Alzheimer’s research has long concentrated on amyloid plaques and other brain-specific pathology, but a large-scale genomic study is redirecting attention toward what happens in the body’s periphery long before cognitive symptoms appear.
According to the announcement, César Cunha at the Novo Nordisk Foundation Center for Basic Metabolic Research in Denmark and colleagues analyzed genetic data from more than 85,000 people with Alzheimer’s disease and 485,000 people without it, drawn from the European Alzheimer and Dementia Biobank. The team also examined gene activity across 5 million single cells from 40 areas of the body and 100 brain regions. When they mapped roughly 1,000 genes carrying variants that raise Alzheimer’s risk, the expression patterns were not concentrated in the brain — they appeared predominantly in the skin, lungs, digestive system, spleen, and 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,” Cunha says. “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.”
Barrier Tissues at the Center
Many of the identified risk genes are linked to immune regulation and appeared most active in barrier tissues — skin, lungs, and gut — whose primary function is defending against pathogens, toxins, and allergens through inflammatory responses. The hypothesis that follows is that Alzheimer’s may originate as peripheral inflammation, with certain genetic variants shaping how intense that inflammation becomes and whether it ultimately reaches the brain.
The data showed peak expression of these variants in people aged 55 to 60, pointing to that decade as a potentially critical window. A separate long-running study in Hawaii, cited by the researchers, found that men with elevated blood inflammation markers in their late 50s had higher rates of Alzheimer’s in their 70s and 80s — a finding that aligns with the genomic picture. “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,” Cunha says, while acknowledging the mechanism connecting peripheral inflammation to eventual neurodegeneration remains unresolved.
Independent Corroboration and Important Caveats
A separate team led by Rezanur Rahman at QIMR Berghofer Medical Research Institute in Australia independently found that Alzheimer’s-associated genetic variants appear to cluster in the skin and lungs. Rahman cautions, however, that additional work is needed to confirm functional roles for these variants in disease development. “Association does not mean causation,” he says.
Donna Wilcock at Indiana University, who was not involved in the research, frames the broader significance: “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.” The findings carry a direct implication for drug development — treatments targeting amyloid in the brain may be intervening too late in a process that begins in peripheral organs decades earlier. The study suggests the field may need to look upstream, toward systemic inflammation, to find earlier and more effective points of intervention.
Photo by Wiki Sinaloa on Unsplash
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