Healthy Lifestyle Offsets Genetic Risk for Dementia

Pauline Anderson

July 15, 2019

LOS ANGELES — Adhering to a healthy lifestyle reduces the risk of developing dementia, even in those at genetic risk of Alzheimer's disease (AD), new research suggests.

Elzbieta Kuzma, PhD

Investigators found that individuals at high genetic risk who followed an unhealthy lifestyle were almost three times more likely to develop dementia within 8 years than those with a low genetic risk and a favorable lifestyle.

Fewer participants with high genetic risk who had a healthy lifestyle developed dementia than their counterparts with an unhealthy lifestyle.

This is the first study to comprehensively investigate whether a healthy lifestyle offsets genetic risk for dementia, study investigator Elzbieta Kuzma, PhD, research fellow in neuroepidemiology, University of Exeter Medical School, England, told Medscape Medical News.

"Although our study does not prove a causal relationship, the take-home message is very optimistic, as our results indicate that living a healthy lifestyle was associated with a reduced dementia risk regardless of genetic risk."

The study sends "a very important public health message," added Kuzma.

"It suggests that healthy lifestyle interventions may help to prevent or delay dementia, even in people with high genetic risk."

The findings were presented here at the Alzheimer's Association International Conference (AAIC) 2019. The study was also published online July 14 in the Journal of the American Medical Association.

Biobank Data

Researchers used data from the UK Biobank study, a population-based cohort of more than 500,000 participants who attended one of 22 assessment centers across the United Kingdom between 2006 and 2010.

From this Biobank, researchers identified 196,383 individuals aged at least 60 years (mean age 64.1 years), 52.7% of them women, who had available genetic information and did not have dementia at baseline.

For each study subject, researchers calculated a polygenic risk score. They used previously published data from genome-wide association studies for AD in those with European ancestry, and included almost 250,000 individual genetic variants that they weighted according to association with AD and then standardized.

The variants included APOE but many others, too, said Kuzma. "It was a really comprehensive polygenic risk score."

From this genetic information, they categorized subjects into low (lowest quintile), intermediate (quintiles 2 to 4), and high (highest quintile) genetic risk for developing dementia.

The research team also developed a healthy lifestyle index for each study subject. They used four well-established dementia risk factors — smoking status, physical activity, diet, and alcohol consumption.

Study subjects self-reported this information on a questionnaire at baseline.

Researchers categorized smoking status as current or not current smoker. They defined regular physical activity as at least 150 minutes of moderate activity per week or 75 minutes of vigorous activity per week — or an equivalent combination.

A healthy diet was based on consumption of at least four of seven commonly eaten food groups that have been linked to cardiometabolic health, better late-life cognition, and reduced dementia risk.

"This would include eating plenty of fruits and vegetables, and plenty of fish and nonprocessed foods," said Kuzma.

Moderate consumption was defined as 0 to 14 g/day for women and 0 to 28 g/day for men.

Researchers weighted and standardized the lifestyle score. Higher scores indicate greater adherence to a healthy lifestyle.

They then categorized the lifestyle scores as favorable (3 or 4 healthy lifestyle factors), intermediate (2 healthy lifestyle factors), and unfavorable (0 or 1 healthy lifestyle factor) lifestyles.

"Someone who doesn't smoke, exercises regularly, drinks alcohol in moderation, and follows a healthy diet would have a favorable lifestyle score, but someone who does not smoke and exercises regularly but exceeds the recommended levels for alcohol consumption and does not have a healthy diet would have an intermediate score, and someone who doesn't do any of those good things would have an unfavorable score," said Kuzma.

Overall, 68.1% of participants followed a favorable lifestyle, 23.6% followed an intermediate lifestyle, and 8.2% followed an unfavorable lifestyle. About 20% had high polygenic risk scores, 60% had intermediate risk scores, and 20% had low risk scores.

Over a median of 8 years of follow up, researchers identified 1769 cases of dementia from hospital records and through linkage with death registry data.

Results showed that compared with low genetic risk, the adjusted hazard ratio (HR) for developing dementia was 1.37 (95% confidence interval [CI], 1.20 - 1.58) for intermediate genetic risk and 1.91 (95% CI, 1.64 - 2.23) for high genetic risk.

"When we included lifestyle factors into this model, the results didn't change," said Kuzma.

Compared with a favorable lifestyle, the adjusted HR for developing dementia in the intermediate group was 1.17 (95% CI, 1.04 - 1.31) and 1.35 (95% CI, 1.15 - 1.58) in the unfavorable group.

"Again, when we added the genetic risk to the model, results did not change. What this set of results tells us is that lifestyle and genetic risk are independently associated with risk of dementia," said Kuzma.

Worst Combination

Researchers next looked at the combination of genetic risk and lifestyle and noted an increasing risk of developing dementia with increasing genetic risk and an increasingly unhealthy lifestyle.

"The worst combination was high genetic risk and unfavorable lifestyle," said Kuzma.

Those with this combination were almost three times more likely to develop dementia compared with those with low genetic risk and favorable lifestyle (HR 2.83; 95% CI, 2.09 - 3.83; P < .001).

A healthy lifestyle reduced dementia risk across all genetic risk groups. Among participants with high genetic risk, 1.13% (95% CI, 1.01% - 1.26%) of those with a favorable lifestyle developed dementia compared with 1.78% (95% CI, 1.38% - 2.28%) with an unfavorable lifestyle (HR, 0.68; 95% CI, 0.51 - 0.90).

"Our results consistently showed that a healthy lifestyle was associated with reduced risk of dementia across genetic risk groups," said Kuzma. "So even people with a high genetic risk can still try to reduce their risk of dementia by following a healthy lifestyle."

A range of mechanisms may help explain why genetic and lifestyle factors are associated with dementia risk. A healthy lifestyle may contribute to dementia risk through cardiovascular and cerebrovascular mechanisms, including reduced oxidative damage, antithrombotic and anti-inflammatory effects, and increased cerebral blood flow, said the study authors.

Although the researchers adjusted for known potential sources of bias, unmeasured confounding and reverse causation is still possible, the authors noted. Another limitation is that lifestyle factors were self-reported and some cases of dementia may have been missed.

However, research shows a good agreement between identified dementia cases and primary care records. "We feel pretty confident about those cases that have been identified," said Kuzma.

An additional possible limitation was that other lifestyle or environmental factors may play a role in determining dementia risk. And as the sample was restricted to volunteers of European ancestry aged 60 to 73 years at baseline, the study may not be generalizable beyond this population.

Exciting Implications

Heather M. Snyder, PhD, senior director of Medical and Scientific Operations, Alzheimer's Association, who chaired the conference press briefing highlighting this and other lifestyle-related studies, said this research "continues to advance our understanding of how lifestyle and other behaviors might counter dementia risk."

Perhaps in the future, researchers will treat AD and other dementias in the same way they treat heart disease, said Snyder. This, she said, means, "looking across the entire life course and using behavioral interventions that might counter the factors that are increasing our risk throughout life."

Commenting on the study for Medscape Medical News, Maria C. Carrillo, PhD, chief science officer, Alzheimer's Association, said it represents important progress in the field.

"This has already been proven in cardiovascular health — that if people inherit cardiovascular disease genes, they can overcome it through lifestyle. The fact that we may be able to do that in Alzheimer's disease dementia is really exciting."

This new information is important for patients with a close relative who has dementia, she added. "The first thing they ask is, 'Am I destined to get this, too?' — and the answer is actually no."

Support for the study was provided by the James Tudor Foundation, Mary Kinross Charitable Trust, Halpin Trust, National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care for the South West Peninsula, National Health and Medical Research Council Australia, National Institute on Aging/National Institutes of Health, and Alan Turing Institute under the Engineering and Physical Sciences Research Council grant. Kuzma, Carrillo, and Snyder have disclosed no relevant financial relationships.

Alzheimer's Association International Conference (AAIC) 2019: Abstract #31424. Presented July 14, 2019.

JAMA. Published online July 14, 2019. Full text

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