Researchers at the University of Chicago’s molecular engineering lab, led by Associate Professor Joyce Chen, conducted a new study that explains why heavy smoking in midlife doubles the risk of developing dementia later in life. They traced the increased risk to a disruption of iron homeostasis in the brain caused by exosomes released from the lungs.
Exosomes are tiny extracellular membrane vesicles (nanoparticles measuring 30–200 nm) that carry information between cells.
Published in Science Advances, the study shows that a nicotine-driven disruption of the lung–brain connection can explain dementia in smokers.
Why smoking’s tie to dementia has long worried scientists
Researchers already knew that heavy smoking in midlife contributes to neurodegenerative disease. Dementia was the least-studied smoking consequence simply because it appears later in life, and many smokers die earlier.
Many theories blamed smoking for damaging the vascular and respiratory systems and for gradually reducing the brain’s oxygen supply.
But the authors of the new paper discovered a previously unknown pathway from the lungs to the brain through pulmonary neuroendocrine cells (PNECs). When exposed to nicotine, these cells release exosomes that disturb iron balance in neurons and trigger dementia-like symptoms.
“This study establishes a clear lung–brain axis that helps explain why smoking is linked to cognitive decline and to the risk of neurodegenerative disease. Understanding how exosomes disrupt iron homeostasis opens new opportunities to protect neurons from smoking-related damage,” said Kui Zhang, a coauthor of the study.
Even if the causal link requires more testing, the study already represents a significant step forward.
“The lungs are not just a passive target for smoke exposure; they act as an active signaling organ that influences brain pathology,” said Joyce Chen.
How the lungs talk to the brain
PNECs are unique cells that combine features of nerve and endocrine cells, and they’re notoriously hard to study. Part of the challenge is that they make up less than one percent of lung cells.
But the team generated enough induced PNECs (iPNECs) for experiments by differentiating human pluripotent stem cells.
When exposed to nicotine, the iPNECs released large numbers of exosomes. Those nicotine-stimulated exosomes were rich in the protein transferrin, which the body uses to regulate iron transport in the bloodstream.
Applied to humans, the model suggests that each puff of a cigarette, cigar, or vape could cause pulmonary PNECs to release substantial amounts of transferrin that alter how the body handles iron.
The release of transferrin would essentially send a false signal that prompts the body to change how it regulates iron levels. The vagus nerve, which runs from the brain to organs throughout the body and controls processes like heartbeat, breathing, and digestion, would carry that signal back to the brain.
“This iron imbalance leads to oxidative stress, mitochondrial dysfunction, and increased expression of alpha-synuclein — hallmarks of neurodegenerative disease,” Joyce Chen summarized.
The study sheds new light on lung–brain interactions and clarifies the role nicotine plays in disrupting that connection.
