HMN 2025: How Controlling hypertension can reduce dementia risk—even when genetics aren’t on your side

Researchers at Yale School of Medicine (YSM) examined two known risk factors for developing dementia—one genetic and one relating to blood vessel damage in the brain. They wanted to know how much a person’s dementia risk might increase if they had both factors.

In their study published recently in Annals of Neurology, the researchers found that while the likelihood of developing dementia does rise if a person has both risk factors, there is a silver lining: The vascular component is within a person’s control, offering a route for minimizing dementia risk even if they have higher genetic risk.

“Our study addressed whether these two known risk factors act additively or multiplicatively to increase the risk of incident all-cause dementia,” says senior author Adam de Havenon, MD, associate professor of neurology at YSM. “We wanted to show that controlling vascular risk factors like high blood pressure could prevent harmful brain changes, meaning that even those with bad genetic luck could avoid the worst outcomes.”

The study used data from the Atherosclerosis Risk in Communities study and the UK Biobank. The team assessed two measures: white matter hyperintensity (WMH) and whether a person was a carrier of the ?4 variant of the APOE gene.

White matter hyperintensity are lesions, or scar tissue, in the brain that show up as bright white spots on magnetic resonance imaging. They’re associated with damage to the small blood vessels in the brain, which can be caused by high blood pressure (hypertension) and can accumulate over time. The APOE gene encodes for a protein involved in transporting fat, such as cholesterol. When people have a certain version of this gene, known as the ?4 variant, they carry a higher risk of developing Alzheimer’s disease.

The researchers found that participants with both high WMH burden and at least one APOE ?4 allele faced elevated dementia risk compared to those with neither risk factor. These effects, however, were additive rather than multiplicative, meaning each factor contributed its own risk increase rather than also exacerbating the effect of the other factor.

“This tells us something really important,” de Havenon explains. “Even if you’ve been dealt a bad genetic hand with APOE ?4, you’re not destined for dementia. The vascular component is modifiable.”

For instance, the health factors that can contribute to the development of WMH can be prevented or slowed through blood pressure management, diabetes control, and other cardiovascular interventions, he says.

“It’s really a two-hit scenario,” says de Havenon. “If you have APOE ?4 and you don’t take care of your vascular health, then you’re in a high-risk group. But having the APOE ?4 genotype is not a foregone conclusion for developing dementia later in life.

“Our analysis suggests that while the gene increases risk, the ultimate outcome is highly dependent on other factors. My hope is that people who find out they have this genetic mutation will be very serious about their vascular risk factors.”

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