Can Lifestyle Choices Offset Dementia Risk Genes? – MedPage Today

A healthy lifestyle was linked to lower long-term risk of dementia for most people, but not those already at high genetic risk for dementia, the population-based Rotterdam study found.

Modifying health and lifestyle factors lowered the risk of dementia in about 73% of people — those already genetically predisposed to low or intermediate dementia risk — but did not offset dementia risk in people who had high-risk apolipoprotein E (APOE) status, reported Silvan Licher, MD, of Erasmus MC-University Medical Center in Rotterdam, the Netherlands, and co-authors, in Nature Medicine.

The findings contrast with those from another population-based study from the UK Biobank earlier this year, which suggested that a healthy lifestyle was associated with a reduced risk of dementia, regardless of genetic risk.

Several differences may account for the seemingly contradictory findings. While both were observational studies based on large databases — the Rotterdam study looked at 6,352 people and the UK Biobank study assessed 196,383 — the UK Biobank study used a polygenic risk score, an index of different genes associated with dementia including APOE, while the Rotterdam study separated APOE from 27 other dementia-risk genetic variants.

“In the UK Biobank study, persons were divided into quintiles of genetic risk using a polygenic risk score that included APOE, with a 1.91 higher risk for persons in the top compared to those in the bottom quintile,” Licher explained. “In the population of the Rotterdam study, APOE-ε4 carriership alone already yielded a three times higher dementia risk compared to non-carriers.”

Dementia was ascertained differently in each study, noted Kenneth Rockwood, MD, of Dalhousie University in Halifax, Nova Scotia, and co-authors in an accompanying editorial. Median follow-up was 8.0 years in the UK Biobank study and 14.1 years in the Rotterdam study, they added.

The UK Biobank cohort was also younger at baseline (mean age 65.1) than the Rotterdam cohort (mean age 69.1), Licher pointed out. “The combination of stronger genetic predisposition and an older age at baseline may have had detrimental consequences for people at high genetic risk in the Rotterdam study regarding dementia, irrespective of their modifiable risk factor profile,” Licher told MedPage Today. “This may suggest that these people need to be targeted earlier for preventative efforts to lower their dementia risk.”

In their study, Licher and colleagues analyzed data from more than 6,300 individuals 55 and older in Rotterdam, looking at dementia incidence over 15 years. Most participants (56.2%) were women; 27.5% had high genetic risk (ε2ε4, ε3ε4, or ε4ε4 genotypes), and most (65.3%) had favorable health and lifestyle factors, including regular physical activity, healthy diet, limited alcohol intake, and non-smoking status.

At a median follow-up of 14.1 years, 915 people (14.4%) had developed dementia. APOE genotype modified the relationship between protective lifestyle factors and dementia (P for interaction=0.023).

In people at low APOE risk (ε2ε2 or ε2ε3), the risk of dementia for participants with an unfavorable lifestyle profile was higher than that for those with a favorable lifestyle (HR 2.51, 95% CI 1.40-4.48). In people at intermediate APOE risk (ε3ε3), this was true, too (HR 1.39, 95% CI 1.04-1.8).

In people at high APOE risk, however, dementia risk did not change across lifestyle profiles. In people at high APOE risk, those with an unfavorable lifestyle had an HR of 1.00 (95% CI 0.79-1.28) for dementia, and those with a favorable lifestyle had an HR of 1.05 (95% CI 0.73-1.50).

“You have to put this research in the overall context of everything we know,” observed Keith Fargo, PhD, director of scientific programs at the Alzheimer’s Association in Chicago, who was not involved with the research. “This study says that adopting multiple healthy lifestyle behaviors is protective. That’s the general take-away of this paper: there are things you can do to protect your brain to reduce your risk of cognitive decline and dementia as you age,” he said in an interview with MedPage Today.

“Putting this paper in the context of everything else we know, including the UK Biobank study, I’m still willing to tell people that no matter who you are, no matter what your genes are, you’re better off adopting healthy lifestyle behaviors than not adopting healthy lifestyle behaviors,” Fargo added.

Meta-analysis of the Rotterdam, UK Biobank, and other observational studies is one way to better understand whether genetic risk for dementia can be modified by a healthful lifestyle, the editorialists noted. “Clinical trials are another, but despite their high standing in the evidence hierarchy, in practice they often exclude the people most at risk,” Rockwood and co-authors wrote.

The Rotterdam study had several limitations, the researchers noted. The components the researchers used to compute lifestyle profiles were measured at baseline and may have changed over time. Stratifying people by both genetic and lifestyle information led to small sample sizes and wide confidence intervals, and the findings need to be replicated in other cohorts.

“The importance of a healthy lifestyle to lower the risk of dementia is increasingly recognized,” Licher stated. “I think these results should not alter that message.”

“It is important to note that several clinical trials are underway that assess multi-domain lifestyle interventions to postpone or prevent dementia — for instance, extended 7-year follow-up of the FINGER trial — and these will ultimately provide more confidence about the efficacy of these preventative interventions across genetically determined dementia risk,” he added.

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