Hypertension may impair blood vessels, neurons, and white matter in the brain well before causing a measurable rise in blood pressure, according to a new preclinical study by Weill Cornell Medicine researchers. These early changes shed light on why hypertension remains a major risk factor for vascular cognitive impairment and Alzheimer’s disease.
Early Cellular Changes Reveal Hidden Brain Impact
The findings, published on November 14 in Neuron, show that hypertension triggers early gene expression changes in individual brain cells, potentially disrupting thinking and memory. This discovery may pave the way for new medications that not only reduce blood pressure but also protect cognitive function.
Although patients with hypertension face a 1.2 to 1.5-fold higher risk of cognitive disorders, the underlying reasons remain unclear. Many antihypertensive drugs effectively lower blood pressure but fail to improve brain health, suggesting that hypertension causes damage independent of blood pressure elevation.
“We found that the major cells responsible for cognitive impairment were affected just three days after inducing hypertension in mice—before blood pressure increased,” said senior author Dr. Costantino Iadecola, Director of the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine. “The bottom line is something beyond blood pressure dysregulation is involved.”
Dr. Anthony Pacholko, a postdoctoral associate in neuroscience, co-led the study.
Hypertension Induces Premature Brain Aging
In earlier research, Dr. Iadecola’s team documented global neuronal dysfunction linked to hypertension. However, advances in single-cell technology have now allowed them to pinpoint specific molecular changes in individual brain cell types.
The researchers induced hypertension in mice using angiotensin, a hormone that elevates blood pressure in humans. They then examined cellular changes at day three—before blood pressure rose—and at day 42, when hypertension and cognitive impairment became evident.
At day three, gene expression shifted dramatically in three key cell types:
• Endothelial cells aged prematurely, showing reduced energy metabolism and elevated senescence markers.
• Interneurons, which balance excitatory and inhibitory signals, showed signs of damage similar to dysfunction seen in Alzheimer’s disease.
• Oligodendrocytes, responsible for producing myelin, failed to activate essential maintenance genes.
As reported by medicalxpress, the team also detected early weakening of the blood-brain barrier, which normally regulates nutrient flow and blocks harmful substances.
By day 42, these abnormalities intensified and coincided with measurable cognitive decline.
“The extent of the early alterations induced by hypertension was quite surprising,” Dr. Pacholko said. “Understanding these early cellular and molecular changes may help us identify ways to block neurodegeneration.”
Existing Drugs Show Promise in Reversing Early Damage
The study also highlights potential therapeutic strategies. Losartan, a widely used antihypertensive drug that blocks the angiotensin receptor, reversed early damage in endothelial cells and interneurons in the mouse model.
“In some human studies, angiotensin receptor inhibitors appear more beneficial for cognitive health than other blood pressure drugs,” Dr. Iadecola noted.
He emphasized that treating high blood pressure remains essential: “Hypertension is a leading cause of damage to the heart and kidneys, and antihypertensive drugs can prevent this, independent of cognitive outcomes.”
Next Steps in Research
Dr. Iadecola’s team is now exploring how premature aging of small blood vessels may trigger interneuron and oligodendrocyte defects. Ultimately, the researchers aim to uncover strategies to prevent—or even reverse—the damaging cognitive effects of hypertension.