Alzheimer’s disease has traditionally been believed to originate in the brain. However, comprehensive genomic analysis indicates that inflammation in distant organs such as the skin, lungs, or intestines may initiate the condition, potentially decades before noticeable memory decline occurs. This shift in understanding could shed light on why Alzheimer’s treatments have been largely ineffective. Current drugs intervene too late; a focus on early-stage inflammation in peripheral organs may be crucial.

“As neuroscientists, we tend to focus on the brain, but this study highlights that the brain is interconnected with the body, and changes elsewhere can impact brain function,” states Donna Wilcock from Indiana University, not involved in the study. “Although Alzheimer’s is a brain disorder, we must consider the entire body when discussing its genesis.”

To explore the genetic underpinnings of Alzheimer’s disease, researchers including Cesar Cunha from Denmark’s Novo Nordisk Foundation Basic Metabolic Research Center analyzed genetic data from the European Alzheimer’s and Dementia Biobank, encompassing over 85,000 individuals with the disease and approximately 485,000 without it. They also evaluated gene activity in 5 million single cells across 40 body regions and 100 brain regions.

The study scrutinized 1,000 genes linked to an increased Alzheimer’s disease risk, surprisingly finding these genes were more abundant in organs like the skin, lungs, and digestive system than in the brain. “It was counterintuitive at first because the expression of these risk genes in brain cells seemed low,” notes Cunha. “Our continued analysis revealed their primary presence in other body parts.”

Many of these Alzheimer’s risk genes are tied to immune regulation and are particularly abundant in barrier tissues like the skin and lungs, which defend against bacteria and toxins through inflammatory responses. “This suggests that Alzheimer’s might initiate due to inflammation in these peripheral organs,” Cunha explains. Genetic variations may even dictate the extent of inflammation and its impact on brain health. Hence, individuals with a family history of Alzheimer’s could be more vulnerable to the disease amidst infections or inflammatory episodes.

Interestingly, the highest expression of these gene variants occurs when individuals reach ages 55 to 60. Inflammation during this period seems likely to trigger Alzheimer’s, corroborated by long-term studies from Hawaii. Inflammatory markers rise in individuals in their late 50s, with those in their 70s and 80s exhibiting increased Alzheimer’s likelihood. “A person could suffer from lung inflammation due to a viral infection at age 55, which might initiate Alzheimer’s 30 years later, but the exact mechanisms remain elusive,” Cunha remarks.

Rezanur Rahman, a researcher at QIMR Berghofer Medical Research Institute, has identified a genetic mutation associated with Alzheimer’s that appears concentrated in the skin and lungs. More research is essential to understand their functional role in symptom progression, Rahman states. “Association does not imply causation.”

Nonetheless, findings imply that individuals with various inflammatory conditions—such as eczema, cold sores, pneumonia, periodontal disease, Lyme disease, syphilis, diabetes, high blood pressure, and intestinal infections—may face heightened Alzheimer’s disease risk in the future. This correlation is particularly robust when inflammation occurs in middle age, around ages 45 to 60, aligning with Cunha’s insights.

Previously, the brain was deemed immune-privileged and largely unaffected by inflammatory processes elsewhere in the body. Bryce Vissel from St. Vincent’s Hospital in Sydney, Australia, among those who first proposed inflammation as a trigger for Alzheimer’s, acknowledges that while initially contentious, new evidence supports that peripheral inflammation from infections or injuries may indeed instigate the disease.Infection or injury can affect brain function.

When inflammation occurs, immune cells are activated, releasing signaling proteins like cytokines that can cross into the brain via the bloodstream. An unpublished study by Vissel and his team indicates that cytokines may disrupt neuronal connections, potentially leading to memory impairment.

Concurrently, research has shown that the blood-brain barrier becomes more permeable with age, allowing inflammatory cytokines and immune cells easier access, which might elucidate why inflammation poses more of a risk during mid-life compared to youth, Cunha notes.

Current theories posit that Alzheimer’s disease stems from the accumulation of misfolded beta-amyloid and tau proteins within the brain. Yet, treatments aimed at eliminating these proteins have yielded minimal success, indicating that such accumulation might be a symptom rather than the core issue. “We’ve been trying to treat the result of the disease, not its cause,” Cunha argues.

Cunha likens this to past mistakes in obesity treatments, which initially targeted excess fat directly, failing until genetic research revealed that mutations connected with obesity are often highly expressed in the brain, disrupting appetite and energy balance. This led to the development of the weight-loss medication semaglutide (marketed as Ozempic and Wegovy), which modulates brain pathways to curb appetite.

If Alzheimer’s originates from peripheral inflammation, its treatment would necessitate a paradigm shift, Cunha asserts. Data indicate that midlife vaccinations may offer protective benefits against Alzheimer’s disease. A recent Californian study revealed that adults receiving both doses of the shingles vaccine recommended for individuals aged 50 and older were 50% less likely to develop Alzheimer’s by age 65. Another investigation found that those aged 50 and older treated with the Bacillus Calmette-Guérin (BCG) vaccine for bladder cancer had a 20% reduced risk of onset.

This phenomenon might arise as vaccines bolster the aging immune system and mitigate inflammation, suggests Wilcock. “At age 55, we should invigorate our immune systems and remind them to stay active, as most vaccinations occur in childhood.”

Beyond vaccinations, several lifestyle interventions have been shown to diminish inflammation and avert Alzheimer’s disease. These include adopting a Mediterranean diet, limiting alcohol consumption, exercising, quitting smoking, and managing blood pressure and cholesterol levels.

Professor Cunha emphasizes that the challenge lies in convincing fellow neuroscientists to recognize peripheral inflammation as a potential contributor to Alzheimer’s disease. “I’ve encountered skepticism at academic conferences, being told, ‘If you aren’t focusing on amyloid, you’re not studying Alzheimer’s disease,'” he shares. “After decades entrenched in amyloid research, adapting one’s perspective can be daunting.”