to answer, because Alzheimer's is the most common form of dementia in many countries. In the United States, at least 10% of people over age 65 have the disease.

As with most diseases, Alzheimer's is probably due to a combination of inherited vulnerability, the presence of other conditions, and social and lifestyle factors. And now scientists are investigating what part, if any, infection might play in Alzheimer's development.

Uncovering biological causes

Alzheimer's disease was first described in 1906, but scientists began unraveling the mystery of its cause just 40 years ago. Today, researchers widely accept that two molecules are found at high levels in the brains of people with Alzheimer's: amyloid-beta, which forms plaques in the brain, and tau, which forms tangles. Both contribute to the death of brain cells (neurons) involved in thinking, leading to dementia.

Amyloid-beta probably is the most important molecule. It shows up earlier than tau. And Tanzi and others have shown that people who inherit a gene that leads them to have high levels of amyloid-beta develop Alzheimer's at a relatively young age. People who inherit two copies of the APOE4 gene variant are at even greater risk of developing Alzheimer's, because they are less able to clear amyloid-beta out of the brain.

Neuroinflammation

Inflammation in the brain (neuroinflammation) is increasingly accepted as an important factor in Alzheimer's. In neuroinflammation, the brain's own immune system cells fight invading microbes or work to heal injury. Unfortunately, that also can cause injury, leading to more neuroinflammation — a vicious cycle that ultimately causes most of the death of neurons.

Both amyloid-beta plaques and tau tangles can trigger neuroinflammation, and so can many microbes (bacteria and viruses). Some microbes can infect the brain and remain there without being completely eradicated by the brain's immune system, potentially leading to chronic, low-grade neuroinflammation. Even infections or other causes of inflammation outside of the brain, anywhere in the body, can send signals to the brain that trigger neuroinflammation.

Infection and Alzheimer's

Some scientists believe infection might do more than cause neuroinflammation. Infection might also play a role in igniting amyloid-beta deposits and tau tangles. "My colleague, the late Rob Moir, and I found that amyloid-beta is deposited in the brain in response to infection. It is a protein that defends against infection: it forms a web that entraps invading microbes," Tanzi says. "In other words, amyloid-beta helps protect our brain from infection. That's the good news. The bad news is that amyloid-beta also damages neurons which, over 10 to 30 years, starts to have obvious effects on cognition, ultimately leading to dementia."

In addition, the chronic low-grade deposition of amyloid-beta leads to tau tangles that also kill neurons and further increase neuroinflammation, which leads to more neuron death. Vicious cycles can develop and be very hard to stop (see "The cycle of neuron damage").

Microbes linked to Alzheimer's

Which microbes might encourage Alzheimer's development? "I think it's very unlikely that just one type of microbe — an 'Alzheimer's germ' — is a cause," says Dr. Anthony Komaroff, editor in chief of the Harvard Health Letter and professor at Harvard Medical School. "Instead, growing evidence suggests that a number of different microbes all can trigger Alzheimer's in some people."

The evidence comes from studies of the brains of rodents and other animals that have been infected with microbes, as well as by finding microbes in the human brain regions most affected by Alzheimer's. Evidence also comes from huge studies showing that the risk of developing Alzheimer's is much higher in people who, decades before, experienced a severe infection. And recent studies suggest that Alzheimer's risk might increase because of shrinkage of the brain and a persistence of several inflammation-related proteins in the blood of people with past infections.

Here are some microbes identified as potential culprits.

Viruses. Some studies have found DNA from herpes simplex virus 1 and 2 (the viruses that cause cold sores and genital sores) more often in the brains of individuals with Alzheimer's than in healthy people. The viral DNA is especially prominent adjacent to amyloid-beta plaques. Published studies have come to contradictory results. Tanzi's laboratory is growing "mini-brains"—groups of human brain cells. When these mini-brains are infected by herpes simplex virus, they start producing amyloid-beta.

Another herpesvirus that can infect the brain, varicella-zoster virus (which causes chickenpox and shingles) also may increase the risk of dementia. A study of almost 150,000 people, published Aug. 14, 2024, by Alzheimer's Research & Therapy, found that people who'd had shingles were more likely to later report problems remembering simple things. Ongoing research is exploring a connection between shingles vaccine and lower Alzheimer's risk.

The virus that causes COVID-19, known as SARS-CoV-2, may also make the brain vulnerable to Alzheimer's. A very large study compared people who had contracted COVID (even mild cases) to people of similar age and sex who had not had COVID, and found that over the next three years, those who'd had COVID were nearly twice as likely to develop Alzheimer's.

Several other viruses (and bacteria) that infect the lung also have been linked to Alzheimer's, though the evidence is more preliminary.

Gum bacteria. Several bacteria that commonly live in our mouths and are causes of gum disease (periodontitis) may increase the risk of Alzheimer's. This is plausible, Tanzi points out, because "our upper teeth offer direct neural paths into the brain." Tanzi's preliminary findings are consistent with a role for gum bacteria. Published studies on the subject come to different conclusions.

Gut bacteria. In the past 25 years, scientists have discovered that the bacteria living in our intestines make substances that affect our health, for better or for worse. "It's one of the most important biomedical discoveries of our lifetime," Dr. Komaroff says. There is some early evidence that these bacteria can affect a person's risk of later developing Alzheimer's. How to change the composition of the gut bacteria to reduce the risk remains to be determined.

Lifestyle factors and Alzheimer's

Many different lifestyle factors are linked to an increased risk for developing Alzheimer's. Examples include smoking (particularly in later life), excessive alcohol use, physical inactivity, insufficient deep sleep, exposure to air pollution, and a diet rich in sugar, salt, and highly processed foods. Many of these lifestyle factors also increase risk for other common chronic conditions, such as high blood pressure, diabetes, and obesity.

"Because making lifestyle changes can be hard, many people hope studying biological causes of Alzheimer's will lead to a 'magic bullet' medicine that prevents or even reverses the disease. That day could come, but probably not in the near future," says Dr. Komaroff.

What you should do

For today, Tanzi suggests that you practice lifestyle adjustments that may reduce your risk of developing the disease (see "Ways to reduce your risk of Alzheimer's disease").

The idea that microbes may trigger some cases of Alzheimer's is unproven, and still not widely accepted, but the evidence is growing stronger. The idea does fit, however, with previous research showing the importance of amyloid-beta, tau, APOE4, and neuroinflammation as causes of Alzheimer's. "Invoking microbes in some cases of Alzheimer's does not replace the older ideas," Dr. Komaroff says. "Instead, it fits with and possibly completes the older ideas."

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