Researchers at Yale School of Medicine examined how genetics and blood vessel damage influence dementia risk. They focused on two known factors: the APOE ε4 gene variant and vascular injury in the brain caused by high blood pressure.
A study published in Annals of Neurology found that while having both risk factors raises the likelihood of dementia, the vascular component is controllable. This offers a way to reduce risk even for those with a genetic predisposition.
“Our study explored whether these two factors act together to increase dementia risk,” said senior author Dr. Adam de Havenon, associate professor of neurology at Yale. “We found that controlling vascular risk factors like hypertension can prevent harmful brain changes, giving people with higher genetic risk a chance to avoid the worst outcomes.”
The researchers analyzed data from the Atherosclerosis Risk in Communities study and the UK Biobank. They measured white matter hyperintensity (WMH)—lesions in the brain linked to small vessel damage—and APOE ε4 carrier status. WMH can develop over time due to high blood pressure and other vascular issues. The APOE gene affects cholesterol transport, and the ε4 variant increases Alzheimer’s risk.
Participants with both high WMH and at least one APOE ε4 allele had higher dementia risk than those with neither factor. However, the risks were additive rather than multiplicative, meaning each factor independently raised the likelihood of dementia.
“Even if you have the APOE ε4 gene, you’re not destined for dementia,” de Havenon said. “The vascular component is modifiable.” Managing blood pressure, controlling diabetes, and addressing other cardiovascular risks can prevent or slow the development of WMH.
“It’s a two-hit scenario,” de Havenon added. “If you have APOE ε4 and poor vascular health, your risk is higher. But genetics alone does not determine your fate. The ultimate outcome depends on controllable factors.”
The findings highlight the importance of proactive vascular health. Individuals who know they carry the APOE ε4 variant can significantly reduce their dementia risk by managing blood pressure and other cardiovascular conditions.
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