Alzheimer’s may start with inflammation in the skin, lungs or gut

Alzheimer’s disease has long been thought of as something that begins inside the brain, but extensive genomic analysis suggests it may initially be triggered by inflammation in distant organs like 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 been disappointing so far, because they work too late in the disease process. Instead, we may need to redirect our efforts toward combating inflammation in other parts of the body.

“As neuroscientists, we tend to be very brain-focused, but this study really highlights the fact that the brain is not disconnected from the rest of the body and that when changes occur in the rest of the body, it affects how the brain functions,” says Donna Wilcock of Indiana University, who was not involved in the research. “Even though Alzheimer’s disease is a brain disease, we need to think about the whole body when we think about how it begins.”

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

In this comprehensive study, researchers looked at 1,000 genes with variants that increase the risk of Alzheimer’s disease. To their surprise, these seemed much less present 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 looked wrong because the expression of these genes in individual brain cells was extremely low,” says Cunha. “But we did more analysis and the more we looked at them, the more we realized that they weren’t really in the brain, but rather in other parts of the body.”

Many of these Alzheimer’s disease risk genes are known to be involved in immune regulation. Additionally, they tend to be more prevalent in barrier tissues – like the skin, lungs and intestines – which regularly defend against germs, toxins and allergens by increasing inflammatory responses. This suggests that Alzheimer’s disease might actually start with inflammation of these non-brain organs, called peripheral organs, Cunha says. Certain genetic variants can influence the degree of peripheral inflammation experienced and its impact on the brain, he says. If so, people with a family history of Alzheimer’s disease who inherit these genetic variants may be more likely to develop Alzheimer’s disease in response to an infection or other inflammatory event.

Intriguingly, the team discovered the highest expression of these genetic variants when people were aged 55 to 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 elevated inflammatory markers in their blood in their late 50s were more likely to develop the disease in their 70s and 80s. “You could have lung inflammation from a viral infection at age 55, and that could translate into Alzheimer’s disease 30 years later. But we don’t know why yet, so there’s a very big piece in this whole puzzle that hasn’t been solved,” Cunha says.

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

Still, the findings build on a series of emerging studies showing that people with all kinds of inflammatory conditions — including eczema, cold sores, pneumonia, gum disease, Lyme disease, syphilis, diabetes, high blood pressure and intestinal infections — are more likely to develop Alzheimer’s disease. This association is particularly strong if inflammation occurs during midlife, between ages 45 and 60, consistent with Cunha and his team’s observations.

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

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

At the same time, research by other groups has shown that the blood-brain barrier becomes more permeable with age, which 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 problematic in midlife than in younger years, Cunha says.

Currently, the dominant understanding of Alzheimer’s disease is that it is caused by an 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 disease rather than a root cause. “The problem is that we are trying to treat the end result of the disease,” says Cunha.

This is similar to previous missteps in the obesity field, he says. In the past, anti-obesity drugs were developed to directly target excess fatty tissue, but they did not work. Then, genomic studies revealed that variants associated with obesity tended to be more highly 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 like Ozempic and Wegovy), which modulates brain pathways to reduce appetite.

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

One promising avenue is that vaccination at midlife appears to protect against Alzheimer’s disease. A recent study in California found that adults who received both doses of the shingles vaccine, recommended for everyone aged 50 or older in the United States, were about 50% less likely to develop Alzheimer’s disease starting at age 65. Another study found that people aged 50 or older who received the Bacillus Calmette-Guérin (BCG) vaccine to treat bladder cancer had a 20% lower risk of getting Alzheimer’s disease.

This may be because vaccines strengthen the aging immune system and thus reduce inflammation, Wilcock said. “At 55, maybe we should shake the immune system by the shoulders and say, ‘Hey, you need to wake up, you still need to work,'” she says. “Because usually we get all our vaccines when we’re kids.”

Besides vaccines, several other interventions have been shown to reduce inflammation and protect against Alzheimer’s disease. These include following a Mediterranean diet, limiting alcohol consumption, exercising, not smoking, and reducing 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. “At conferences, I’ve been told, ‘If you’re not studying amyloid, you’re not studying Alzheimer’s disease,'” he says. “Obviously, if you’ve been focused on amyloid for 30 or 40 years, it can be difficult to change your perspective.”