Genetic risk combined with cardiovascular factors may help predict and delay dementia

Combining genetic risk with cardiovascular disease risk factors—such as high LDL cholesterol, obesity, and hypertension—may predict who is more likely to develop dementia, according to a new study led by UC San Francisco.

This expanded view is more hopeful for those worried about dementia. While genes account for about half the risk of developing dementia and cannot be changed, the other half is determined by factors like social isolation, uncorrected hearing loss, and physical inactivity, which can be addressed.

“With Alzheimer’s disease, you may have several vascular diseases involved, like hypertension and diabetes,” said corresponding author Shea Andrews, Ph.D. “If you make lifestyle changes and improve control of illnesses like these, you could reduce the amount of overall damage to the brain, potentially delaying or even preventing symptoms.”

The study used data from about 3,500 adults who had contributed to the NACC and the Alzheimer’s Disease Neuroimaging Initiative. The paper is published in the journal Alzheimer’s & Dementia.

The average age of the people in the cohort was 75. None had dementia at the start of the six-year study but approximately 1 in 4 had mild cognitive impairment (MCI), which usually precedes it. By the study’s end, 1 in 7 had died and 1 in 4 of the surviving participants with normal cognition or MCI had progressed to dementia.

The researchers found that risk was impacted by four factors:

• Having a parent or sibling with dementia
• Inheriting at least one copy of a gene variant called APOE4 that is strongly associated with Alzheimer’s
• Having a high polygenic risk score that reflects many smaller genetic effects
• Having a high cardiovascular risk score

The researchers also looked for rare mutations associated with early-onset Alzheimer’s but none of the participants had them.

The more risk factors a person had, the more likely they were to develop dementia. One factor increased the risk by 27%; two increased it by 83%; three by 100%; and four increased the risk fivefold.

“We haven’t had a precision medicine approach to help patients reduce their modifiable risks before, because Alzheimer’s couldn’t be diagnosed or treated,” Andrews said. “But now we have treatments that may slow disease progression, particularly in its earliest stage, which can be identified with a blood test or a specialized type of brain imaging called a PET scan.”

He added that genetic data relating to dementia is expected to be more readily available in a few years.

“An optimal scenario for using this data might involve a patient sharing their concerns about dementia with their family doctor following a parent’s diagnosis,” he said. “The physician would then discuss the genetic data and collaborate with them on ways to lower modifiable risks.”

A heightened awareness of the role of non-genetic factors could help those who are at increased risk of developing dementia.

“I think focusing on what patients can control gives them agency and ownership,” said Kristine Yaffe, MD, who has been at the forefront of investigating the role of modifiable risk factors in dementia and is the paper’s senior author. “This allows them to take proactive steps, rather than wait for symptoms to emerge.”