Cumulative Midlife Vascular Risk Factors Associated With Increased Brain Amyloid

Deborah Brauser  

April 13, 2017

Having a progressively higher number of midlife vascular risk factors is significantly associated with later development of high levels of brain amyloid deposition, suggest cohort findings from the ongoing Atherosclerosis Risk in Communities (ARIC) trial.

The ARIC-PET [positron emission tomography] Amyloid Imaging Study, which included more than 300 participants aged 45 to 64  years, showed that those who had one vascular risk factor at baseline were more likely than those with no risk factors to have elevated amyloid standardized uptake value ratio (SUVR) at follow-up more than 20 years later.

Those with two or more risk factors were more than twice as likely to have high amyloid SUVR. However, the only individual vascular risk factor significantly associated with later amyloid level was an elevated body mass index (BMI).

"Our study emphasizes that middle age is really a critical time during which vascular health should be evaluated," lead author, Rebecca F. Gottesman, MD, PhD, associate professor of neurology and epidemiology at Johns Hopkins University School of Medicine, Baltimore, Maryland, told Medscape Medical News.

Dr Rebecca F. Gottesman

"Certainly our observational study does not prove that controlling these risk factors will make a difference in lowering risk for Alzheimer's," added Dr Gottesman. "But by showing this potential direct connection, it further emphasizes the potential damage that can be done by having decades of some combination of uncontrolled…diabetes, high cholesterol, obesity, or smoking."

The findings were published online April 11 in JAMA.

Asked for comment, Keith Fargo, PhD, director of scientific programs and outreach for the Alzheimer's Association, called this "a very important study" because it shows how critical vascular risk factors are to the aging brain.

Dr Keith Fargo

"I think many people think when it comes to Alzheimer's disease, there's nothing they can do about it as they get older," he said to Medscape Medical News. "The vast majority develop symptoms after the age of 65, but we're learning more and more that modifiable midlife risk factors, such as exercise, have an effect."

Contributor to Brain Changes?

Dr Gottesman agreed, noting that although there are currently no ways to effectively treat or prevent Alzheimer's disease, there are proven ways to prevent and treat vascular risk factors.

"Other studies have demonstrated that these risk factors are associated with a higher risk for dementia, including Alzheimer's, but this might just be because people with vascular risk factors have vascular changes in the brain that directly affect thinking and memory. And if those people also have Alzheimer's-type changes occurring, they might be more likely to be clinically diagnosed with dementia," she explained.

"The other option, which is what we were testing in this study, is that the reason for the observed association between vascular risk factors and Alzheimer's is because vascular risk factors directly lead to some of the pathologic changes in the brain that cause Alzheimer's, rather than just being a type of co-occurring pathology."

The ARIC-PET study included 322 participants from ARIC (mean age, 52 years; 58% women; 57% white, 43% black) who provided data on their vascular risk factors and who did not have dementia at baseline.

Vascular risk factors were defined as a BMI of 30 or greater, being a current smoker, having hypertension or diabetes, and having a total cholesterol level greater than 200 mg/dL.

At follow-up (mean, 23.5 years), SUVR was measured for all using florbetapir PET. An SUVR greater than 1.2 was considered elevated.  

Results showed that 50.9% of all participants had elevated SUVR. At baseline and at follow-up, respectively, the following were seen:

  • 65 participants had no vascular risk factors, of whom 30.8% had elevated amyloid SUVR;

  • 123 had one vascular risk factor, with 50.4% having elevated SUVR; and

  • 134 had two to four vascular risk factors, with 61.2% having elevated SUVR.

None of the participants had five or more risk factors. Associations between SUVR and the risk factors did not differ by race.

In addition, the findings "were not supportive of a significant difference in association among people who were or were not carriers of an APOE Ɛ4 allele," write the researchers. However, they note that the study may have been underpowered for this evaluation.

After adjustment for age, sex, race, education level, and APOE genotype, those with an elevated BMI at baseline had an odds ratio (OR) of 2.06 for elevated SUVR at follow-up vs those with a normal BMI (95% confidence interval [CI], 1.16 - 3.65).

The risk for elevated amyloid increased with an increasing number of risk factors.

Table. Having vs Not Having Vascular Risk Factors for Elevated Amyloid SUVR

Number of Risk Factors

Adjusted OR (95% CI)


1.88 (0.95 - 3.72)


2.88 (1.46 - 5.69)

Vascular risk factors that appeared in late life were not significantly associated with elevated SUVR at follow-up (OR for those with two or more factors, 1.66; 95% CI, 0.75 - 3.69).

Overall, the results "are consistent with a role of vascular disease in the development of Alzheimer's disease," write the investigators.

"Take Control Now"

Dr Fargo, who was not involved with this research, noted that it hasn't been understood before whether these cardiovascular risk factors increase the risk for Alzheimer's "because they make your brain less healthy, and you may develop dementia symptoms with fewer [brain] plaques and tangles because you also have vascular problems.

"But what this paper is showing is that those vascular risk factors are actually associated with having more plaque," he said. 

He added that he was a little surprised that more individual risk factors weren't associated with amyloid deposition but agreed with the investigators' speculation that that could have been due to the study being underpowered.

"But the cumulative effect was there," said Dr Fargo. As for the individual factors, "that's why you do more studies with bigger samples."

That said, he pointed out that the fact that BMI was a significant risk factor, and that it's modifiable, is a reason for optimism.

"At the Alzheimer's Association, we are big champions of people taking their health into their own hands and believe that there are a number of things that people can do to reduce risk for cognitive decline as they age, and to potentially reduce their risk for dementia."

In fact, the association offers "10 Ways to Love Your Brain" on their website, based on a review of modifiable risk factors that they published in 2015 at the request of the World Dementia Council.

Dr Fargo said that the take-home message from the current study for clinicians is to encourage patients to control their vascular risk factors now, "especially through exercise, diet, and taking medications needed to control blood pressure," so that it will pay off in the long run.

"This adds to the body of evidence about controlling your risk factors at midlife to save your brain as you age."

The ARIC-PET study is funded by the National Institute on Aging. The main ARIC study is supported by the National Heart, Lung, and Blood Institute. Avid Radiopharmaceuticals provided the florbetapir isotope that was used. Dr Gottesman reports serving as associate editor for Neurology and receiving research support from the National Institutes of Health. Disclosures for the coauthors are in the paper.

JAMA. Published online April 11, 2017. Abstract

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