Smoking Linked to Brain Changes That Can Increase Dementia Risk
From the Editor’s Desk
April 15, 2026
A new study has found that smoking may increase the risk of dementia by triggering a chain of biological events that starts in the lungs and ends up damaging brain cells. The findings offer the clearest biological explanation to date for a link that population studies have observed for years without being able to fully explain.
The lung cells causing this process are called pulmonary neuroendocrine cells, which are extremely rare, making up less than one percent of all lung cells, explains the study published in Science Advances in April 2026. They sit along the airway walls where they act as sensors, detecting substances that enter the lungs. They are directly connected to the brain through the vagus nerve, a major nerve that runs from the brain down through the neck and chest and communicates with the lungs.
Because these cells are so rare and difficult to grow in a laboratory, the researchers used human stem cells to generate a working version of them for the study, and confirmed through genetic analysis that the lab-grown cells closely matched the real thing, says the study, which was led by researchers at the Pritzker School of Molecular Engineering and the Ben May Department for Cancer Research at the University of Chicago, with co-authors from institutions in New York, Virginia, Hong Kong and Shanghai.
When these cells are exposed to nicotine, they release significantly more tiny particles than they normally would, about 2.8 times the usual amount. These particles, called exosomes, are microscopic packages that cells use to send chemical signals to other cells throughout the body. They travel through bodily fluids and are absorbed by whatever cells they reach. In this case, the exosomes produced by nicotine-exposed lung cells carry unusually high amounts of a protein called serotransferrin, which is involved in transporting iron around the body.
When neurons, the cells that make up the brain and nervous system, absorb these iron-loaded exosomes, iron begins to accumulate inside them at levels their internal systems cannot manage. The body normally keeps iron in careful balance inside cells, because too much of it can be destructive.
In this study, the excess iron set off a damaging process called oxidative stress, in which harmful molecules build up inside cells and erode their structure and function. The affected neurons also showed falling energy levels, reduced ability to generate the fuel cells need to function, and declining capacity to carry out basic operations, says the study.
All of these changes are associated with neurodegenerative diseases, the category of conditions that includes dementia and Parkinson’s disease. The affected neurons additionally showed elevated levels of a protein called alpha-synuclein, whose abnormal accumulation is a known feature of several neurodegenerative conditions, according to the study. In other words, the changes observed in the neurons matched patterns seen in diseased brain tissue from people with Alzheimer’s disease, the most common form of dementia.
The researchers confirmed these effects in mice given nicotine injections every other day for two weeks. Those animals performed noticeably worse than untreated mice on a series of memory and recognition tests, including tasks that measured their ability to identify new objects and navigate a maze. Brain tissue from the nicotine-treated mice showed markers of inflammation and activation of immune cells in the brain, further supporting the idea that the signals originating in the lungs were producing measurable neurological changes.
To test whether the damage could be stopped, the researchers used a drug that blocks the doorway through which iron enters neurons. When they gave this drug to neurons that had been exposed to nicotine-driven exosomes, iron accumulation fell, energy levels recovered and oxidative stress was reduced. The same result was obtained when the iron entry mechanism was disabled genetically. This suggests the pathway is potentially interruptible, though the researchers were careful to note that the study was designed to identify the mechanism rather than develop or test a treatment.
Looking at lung tissue from human smokers, the researchers found that smokers had more of these specialised lung cells than non-smokers, and that those cells showed higher activity of genes associated with producing exosomes and handling iron. Neurons in the lungs of smokers also showed elevated levels of the same iron transport proteins that were raised in the laboratory experiments, indicating the same process was occurring in real human tissue.
The researchers cautioned that while the laboratory experiments support a direct causal link, the evidence from human lung tissue and brain scans remains associative, meaning the patterns are consistent with the theory but do not by themselves prove it. They said further studies in living animals, in which the pathway is deliberately blocked, would be needed to confirm the full picture.
They also noted that the cellular stress and iron imbalance identified in the study can develop before any visible symptoms of neurological disease appear, which raises the possibility that the damage accumulates quietly over many years of smoking before it becomes detectable.
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