The correlation between smoking and neurodegeneration is well-documented, with one study from 2011 finding heavy smoking in midlife was associated with a greater than 100% increase in risk of dementia, Alzheimer's and vascular dementia more than two decades later.
Dementia is a less-studied impact of smoking for a simple, terrible reason . It occurs later in life and smokers tend to die younger.
Many of the theories around smoking and dementia relate to smoking's impact on the vascular and respiratory systems – essentially choking the flow of oxygen to the brain over decades of tobacco use. But a new study from the University of Chicago published today in Science Advances suggests nicotine-triggered miscommunication between the lungs and the brain could be involved.
Their work found a previously unmapped route from the lungs to the mind through pulmonary neuroendocrine cells (PNECs). When exposed to nicotine, these cells release exosomes that disrupt the iron balance in neurons, triggering symptoms often found in dementia patients.
"This research establishes a clear 'lung-brain' axis that helps explain why cigarette smoking is linked to cognitive decline and neurodegenerative risks," said UChicago postdoctoral researcher Kui Zhang, co-first author of the new work. "By understanding how these exosomes perturb iron homeostasis, we open new doors for protecting neurons from smoke-induced damage."
Whether this proves to be a causal link for dementia or not, the research itself is a powerful advance in scientists' understanding of the lungs.
"It reveals that the lung is not just a passive target of smoke exposure, but an active signaling organ influencing brain pathology," said corresponding author Asst. Prof. Joyce Chen of the UChicago Pritzker School of Molecular Engineering (UChicago PME) and the Ben May Department for Cancer Research .
From lung to brain
PNECs are unique lung cells that blend the functions of both nerve cells and endocrine cells. Speaking the languages of both synapse and hormone, they are important sensors for the airway, but difficult to study.
"The primary challenge was the extreme rarity of PNECs, which make up less than 1% of lung cells, making them nearly impossible to isolate and study in depth," Zhang said.
To research these elusive but important cells, the team generated induced PNECs (iPNECs) by differentiating human pluripotent stem cells, in numbers large enough to research in the lab.
When exposed to nicotine, the iPNECs emitted great quantities of exosomes, tiny particles that contain biological material like proteins, lipid or nucleic acids. Most cell types produce exosomes, but the particular exosomes the iPNECs produced in response to nicotine were rich in a protein called serotransferrin, which the body uses to regulate the flow of iron through the bloodstream.
Applying this model to the human body could mean that with every puff of cigarette, cigar or vape, the lung's natural PNECs blast out massive amounts of a material that impacts how the body handles iron.
"This nicotine will have an impact on the PNEC, and this PNEC will release a massive amount of exosomes, and that causes perturbation in terms of iron homeostasis," said co-first author Abhimanyu Thakur, who was with UChicago PME and the Ben May Department during the research and is now at Harvard Medical School's Department of Neurosurgery. "We are finding neurodegeneration-related markers, which are going up, and which can be linked with many cognitive and dementia-related diseases."
Work ahead
This blast of serotransferrin would essentially be telling the body – wrongly – to change how it regulates iron. The vagus nerve, which snakes from the brain to organs throughout the body, regulating involuntary movement like heartbeats, breathing and digestion, would carry this message back to the brain.
"This iron dyshomeostasis drives oxidative stress, mitochondrial dysfunction, and increased α-synuclein expression – hallmarks of neurodegenerative disease," Chen said.
An iron imbalance in neurons can also wrongly trigger ferroptosis, a form of programmed cell death, in cells that weren't supposed to die. Previous research has associated ferroptosis with both Alzheimer's and Parkinson's, but much more study is needed before any causal link can be claimed.
The team is next looking to see if blocking the exosomes – the original source of the signal – could have therapeutic applications. While direct impact on humans is still years off, the research advances scientists' understanding of how the brains and lungs communicate.
"Understanding these cross-organ communication pathways is critical for developing better prevention and intervention strategies for neurodegenerative diseases," Chen said.
Citation: "Pulmonary Neuroendocrine Cell-derived Exosomes Regulate Iron Homeostasis and Oxidative Stress in Lung Neurons," Thakur et al, Science Advances, April 8, 2026. DOI: 10.1126/sciadv.ady2696
