A new genomic analysis suggests that Alzheimer's disease may begin with inflammation in organs like the skin, lungs, or gut, potentially decades before brain symptoms appear. Researchers analyzed genetic data from hundreds of thousands of people and found risk genes more active outside the brain. This perspective could reshape prevention and treatment strategies.
Alzheimer's disease has traditionally been seen as originating in the brain, but a detailed genomic study challenges this view. Cesar Cunha and his team at the Novo Nordisk Foundation Center for Basic Metabolic Research in Denmark examined genetic data from more than 85,000 individuals with Alzheimer's and 485,000 without, drawn from the European Alzheimer and Dementia Biobank. They also assessed gene activity in 5 million single cells across 40 body areas and 100 brain regions.
The analysis focused on 1,000 genes linked to increased Alzheimer's risk. Surprisingly, these genes appeared far less in brain cells and more prominently in organs such as the skin, lungs, digestive system, spleen, and circulating immune cells. "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," Cunha noted. Further checks confirmed the pattern, with many genes tied to immune regulation and concentrated in barrier tissues that combat germs, toxins, and allergens through inflammation.
This points to peripheral inflammation as a possible trigger, where genetic variants might heighten responses to infections or events, eventually impacting the brain. The highest gene expression occurred between ages 55 and 60, aligning with a Hawaiian study showing men with elevated blood inflammation markers in their late 50s were more prone to Alzheimer's in their 70s and 80s. Cunha suggested that a lung infection at 55 could contribute to the disease 30 years later, though the exact mechanism remains unclear.
Supporting evidence includes work by Rezanur Rahman at QIMR Berghofer Medical Research Institute, who found similar gene clusters in skin and lungs, while cautioning, "Association does not mean causation." Broader research links midlife inflammatory conditions—like eczema, pneumonia, gum disease, diabetes, and gut infections—to higher Alzheimer's risk, especially around ages 45 to 60.
Experts like Donna Wilcock at Indiana University emphasized the body's interconnectedness: "Even though Alzheimer’s is a brain disease, we need to think about the whole body when we think about how it begins." Bryce Vissel at St Vincent’s Hospital in Sydney added that cytokines from peripheral inflammation can cross into the brain, potentially damaging neural connections as the blood-brain barrier weakens with age.
Current treatments targeting beta-amyloid and tau proteins have shown limited success, possibly because they address late-stage effects. Cunha compared this to past obesity research, where focusing on fat tissue failed until brain pathways were targeted, leading to drugs like semaglutide. If peripheral inflammation drives Alzheimer's, new approaches might include midlife vaccinations; a California study found shingles vaccine recipients had 50 percent lower risk by age 65, and BCG vaccine users a 20 percent reduction.
Other inflammation-reducing measures, such as a Mediterranean diet, exercise, not smoking, limiting alcohol, and managing blood pressure and cholesterol, also show protective effects. Cunha faces resistance in the field, recalling conference comments: "If you’re not studying amyloid, you’re not studying Alzheimer’s." The study is available on medRxiv with DOI: 10.64898/2026.02.09.26344392.
