Alzheimer’s disease can start with inflammation in the skin, lungs, or intestines

Alzheimer’s disease has long been thought to originate in the brain, but an in-depth genomic analysis suggests that it may initially be triggered by inflammation in distant organs such as the skin, lungs or gut – perhaps decades before a person’s memory begins to decline. This radical reframing of the disease may explain why Alzheimer’s drugs have so far been disappointing because they act too late in the disease process. Instead, we may need to redirect our efforts to address inflammation in other parts of the body.

“As neuroscientists we tend to be very brain-centric, but this study really sheds light on the fact that the brain is not disconnected from the rest of the body, and when there are changes in the rest of the body, it affects how the brain works,” he says. Donna Wilcock at Indiana University, who was not involved in the research. “Even though Alzheimer’s is a brain disease, we have to think about the whole body when we think about how it starts.”

To investigate the genetic basis of Alzheimer’s disease, César Cunha at the Novo Nordisk Foundation Center for Basic Metabolic Research in Denmark, and his colleagues studied genetic data from more than 85,000 people with the disease and 485,000 people without it from the European Biobank for Alzheimer’s and Dementia. They also analyzed gene activity in 5 million individual cells from 40 body regions and 100 brain regions.

As part of this deep dive, the researchers examined 1,000 genes with variants that increase the risk of Alzheimer’s disease. To their surprise, they appeared to be much less abundant in the brain than in other organs such as the skin, lungs, digestive system and spleen, as well as in various types of immune cells circulating in the blood. “I kept looking at the graph and it seemed wrong because the expression of these genes in individual cells in the brain was extremely low,” says Cunha. “But we did more analysis and the more we looked at it, the more we realized that they really weren’t in the brain, they were mostly in other parts of the body.”

Many of these Alzheimer’s disease risk genes are known to be involved in immune regulation. What’s more, they tended to be most abundant in barrier tissues—such as the skin, lungs, and gut—that regularly defend against germs, toxins, and allergens by increasing inflammatory responses. This suggests that Alzheimer’s disease may actually start with inflammation in these non-brain organs, known as peripheral organs, Cunha says. Certain genetic variants can affect the degree of peripheral inflammation and whether it will affect the brain, he says. If so, people with a family history of Alzheimer’s disease who inherit these genetic variants may be more susceptible to developing Alzheimer’s disease in response to an infection or other inflammatory event.

Interestingly, the team found the highest expression of these gene variants when people were between the ages of 55 and 60, suggesting that inflammation during this window is most likely to lead to Alzheimer’s disease. This is supported by a long-term study in Hawaii that found that men with increased markers of inflammation in their blood in the late 50s they were more likely to develop the condition in their 70s and 80s. “At 55, you can get inflammation in your lungs from a viral infection, and 30 years later it could translate into Alzheimer’s disease. But we don’t know why yet, so there’s a very big piece of this whole puzzle that hasn’t been solved,” Cunha says.

Rezanur Rahman at the QIMR Berghofer Medical Research Institute in Australia and colleagues also recently found that genetic variants associated with Alzheimer’s disease they seem to cluster in the skin and lungs. But more work is needed to show that they actually play a functional role in the development of the condition, Rahman says. “Association does not imply causation.”

However, the findings come from a number of emerging studies that show that people with all kinds of inflammatory conditions—including eczema, cold sores, pneumoniagum disease, Lyme disease, syphilis, diabetes, high blood pressure and intestinal infection – are more likely to develop Alzheimer’s later. This association is particularly strong if inflammation occurs in middle agearound the ages of 45 to 60, which is consistent with the observations of Cunha and his team.

In the past, the brain was considered an immune-privileged organ that was unaffected by inflammatory processes occurring elsewhere in the body, he says Bryce Vissel at St Vincent’s Hospital in Sydney, Australia. Vissel and his colleagues were one of the first groups to propose inflammation as a driver of Alzheimer’s disease, which was not widely accepted at the time, but now several teams have shown that peripheral inflammation in response to infection or injury can actually affect the brain.

During inflammation, immune cells are activated and signaling proteins such as cytokines are released, which are now known to travel from the blood to the brain. In unpublished research, Vissel and his colleagues showed that cytokines can activate processes that damage the connections between brain cells, which can be a precursor to memory problems.

At the same time, research by other groups has shown that the blood-brain barrier is becoming more permeable with agewhich may allow greater penetration of inflammatory cytokines and immune cells from the blood into the brain. This could explain why inflammation seems to be more of a problem in middle age than in younger years, Cunha says.

Currently, the prevailing understanding of Alzheimer’s disease is that it is caused by the accumulation of misfolded beta-amyloid and tau proteins in the brain. However, drugs that remove these proteins have had limited success, suggesting that their accumulation is a response to the condition rather than the underlying cause. “The problem is that we were trying to treat the end result of the disease,” says Cunha.

This is similar to the missteps previously made in obesity, he says. Medicines for obesity have been developed in the past it directly targets excess adipose tissuebut they didn’t work. Then, genomic studies revealed that variants associated with obesity tended to be more expressed in the brain, causing dysregulation of appetite and energy balance. This led Novo Nordisk to develop the weight loss drug semaglutide (sold under names such as Ozempic and Wegovy), which modulates brain pathways and reduces appetite.

If Alzheimer’s disease is indeed caused by peripheral inflammation, we will have to take different approaches to treating it, Cunha says.

One promising lead is that vaccination in middle age appears to be protective against Alzheimer’s disease. A recent study in California found that adults who received both doses of the shingles vaccine, which is recommended for everyone age 50 and older in the U.S., were about 50 percent less chance of developing Alzheimer’s disease aged 65 and over. Another study found that people age 50 or older who received the Bacillus Calmette-Guérin (BCG) vaccine as a treatment for bladder cancer had 20 percent lower risk get Alzheimer’s.

This may be because vaccines give the aging immune system a boost and thereby reduce inflammation, says Wilcock. “At 55, maybe we need to shake the immune system by the shoulders and say, ‘Hey, you’ve got to wake up, you’ve still got to work,'” he says. “Because we generally get all our vaccinations when we’re kids.”

In addition to vaccines, there are several other interventions that have been shown to reduce inflammation and protect against Alzheimer’s disease. These include catering and Mediterranean dietlimiting alcohol consumption, exercising, not smoking and lowering blood pressure and cholesterol.

Cunha says the challenge now is to convince other neuroscientists to consider peripheral inflammation as a potential driver of Alzheimer’s disease in the brain. “I’ve been told at conferences, ‘If you’re not studying amyloid, you’re not studying Alzheimer’s,'” he says. “Obviously, if you’ve been focusing on amyloid for 30 or 40 years, it can be hard to change your perspective.”

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