Traditionally, Alzheimer’s disease has been understood as originating within the brain itself. However, extensive genomic analysis now suggests a different narrative, proposing that the disease is initially ignited by inflammation occurring in distant organs, such as the skin, lungs, or gut. This inflammatory trigger may take place decades before any noticeable decline in a person’s memory.
This significant re-evaluation of Alzheimer’s could help clarify why numerous drugs developed to combat the disease have yielded disappointing results. These treatments often intervene too late in the disease’s progression. Consequently, a shift in strategy might be necessary, focusing efforts on managing inflammation in other parts of the body.
Dr. Donna Wilcock of Indiana University, who was not involved in the study, noted the ingrained focus of neuroscientists on the brain. She emphasized, “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.” She added, “Even though Alzheimer’s is a brain disease, we need to think about the whole body when we think about how it begins.”
Investigating Genetic Links Across the Body
To delve into the genetic factors underpinning Alzheimer’s disease, Dr. Cesar Cunha and his colleagues at the Novo Nordisk Foundation Center for Basic Metabolic Research in Denmark undertook a comprehensive study. They examined genetic data from over 85,000 individuals diagnosed with Alzheimer’s and an additional 485,000 individuals without the condition, drawing from the European Alzheimer and Dementia Biobank. Their analysis extended to gene activity within approximately 5 million individual cells across 40 different body areas and 100 brain regions.
The researchers specifically focused on 1,000 genes known to have variants that elevate the risk of Alzheimer’s disease. Surprisingly, they discovered that these genes appeared with far less frequency in the brain compared to other organs. Prominent among these were the skin, lungs, digestive system, and spleen, as well as various types of immune cells present in the bloodstream.
Dr. Cunha recounted his initial surprise: “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.” He continued, “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.”
Immune Regulation and Peripheral Inflammation
A significant portion of these Alzheimer’s risk genes are already understood to play a role in immune regulation. Moreover, they were most commonly found in barrier tissues—such as the skin, lungs, and gut—which are crucial for defending against pathogens, toxins, and allergens through inflammatory responses.
This observation suggests that Alzheimer’s disease might effectively begin with inflammation in these non-brain, or peripheral, organs. Dr. Cunha hypothesized that certain genetic variants could influence the severity of peripheral inflammation experienced and its subsequent impact on the brain. If this is the case, individuals with a family history of Alzheimer’s who inherit these specific genetic variants might be more susceptible to developing the disease following an infection or other inflammatory event.
Timing of Inflammation and Future Implications
Interestingly, the research team identified the highest activity of these gene variants in individuals between the ages of 55 and 60. This finding implies that inflammation occurring during this specific period may have the strongest likelihood of eventually leading to Alzheimer’s disease.
This hypothesis is indirectly supported by a long-term study conducted in Hawaii. That study revealed that men exhibiting elevated inflammation markers in their blood during their late 50s were more prone to developing Alzheimer’s in their 70s and 80s. Dr. Cunha mused, “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.”
Further research by Rezanur Rahman and colleagues at the QIMR Berghofer Medical Research Institute in Australia also indicated that genetic variants associated with Alzheimer’s disease appear to concentrate in the skin and lungs. However, Rahman stressed that more investigation is necessary to confirm their functional roles in disease development, stating, “Association does not mean causation.”
Broader Connections to Inflammatory Conditions
These findings align with a growing body of research demonstrating a higher likelihood of developing Alzheimer’s disease later in life among individuals with various inflammatory conditions. These include eczema, cold sores, pneumonia, gum disease, Lyme disease, syphilis, diabetes, high blood pressure, and gut infections.
The association appears particularly pronounced when inflammation occurs during midlife, roughly between the ages of 45 and 60. This timeframe correlates with the observations made by Dr. Cunha and his team.
The Brain’s Shifting Immune Status
According to Dr. Bryce Vissel of St. Vincent’s Hospital in Sydney, Australia, the brain was historically considered an immune-privileged site, unaffected by inflammation elsewhere in the body. “We were one of the early groups suggesting inflammation as a driver of Alzheimer’s disease, which wasn’t widely accepted,” he commented.
However, multiple research groups have now established that peripheral inflammation, triggered by infections or injuries, can indeed influence the brain. During inflammatory processes, immune cells become active, and signaling proteins like cytokines are released. Both these activated cells and cytokines are known to cross from the bloodstream into the brain.
Dr. Vissel and his team have presented unpublished findings indicating that cytokines can initiate processes that damage the connections between brain cells, potentially serving as a precursor to memory impairment. Concurrently, other researchers have found that the blood-brain barrier becomes more permeable with age. This increased permeability might permit greater infiltration of inflammatory cytokines and immune cells from the blood into the brain, explaining why inflammation seems more problematic in midlife than in earlier years.
Rethinking Alzheimer’s Treatment Strategies
The prevailing understanding of Alzheimer’s disease currently attributes its cause to the accumulation of misfolded beta-amyloid and tau proteins within the brain. Despite this, therapeutic interventions designed to clear these proteins have shown limited success. This suggests that their accumulation might be a consequence of the disease rather than its primary driver. Dr. Cunha stated, “The issue is that we’ve been trying to treat the end result of the disease.”
He drew a parallel to past approaches in obesity research. Initially, obesity drugs were developed to target excess fat tissue directly, but these proved ineffective. Subsequent genomic studies revealed that variants associated with obesity were often more highly expressed in the brain, leading to disruptions in appetite and energy balance. This insight paved the way for the development of weight-loss medications like semaglutide (marketed as Ozempic and Wegovy), which modulate brain pathways to reduce appetite.
If peripheral inflammation is indeed a significant cause of Alzheimer’s disease, the strategies for its treatment will need to be fundamentally different, Dr. Cunha observed.
Promising Vaccinations and Lifestyle Factors
One particularly promising avenue of research involves the potential protective effects of midlife vaccinations against Alzheimer’s disease. A recent study in California indicated that adults who received both doses of the shingles vaccine (recommended for individuals 50 and older in the U.S.) exhibited approximately a 50% lower risk of developing Alzheimer’s by age 65 and beyond.
Another study found that individuals aged 50 and older who received the Bacillus Calmette-Guérin (BCG) vaccine for bladder cancer treatment had a 20% reduced risk of developing Alzheimer’s.
Dr. Wilcock suggested that vaccines might bolster the aging immune system, thereby reducing inflammation. “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 remarked. “Because generally, we do all our vaccinations when we’re children.”
Beyond vaccinations, several other interventions have demonstrated an ability to lower inflammation and offer protection against Alzheimer’s disease. These include adhering to a Mediterranean diet, moderating alcohol consumption, engaging in regular exercise, avoiding smoking, and managing blood pressure and cholesterol levels.
Bridging the Gap in Scientific Understanding
Dr. Cunha highlighted the current challenge of persuading other neuroscientists to consider peripheral inflammation as a potential catalyst for Alzheimer’s disease within the brain. He recounted experiences at conferences where he was told, “If you’re not studying amyloid, you’re not studying Alzheimer’s.” He acknowledged, “Obviously, if you’ve been focusing on amyloid for 30 or 40 years, it might be hard to change your point of view.”