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Worsening Cardiovascular Risk Profile Linked to Cognitive Decline and Dementia

Article In Brief

Researchers tracked the link between cardiovascular disease (CVD) and dementia for approximately 25 years, finding that individuals whose CVD risk factors increase sharply over a period of years and decades are more than three times more likely to develop Alzheimer's disease or vascular dementia than are people whose CVD risk remains relatively steady. Our experts said the results demonstrate the need to pay greater attention to patients' CVD risk factors.

Individuals whose cardiovascular disease (CVD) risk factors increase substantially over a period of years and decades are more than three times more likely to develop Alzheimer's disease or vascular dementia than are people whose CVD risk remains relatively steady.

While previous studies have documented a link between CVD and dementia, the new study, published in Neurology online on April 20 is one of the first to prospectively trace the trajectory of the two disease states across 20 to 25 years.

“The longitudinal, cumulative trajectory of cardiovascular risk is predictive of dementia risk and associated with the emergency of memory decline,” the study concluded.

The findings were based on an analysis of data from the Betula study, a prospective, longitudinal, multicohort study of aging, memory, and data collected between 1988 and 2014 from 1,244 individuals based in the city of Umeå, Sweden. The community-dwelling participants were healthy at baseline.

Investigators from Umeå University used the Framingham Risk Score to measure cardiovascular risk in the participants every five years. They found that the risk score changed only minimally in 22 percent of participants, increased moderately in 60 percent, and increased at an accelerated pace in 18 percent.

Compared with participants with a stable risk trajectory, those with an accelerated trajectory had a 3.3 to 5.7-fold higher risk of developing Alzheimer's disease (AD) over the course of the study (95 percent confidence interval: 1.9 to 6.7 times increased risk after 25 years).

The participants whose CVD risk increased at an accelerated pace also had 3.3 to 4.1 times greater risk of developing vascular dementia (VaD; 95 percent CI: 1.5 to 7.6), and a slightly increased risk of memory decline (95 percent CI: 1.0 to 1.5).

The benefit of a stable cardiovascular risk trajectory, on the other hand, appeared to partially mitigate the risk of Alzheimer's disease for APOE4 carriers.

“It has been shown that the stand-alone measurements of cardiovascular risk are predictive of later dementia, yet there are very few studies that have, or are even able, to examine the trajectory of that risk,” said the first author of the paper, Bryn Farnsworth von Cederwald, PhD, a postdoctoral fellow in Umeå University's department of integrative medical biology.

“We wanted to find out if alternate trajectories, starting from similar risk levels, could lead to different outcomes,” he told Neurology Today.

Physicians who were not involved with the study said the results demonstrate the need for neurologists to pay greater attention to their patients' CVD risk factors.

“If a patient with Parkinson's disease also happens to smoke and have high blood pressure, as neurologists we tend to focus on the Parkinson's and not the cardiovascular risk,” said Michelle C. Johansen, MD, assistant professor of neurology and attending physician in the cerebrovascular division at the Johns Hopkins Hospital. “I am hoping that this and other recent studies will alert neurologists to pay more attention to these risk factors, which are among the few that patients and physicians can modify to avoid dementia.”

Study Details

Prior to the paper by Dr. Farnsworth von Cederwald, only a handful of previous studies have examined CVD risk longitudinally in relation to cognitive decline and dementia. In 2021, a paper by Hakala et al in Circulation followed a population-based cohort of 3,596 children who were aged 3 to 18 years old at the beginning of the study for 31 years. They found that elevated systolic blood pressure, high serum total cholesterol, and obesity that worsened from childhood to midlife were inversely associated with midlife cognitive performance.

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“Although the Framingham Risk Score is stratified by sex, future research should examine whether there are sex differences in the trajectories of the FRS and dementia risk.”—DR. MICHELLE M. MIELKE

Another paper, by Wagner et al in JAMA Psychiatry, described a case-control study in which adults at least 65 years old received six home visits during the 15 years between 1999 and 2014. During that time, 785 participants developed dementia, while 3,140 did not. They found that rising blood-glucose levels over the 15-year span increased the risk for developing dementia, as did falling blood pressure and body-mass index.

Yet no previous study had used such a well-validated, multi-variable measure of CVD risk as the Framingham Risk Score. Dr. Farnsworth von Cederwald and colleagues used the office-based version of the score, which measures age, gender, systolic blood pressure, blood-pressure medication usage, BMI, smoking status, and diabetes diagnosis. The aggregated score represents the likelihood of any CVD event within 10 years.

Diagnosis of AD and VaD were clinically determined and based on the DSM-IV criteria. To increase diagnostic precision, a physician also checked computerized medical records without knowledge of the clinical diagnosis.

The classification of average, stable or accelerated CVD risk trajectories were calculated in relation to participants' age and baseline risk. Given that CVD risk tends to increase with age, the average group did have a steady increase in their Framingham score. Accelerated CVD risk was defined as a rate of change one standard deviation above the mean, while stable risk was defined as a standard deviation below the mean.

“Those who maintained a stable cardiovascular risk profile had a reduced risk of developing dementia compared to those who had an average or accelerated profile,” Dr. Farnsworth von Cederwald said.

The finding that APOE4 carriers did not have an increased risk of AD if they maintained a stable CVD profile was particularly noteworthy, he said. “This is potentially a sign that maintaining a stable CVD risk could mitigate the increased genetic risk associated with APOE4,” he said.

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“If a patient with Parkinsons disease also happens to smoke and have high blood pressure, as neurologists we tend to focus on the Parkinsons and not the cardiovascular risk. I am hoping that this and other recent studies will alert neurologists to pay more attention to these risk factors, which are among the few that patients and physicians can modify to avoid dementia.”—DR. MICHELLE C. JOHANSEN

Expert Commentary

The principal investigator of the Framingham Heart Study said that the new study offered support for an association long known in epidemiology: the so-called horse racing effect.

“The faster a horse is gaining speed, the likelier it is to reach the finish line first,” said Vasan Ramachandran, MD, FACC, FAHA, the Jay and Louise Coffman Professor in Vascular Dementia and chief of the section of preventive medicine at Boston University Schools of Medicine and Public Health. “In this case, the finish line is the development of dementia. So, the faster a person's CVD risk profile is increasing, the more likely they are to develop memory loss, Alzheimer's disease, or vascular dementia.”

Because modifying CVD risk factors are currently among the only ways to reduce the risk of dementia, Dr. Ramachandran said he hopes that neurologists will take note of those risk factors in all their patients, no matter their primary presenting signs, symptoms, or diagnosis.

“You can ask them if they smoke, and if they are complying with their medicines for blood pressure, blood sugar, and cholesterol,” Dr. Ramachandran said. “Referring them when indicated to an endocrinologist or a cardiologist might be the best way you can care for their cognitive functions.”

Dr. Johansen said the study demonstrates the need for patients with CVD risk factors to get them under control as early as possible.

Michelle M. Mielke, PhD, the chair of the department of epidemiology and prevention at Wake Forest School of Medicine, noted that a paper published earlier this year in Neurology reported that women with vascular conditions had greater cognitive decline than men with the conditions.

“Although the Framingham Risk Score is stratified by sex, future research should examine whether there are sex differences in the trajectories of the FRS and dementia risk,” said Dr. Mielke, who is also professor of international medicine in the section on gerontology and geriatric medicine.

Walter A. Kukull, PhD, an epidemiologist specializing in the study of Alzheimer's risk, said, “The paper is a step in the right direction toward distinguishing whether cardiovascular disease progression works synergistically, antagonistically, or independently from neurocognitive disease.”

“In that regard, the study's reliance on DSM-IV is a little unfortunate, since it attempts to separate AD as a symptom-based diagnosis from multi-infarct dementia in an exclusionary way—even though the authors recognize that the pathological features very frequently occur together,” said Dr. Kukull, professor of epidemiology at the University of Washington in Seattle, and director of the National Alzheimer's Coordinating Center.

In February, Dr. Johansen presented the results of a study at the International Stroke Conference showing no significant decline in any measure of cognition soon after a heart attack, but a significant decline in memory, executive functioning, and global cognition during the course of several years following.

“We need to realize that what's going on in the heart and brain are related,” she said in a statement announcing her study's results. “Managing risk factors to prevent a heart attack is actually good for your brain as well.”

In an interview with Neurology Today, Dr. Johansen applauded Dr. Farnsworth von Cederwald's group for using the Framingham risk score and a prospective design that followed participants for 20 to 25 years.

“That's a nice long period of follow-up,” Dr. Johansen said. “And they had a large cohort of over a thousand participants.

Link Up for More Information

• Farnsworth von Cederwald B, Josefsson M, Wåhlin A, et al. Association of cardiovascular risk trajectory with cognitive decline and incident dementia https://n.neurology.org/content/early/2022/04/20/WNL.0000000000200255. Neurology 2022; Epub 2022 Apr 20.
    • Hakala JO, Pahkala K, Juonala M, et al. Cardiovascular risk factor trajectories since childhood and cognitive performance in midlife: The Cardiovascular Risk in Young Finns Study https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.052358. Circulation 2021;143(20):1949–1961.
    • Wagner M, Helmer C, Tzourio C, et al. Evaluation of the concurrent trajectories of cardiometabolic risk factors in the 14 Years before dementia https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2694709. JAMA Psychiatry 2018;75(10):1033–1042.
    • Yaffe K, Bahorik AL, Hoang TD, et al. Cardiovascular risk factors and accelerated cognitive decline in midlife: The CARDIA Study https://n.neurology.org/content/95/7/e839. Neurology 2020, 95 (7) e839–e846.
    • Pettigrew C, Soldan A, Wang J, et al. Association of midlife vascular risk and AD biomarkers with subsequent cognitive decline https://n.neurology.org/content/95/23/e3093. Neurology 2020; 95(23):e3093–e3103.