From the Journals

Genotype may affect lifestyle’s influence on dementia risk

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Study supports lifestyle modification for risk reduction

The study by Dr. Licher and associates shows a clinically significant impact of a healthy lifestyle in reducing dementia. But what is surprising is that the effect was not seen in genetically higher-risk people.

Dr. Richard J. Caselli, professor of neurology at the Mayo Clinic in Scottsdale, Ariz., and associate director and clinical core director of Mayo’s Alzheimer’s Disease Center.

Dr. Richard J. Caselli

About half of patients with dementia are apolipoprotein E epsilon-4 allele (APOE4) carriers, meaning half are not. Of those, most patients have a genotype with two APOE3 alleles, which is shared by the largest proportion of the human race. So, having a protective lifestyle could have a big public health impact if people comply with it.

If anything, the results strengthen our recommendations to people interested in lowering their risk for dementia with lifestyle modification. Bear in mind that APOE testing is not done routinely, so the vast majority of our patients do not know their APOE genotype. Since a healthy lifestyle can benefit the majority of the population (around 75%), even if it is less or ineffective in the APOE4 carrier group (about 25% of the population), it is certainly something to recommend. Of course, health care professionals already recommend heart healthy habits, which have an equivalent benefit, and sadly, adherence is relatively low. Adding that lifestyle modification may help prevent dementia might improve patient compliance. Starting healthy lifestyles as early in life as possible may be the key. It is less effective if we wait until we already have memory loss.

Finally, the study results regard relative risk, a concept that many fail to fully grasp. A person can still get dementia in any of the categories, including the “best one” (low genetic and lifestyle risk). It’s a matter of the odds being better or worse, but there is no guarantee of a positive or negative outcome.

Richard J. Caselli, MD, is professor of neurology at the Mayo Clinic Arizona in Scottsdale and associate director and clinical core director of the Arizona Alzheimer’s Disease Center, Phoenix. He made these comments in an interview.



Among older adults with low and intermediate genetic risk for dementia, favorable modifiable health and lifestyle factors are associated with lower likelihood of dementia. But among people at high genetic risk for dementia, these potentially modifiable factors – not smoking, not having depression or diabetes, getting regular physical activity, avoiding social isolation, and following a healthy diet – may not have protective associations, according to research published in Nature Medicine.

Recent analyses have indicated that eliminating known modifiable risk factors for dementia at a population level could prevent one-third of dementia cases, but prevention trials “have yielded inconsistent results so far,” wrote first author Silvan Licher, MD, of the department of epidemiology at Erasmus University Medical Center Rotterdam (the Netherlands) and his colleagues.

“Prior studies have mostly focused on the risk of dementia associated with an individual protective factor, yet the combination of multiple factors may yield more beneficial effects than the individual parts,” they wrote. “Combining data about a number of factors is also important because it takes into account the multifactorial nature of late-life dementia. We used data from the Rotterdam Study to determine to what extent a favorable profile based on modifiable risk factors is associated with a lower risk of dementia among individuals at low, intermediate, or high genetic risk.”

Grouped by APOE genotype

Patients who were apolipoprotein E epsilon-4 allele (APOE4) carriers (i.e., APOE2 and 4, APOE3 and 4, or two APOE4) were classified as having high genetic risk (n = 1,747). Other APOE genotypes were considered intermediate risk (n = 3,718 with two APOE3 alleles) or low risk (n = 887 with either two APOE2 alleles or APOE2 and 3).

The researchers measured six potentially modifiable lifestyle or health factors that “have been implicated in a lower risk of dementia.” Modifiable risk scores ranged from 0 to 6. Participants were classified as having an unfavorable profile (0-2 protective factors), an intermediate profile (3-4 protective factors), or a favorable profile (5-6 factors).

The researchers calculated the relative risk of developing dementia using a Cox proportional hazards model and the absolutely risk using competing risk models.

In all, 56.2% of the participants were women, the average age was about 69 years, and patient characteristics were similar across the categories of APOE risk. APOE4 carriers received dementia diagnoses at a younger age, more often had a parental history of dementia, and had higher total cholesterol levels, compared with noncarriers. In all, 915 people received a dementia diagnosis, of whom 739 received a diagnosis of Alzheimer’s disease. The other 2,644 participants died free from dementia. The median follow-up was 14.1 years.

“Dementia risk was significantly higher among participants at high or intermediate APOE risk, compared with those at low APOE risk,” the researchers said. In addition, the risk of dementia increased in participants who had fewer protective factors. Those with 0-2 protective factors had a 29% higher risk of dementia, compared with participants with 5 or 6 protective factors, after adjusting for age, sex, level of education, parental history of dementia, history of stroke, systolic blood pressure, and total and high-density lipoprotein cholesterol.


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