New research from Weill Cornell Medicine reveals that high blood pressure harms brain vessels, neurons, and white matter long before a measurable rise in blood pressure is seen. These early changes help explain why hypertension is a major risk factor for cognitive disorders such as vascular cognitive impairment and Alzheimer’s disease.
The preclinical study, published on 14 November in Neuron, shows that the early stages of hypertension trigger gene‑expression shifts in distinct brain cells, disturbing thinking and memory. This insight could pave the way for drugs that lower blood pressure while also protecting cognition.
Patients with hypertension have a 1.2 to 1.5‑fold higher likelihood of developing cognitive disorders than those without the condition, but the underlying cause has been unclear. Although many antihypertensive medications successfully lower high blood pressure, they rarely improve brain function, suggesting that vascular changes can harm the brain independently of the pressure itself.
"We discovered that the principal cells involved in cognitive decline were altered just three days after inducing hypertension in mice—before any rise in blood pressure," said senior author Dr. Costantino Iadecola, director of the Feil Family Brain and Mind Research Institute. "This indicates that factors beyond blood‑pressure dysregulation are at play."
Dr. Anthony Pacholko, a postdoctoral associate in neuroscience at Weill Cornell, co‑led the work.
Earlier studies by Dr. Iadecola’s group showed that hypertension affects neuron function worldwide, but recent advances in single‑cell techniques allowed the team to dissect the molecular events in specific brain cell types.
To model hypertension, researchers injected angiotensin, a hormone that elevates blood pressure, into mice. They then examined the impact on brain cells three days later (prior to any measurable blood‑pressure increase) and after 42 days (when blood pressure was high and cognitive performance was impaired).
At day 3, gene expression changed dramatically in three cell populations: endothelial cells that line blood vessels, interneurons that balance excitatory and inhibitory signals, and oligodendrocytes that produce the myelin sheath.
Endothelial cells exhibited signs of premature aging, with reduced energy metabolism and increased senescence markers. The study also found early disruption of the blood‑brain barrier, the system that regulates nutrient entry into the brain and blocks harmful substances.
Interneurons suffered damage that led to an imbalance between inhibitory and excitatory activity, a pattern also seen in Alzheimer’s disease. Meanwhile, oligodendrocytes down‑regulated genes necessary for their maintenance and renewal, threatening the integrity of neuronal communication.
Gene‑expression changes amplified by day 42, coinciding with observable cognitive decline, further underscored the progressive nature of hypertension‑induced brain damage.
"The magnitude of the early alterations produced by hypertension was unexpected," Dr. Pacholko said. "Understanding these cellular and molecular early events may reveal strategies to halt or reverse neurodegeneration."
An existing antihypertensive drug, losartan, blocks the angiotensin receptor. "Some human studies suggest that angiotensin‑receptor blockers might offer greater cognitive protection than other blood‑pressure lowers," Dr. Iadecola noted. In mouse experiments, losartan reversed the early endothelial and interneuron damage caused by hypertension.
"Hypertension is a leading cause of damage to the heart and kidneys—issues effectively managed by antihypertensive therapy. Regardless of cognitive concerns, treating high blood pressure remains essential," Dr. Iadecola emphasized.
The team is now exploring how the premature aging of small blood vessels induced by hypertension may trigger dysfunction in interneurons and oligodendrocytes. They hope to identify optimal approaches to prevent or reverse the devastating cognitive effects of high blood pressure.