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

Alzheimer’s disease has long been thought to originate in the brain, but a thorough 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 reshaping of the disease may explain why Alzheimer’s drugs have been disappointing to date, because they work too late in the disease process. Instead, we may need to redirect our efforts towards inflammation in other parts of the body.

“As neuroscientists, we tend to be very brain-centric, but this study really shines a spotlight on the fact that the brain is disconnected from the rest of the body, and when changes happen in the rest of the body, it affects how the brain works,” says Donna Wilcock of 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 explore the genetic basis of Alzheimer’s disease, Cesar 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 condition and 485,000 people without it from the European Alzheimer and Dementia Biobank. They also analyzed gene activity in 5 million single cells from 40 areas of the body 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, these appeared to show up far less 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 single cells in the brain was extremely low,” says Cunha. “But we ran more analyzes and the more we looked at it, the more we realized that they weren’t really in the brain, they were mostly in other parts of the body.”

Many of these Alzheimer’s risk genes are known to be involved in immune regulation. Moreover, they tended to be most prevalent in barrier tissues – such as the skin, lungs and gut – which regularly defend themselves against bacteria, toxins and allergens by developing inflammatory responses. This suggests that Alzheimer’s disease may actually start with inflammation in these non-brain organs, known as peripheral organs, says Cunha. Certain genetic variants can affect the degree of peripheral inflammation experienced and whether it continues to 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 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 men with elevated markers of inflammation in their blood in their late 50s were more likely to develop the condition in their 70s and 80s. “You can get inflammation of the lungs from a viral infection when you’re 55, and that can translate to Alzheimer’s 30 years later. But we don’t know why yet, so there’s a very big piece of this whole puzzle that hasn’t been figured out,” says Cunha.

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

Still, the findings build on a series of new 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 down the road. This association is particularly strong if the inflammation occurs in midlife, around ages 45 to 60, according to Cunha and his team’s observations.

Previously, the brain was considered an immune-privileged organ that was not affected by inflammatory processes occurring elsewhere in the body, says Bryce Vissel at St Vincent’s Hospital in Sydney, Australia. Vissel and his colleagues were one of the early groups to suggest 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 cross from the blood to the brain. In unpublished research, Vissel and his colleagues have shown that cytokines can activate processes that damage connections between brain cells, which can be a precursor to memory problems.

At the same time, research from other groups has shown that the blood-brain barrier becomes more permeable with age, which can allow greater penetration of inflammatory cytokines and immune cells from the blood into the brain. This may explain why inflammation appears to be more problematic in mid-life than in younger years, says Cunha.

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 the condition, rather than an underlying cause. “The problem is that we have tried to treat the end result of the disease,” says Cunha.

This is similar to missteps that were previously taken in the field of obesity, he says. In the past, obesity drugs were developed to directly target excess adipose tissue, but they did not work. Subsequently, genomic studies showed that variants associated with obesity tended to be more expressed in the brain, causing dysregulation of appetite and energy balance. This led to Novo Nordisk’s development of the weight loss drug semaglutide (sold under names such as Ozempic and Wegovy), which modulates brain pathways to reduce appetite.

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

One promising clue is that vaccination in mid-life appears to be protective against Alzheimer’s disease. A recent California study found that adults who received both doses of the shingles vaccine, which is recommended for anyone age 50 or older in the United States, were about 50 percent less likely to develop Alzheimer’s disease at age 65 and older. Another study found that people age 50 or older who received the Bacillus Calmette-Guérin (BCG) vaccine as a bladder cancer treatment had a 20 percent lower risk of developing Alzheimer’s.

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

Aside from vaccines, there are several other interventions that have been shown to reduce inflammation and protect against Alzheimer’s disease. These include eating a Mediterranean diet, limiting alcohol intake, 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. “At conferences, I’ve been told, ‘If you don’t study amyloid, you don’t study Alzheimer’s,'” he says. “Of course, if you’ve been focused on amyloid for 30 or 40 years, it can be difficult to change your point of view.”