Smoking cigarettes may raise dementia risk by triggering harmful chemical signals from the lungs to the brain, finds new research.
The study adds deeper understanding to a well-documented correlation between smoking and neurodegeneration.
One study from 2011 found heavy smoking in midlife was associated with a more than doubled risk of Alzheimer’s and other forms of dementia decades later.
Many of the theories around this connection 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 the new study published in Science Advances points to the involvement of nicotine-triggered miscommunication.
“This research establishes a clear ‘lung-brain’ axis that helps explain why cigarette smoking is linked to cognitive decline and neurodegenerative risks,” says University of Chicago postdoctoral researcher Kui Zhang, co-first author of the new work. “By understanding [this link], we open new doors for protecting neurons from smoke-induced damage.”
The researchers found a previously unmapped route from the lungs to the mind through pulmonary neuroendocrine cells (PNECs). When exposed to nicotine, these cells release exosomes—tiny particles that transport cellular products and waste—that disrupt the iron balance in neurons, triggering symptoms often found in dementia patients.
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,” says the paper’s corresponding author Assistant Professor Joyce Chen, from UChicago’s Pritzker School of Molecular Engineering (UChicago PME) and the cancer research department.
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 says.
To research these elusive but important cells, the team generated induced PNECs (iPNECs) from human pluripotent stem cells in numbers large enough to research in the lab.
When exposed to nicotine, the iPNECs emitted great quantities of exosomes. Most cell types produce exosomes, but those made by the iPNECs 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 a cigarette, cigar, or vape, the lung’s natural PNECs blast out massive amounts of a material that affects how the body handles iron.
“We are finding neurodegeneration-related markers, which are going up, and which can be linked with many cognitive and dementia-related diseases,” says 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.
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 [dysregulation] drives oxidative stress, mitochondrial dysfunction, and increased α-synuclein [protein] expression—hallmarks of neurodegenerative disease,” Chen says.
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 brain and lungs communicate.
“Understanding these cross-organ communication pathways is critical for developing better prevention and intervention strategies for neurodegenerative diseases,” Chen says.
Source: University of Chicago
