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

Alzheimer’s disease has long been viewed as something that originates inside the brain, but an in-depth 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 starts to decline. This radical reframing of the disease may explain why Alzheimer’s drugs have been disappointing to date, because they act too late in the disease process. Instead, we may need to redirect our efforts towards addressing 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 not disconnected from the rest of the body, and when changes happen in the rest of the body, it affects how the brain functions,” says Donna Wilcock at Indiana University, who wasn’t involved in the research. “Even though Alzheimer’s 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 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 analysed 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 1000 genes with variants that increase the risk of Alzheimer’s disease. To their surprise, these seemed to show up far less in the brain than in other organs like 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 analyses and the more we looked at it, the more we realised they really weren’t 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. What’s more, they tended to be most prevalent in barrier tissues – like the skin, lungs and gut – that regularly defend against germs, toxins and allergens by mounting inflammatory responses. This hints that Alzheimer’s disease may actually start off with inflammation in these non-brain organs, known as peripheral organs, says Cunha. Certain genetic variants may influence the degree of peripheral inflammation experienced and whether it goes on to affect the brain, he says. If so, people with family histories 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.

Intriguingly, 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-running study in Hawaii that found that men with raised markers of inflammation in their blood in their late 50s were more likely to develop the condition in their 70s and 80s. “You might get inflammation in your lungs from a viral infection when you’re 55, and that could translate to Alzheimer’s 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 figured out,” says Cunha.

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

Nevertheless, the findings build on a raft of emerging studies showing that people with all sorts of inflammatory conditions – including eczema, cold sores, pneumonia, gum disease, Lyme disease, syphilis, diabetes, high blood pressure and gut infections – are more likely to develop Alzheimer’s disease down the track. This association is particularly strong if the inflammation occurs during midlife, around age 45 to 60, consistent with Cunha and his team’s observations.

In the past, the brain was considered an immune-privileged organ that wasn’t 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 suggesting inflammation as a driver of Alzheimer’s disease, which wasn’t widely accepted at the time, but now several teams have shown that peripheral inflammation in response to infections or injuries can indeed affect the brain.

During inflammation, immune cells are activated and signalling proteins like cytokines are released, both of which are now known to cross from the blood into the brain. In unpublished research, Vissel and his colleagues have shown 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 during midlife than in younger years, says Cunha.

Currently, the dominant understanding of Alzheimer’s disease is that it is caused by a build-up of misfolded beta-amyloid and tau proteins in the brain. However, drugs that clear out these proteins have had limited success, hinting that their accumulation is a response to the condition, rather than a fundamental cause. “The issue is that we’ve been trying to treat the end result of the disease,” says Cunha.

This is similar to missteps that were previously taken in the obesity field, he says. In the past, obesity drugs were developed to directly target excess fat tissue, but they didn’t 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 to Novo Nordisk’s development of the weight-loss drug semaglutide (sold under names like Ozempic and Wegovy), which modulates brain pathways to reduce appetite.

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

One promising lead is that vaccination in midlife seems 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 anyone aged 50 or over in the US, were about 50 per cent less likely to develop Alzheimer’s disease by age 65 and onwards. Another study found that people aged 50 or older who received the Bacillus Calmette-Guérin (BCG) vaccine as a bladder cancer treatment had a 20 per cent lower risk of getting Alzheimer’s.

This may be because vaccines give the ageing immune system a boost and thus reduce inflammation, says Wilcock. “At 55, maybe we need to shake the immune system by the shoulders and say: ‘Hey, you gotta wake up, you still need to be working’,” she says. “Because generally, we do all our vaccinations when we’re children.”

Aside from vaccines, there are several other interventions that have been shown to lower 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’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 might be hard to change your point of view.”