Research has long established a strong correlation between smoking and neurodegenerative disorders. A study conducted in 2011 reported that heavy smoking during midlife increased the risk of dementia, Alzheimer’s disease, and vascular dementia by more than 100% after two decades. However, dementia remains a relatively less-studied consequence of smoking. One key reason is that dementia typically develops later in life, whereas many long-term smokers experience premature mortality due to other smoking-related illnesses.
Traditional Explanations: Impact on Oxygen Supply to the Brain
Most existing theories link smoking-related cognitive decline to damage in the vascular and respiratory systems. Over years of tobacco use, smoking gradually impairs blood vessels and lung function, thereby reducing the oxygen supply to the brain. This chronic reduction in oxygenation may contribute to neuronal damage and cognitive deterioration over time.
Discovery of a Lung–Brain Communication Pathway
However, a recent study from the University of Chicago, published in Science Advances, proposes a new biological mechanism. The researchers identified a previously unknown lung–brain signaling pathway involving pulmonary neuroendocrine cells (PNECs). When exposed to nicotine, these specialized lung cells release microscopic particles called exosomes, which interfere with iron balance in neurons. This disruption may trigger cellular changes commonly observed in dementia.
Kui Zhang, a postdoctoral researcher at the University of Chicago and co-first author of the study, explained that the research establishes a clear “lung–brain axis” that helps explain the link between cigarette smoking and neurodegenerative risks. According to him, understanding how these exosomes disturb iron regulation could open new avenues to protect neurons from smoke-induced damage.
Lungs as Active Signalling Organs
Importantly, the findings also redefine the role of the lungs in disease mechanisms. Traditionally, researchers viewed the lungs as passive organs affected by smoke exposure. However, the new evidence suggests that the lungs actively send biological signals that may influence brain pathology.
Joyce Chen, Assistant Professor at the University of Chicago’s Pritzker School of Molecular Engineering and corresponding author of the study, stated that the research demonstrates how the lungs can function as active signalling organs that affect neurological health.
Understanding the Role of Pulmonary Neuroendocrine Cells
Pulmonary neuroendocrine cells are unique lung cells that combine features of both nerve cells and hormone-secreting endocrine cells. Because they communicate through both neural signals and hormonal pathways, they act as important sensors within the airway. Nevertheless, studying these cells has proven difficult because they are extremely rare, constituting less than 1% of lung cells.
To overcome this challenge, researchers generated induced pulmonary neuroendocrine cells (iPNECs) in the laboratory by differentiating human pluripotent stem cells. This approach allowed the scientists to produce sufficient numbers of these cells for detailed study.
Nicotine Exposure Triggers Release of Iron-Regulating Exosomes
When researchers exposed the induced PNECs to nicotine, the cells released large quantities of exosomes, tiny vesicles that transport biological materials such as proteins, lipids, and nucleic acids between cells. While many cell types produce exosomes, those released by nicotine-exposed PNECs contained high levels of serotransferrin, a protein responsible for regulating iron transport in the body.
Consequently, repeated nicotine exposure—such as through cigarettes, cigars, or vaping—could stimulate the lungs to release these iron-regulating particles. According to co-first author Abhimanyu Thakur, currently at Harvard Medical School’s Department of Neurosurgery, the surge of exosomes may disrupt iron balance in neurons. As a result, researchers observed increased levels of markers associated with neurodegeneration and cognitive disorders.
Iron Imbalance and Neuronal Damage
As reported by medicalxpress, the study suggests that these signals travel from the lungs to the brain through the vagus nerve, a major neural pathway that regulates involuntary body functions such as breathing, heart rate, and digestion.
Once in the brain, the disrupted iron balance may trigger oxidative stress, mitochondrial dysfunction, and increased expression of α-synuclein, which are well-known hallmarks of neurodegenerative diseases. In addition, iron imbalance can activate ferroptosis, a type of programmed cell death linked to conditions such as Alzheimer’s and Parkinson’s disease.
Future Directions and Therapeutic Possibilities
Although the findings do not yet establish a definitive causal link between smoking and dementia, they significantly advance scientific understanding of how the lungs and brain communicate. The research team is now investigating whether blocking these exosomes—the source of the harmful signal—could lead to potential therapeutic strategies.
While clinical applications may still be years away, the discovery highlights the importance of studying cross-organ communication pathways. As Chen noted, understanding these biological connections will be crucial for developing better prevention and treatment strategies for neurodegenerative diseases.