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Health and Lifestyle Factors Can Mitigate Dementia Risk in Those with Low Genetic Risk
People with High Genetic Risk Have Fewer Clear Benefits

Article In Brief

A new study asked: Do lifestyle and modifiable factors matter in individuals with genetics that predispose them to the disease? It found it did.

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Healthy lifestyle habits can help mitigate the risk of dementia among those with low and intermediate genetic risk profiles, but not among those at the highest genetic risk, according to findings published in the September issue of Nature Medicine.

The trial applied long-term data to a question that has generated varied results in other studies, mostly with shorter follow-up: When it comes to dementia risk, how much do lifestyle and modifiable factors matter in those with genetics that predispose them to the disease?

Study Design, Findings

Researchers at Erasmus University in the Netherlands examined data for more than 6,500 people age 55 and older who were tracked for an average of 14 years in the Rotterdam Study, which began in 1989 to investigate risk factors for cardiovascular, neurological and other diseases in the elderly. They assigned participants a genetic risk score for dementia using two approaches—by looking at APOE genotype and by looking at a polygenic risk score based on 27 variants.

Those with APOE genotypes—e2e4, e3e4, or e4e4—were considered to be APOE high-risk, and those with other APOE genotypes were considered intermediate or low risk. With the polygenic approach, study participants were given a weighted score and divided into three groups.

Researchers, led by M. Kamran Ikram, MD, PhD, associate professor of neurology and epidemiology at Erasmus, also measured health and lifestyle, or “protective” factors that have been linked with lowering dementia risk: not smoking, being free of depression, not having diabetes, doing regular physical activity, avoiding social isolation, and adhering to a healthy diet, including limiting alcohol consumption. Participants were given a score of 0 to 6 depending on how many factors that applied to them. Having two or fewer protective factors was considered an unfavorable profile, three or four considered intermediate, and five or six was considered favorable.

“APOE genotype significantly modified the association between protective factors and dementia,” the researchers wrote.

Those with a low or intermediate APOE risk but an unfavorable protective profile had a risk of dementia that was higher than those with a favorable protective profile, with a hazard ratio of 2.51. But among those at high APOE risk, the researchers found no difference in dementia risk between those with unfavorable or intermediate protective profiles and those with a favorable protective profile.

Researchers found that among those at a low APOE risk, the average expected absolute risk of developing dementia in 15 years was 32.1 percent for those with an unfavorable profile and 12.6 percent for those with a favorable protective profile. That difference was 22 percent compared with 13.5 percent for those with an intermediate APOE risk. For those at high APOE risk, the 15-year expected risk was largely unchanged in the favorable profile group compared to the unfavorable profile group.

Their analysis found that the protective associations from favorable risk profiles tended to be stronger for younger people than older people, with most pronounced effects for younger people with low APOE risk.

Researchers found similar results when they looked at polygenic risk scores.

The findings expand the evidence base for understanding how factors that are within people's power to change can alter their risk even when they are genetically predisposed to develop dementia. In the Cardiovascular Risk Factors, Aging and Dementia study that examined the effects of multiple protective factors in the middle-aged, researchers found that APOE-e4 carriers were especially prone to dementia if they had hazardous factors in midlife.

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“Lifestyle habits should be a focus of dementia risk management, particularly since Alzheimers has no cure. I think more data are needed to conclude the role of lifestyle factors in individuals with the genetic predisposition of dementia.”—DR. KLODIAN DHANA

The Prevention of Dementia by Intensive Vascular Care trial, with six years of follow-up, found that intensive vascular care management in primary care had no overall benefit on dementia incidence, including between APOE-e4 carriers and non-carriers. The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) trial, which looked at effects of lifestyle interventions on cognitive performance, found similar benefits for APOE-e4 carriers and non-carriers over two years of follow-up.

“Our findings provide a less optimistic outlook for individuals at high genetic risk of dementia, yet they may have important implications for the design of future clinical trials,” the researchers wrote. “Considering the earlier age at onset of dementia among APOE-e4 carriers compared with non-carriers, our results imply that these individuals need to be targeted earlier in the disease process (for example, midlife or even earlier) to influence their risk.”

They also said that other interventions than lifestyle improvements should be studied further, including drugs that lower lipid levels.

“On the positive side, results from this study show that avoiding an unhealthy lifestyle could potentially prevent or postpone the onset of dementia in most individuals in the population (73 percent), namely those at low and intermediate genetic risk,” they said. “Among those, the majority were categorized as having a favorable profile (66 percent), yet room for improvement is still substantial because potential relative risk reductions of up to 30 percent can be achieved when individuals adhere to the lifestyle factors that confer a favorable risk profile.”

Expert Commentary

Steven T. DeKosky, MD, FAAN, professor of neurology at the University of Florida in Gainesville, cautioned that although the patients in the study were followed prospectively, it isn't known where they were in their disease course when they began to be followed.

Dr. DeKosky said that although no benefit was seen for the high-risk group, these lifestyle habits are advisable regardless. Moreover, gene-related and amyloid-reducing therapies being developed could help bridge the divide between those at genetic lower-risk and higher-risk.

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“I dont think the message of this [report] was you should just give up if you turn out to have a high risk. First of all, most people dont know if they do or not.” In addition, some patients with high-risk genetics do not follow the average trend and “genetics is not necessarily destiny.”—DR. STEVEN T. DEKOSKY

“Many of the medications that we are trying to find now to use are directed to what we think is the mechanism by which we believe that allele does its damage, both by trying to convert your e4 into an e3 type, or even e2 which is beneficial but rare, and getting rid of amyloid,” Dr. DeKosky said. “It may well be that a combination of a medication that decreases the pathological changes in those who do not have the genetic advantage will bring them closer to people who have a genetic advantage.”

He added, “I don't think the message of this [report] was you should just give up if you turn out to have a high risk. First of all, most people don't know if they do or not.” In addition, some patients with high-risk genetics do not follow the average trend and “genetics is not necessarily destiny.”

That a stronger effect was seen in younger people is further reason to emphasize to people the importance of healthy lifestyle habits earlier in life.

“Midlife appears to be the major place where a great deal of risk is incurred or avoided,” he said. “There's a chance for people in that younger age cohort to begin now making sure that when they look back at their midlife they will have been doing the things that appear to lower risk.”

Klodian Dhana, MD, assistant professor of neurology at Rush University, who has studied dementia and lifestyle habits, said the study offers further evidence of the link between lifestyle and dementia risk.

“This is an additional study [among other publications], which is in favor of promoting a healthy lifestyle to reduce the risk of cognitive decline and Alzheimer's disease,” Dr. Dhana said.

He said the findings were surprising in that they contradict other findings, including the FINGER trial data, as well as data from the large population-based study that used data from the UK Biobank, which found genetic risk could be offset by adhering to a healthy lifestyle.

“Lifestyle habits should be a focus of dementia risk management, particularly since Alzheimer's has no cure,” he said. But he added, “I think more data are needed to conclude the role of lifestyle factors in individuals with the genetic predisposition of dementia.”

Disclosures

The study authors declared no competing interests.

Link Up for More Information

• Licher S, Ahman S, Karamujić-Čomić, et al. Genetic predisposition, modifiable-risk actor profile and long-term dementia risk in the general population https://www.nature.com/articles/s41591-019-0547-7. Nat Med 2019; 019;25(9):1364–1369.