Midlife Choices May Offset Genetic Risk for Dementia, Stroke, Late-Life Depression

Healthier lifestyle behaviors in midlife were linked with better outcomes in people with genetic predisposition for age-related brain diseases, longitudinal data from the U.K. Biobank showed.

Over about 12 years of follow-up, each 5-point improvement in Brain Care Score was tied to a reduced risk of dementia (HR 0.82, 95% CI 0.78-0.85), stroke (HR 0.70, 95% CI 0.68-0.73), and late-life depression (HR 0.65, 95% CI 0.63-0.67), reported Christopher Anderson, MD, MMSc, of Massachusetts General Hospital in Boston, and colleagues.

For all three outcomes, incidence was higher among people with high genetic risk. However, this increased risk was offset for individuals with higher Brain Care Scores, the researchers said in Neurology.

In participants with high genetic risk, incident rates for high versus low Brain Care Scores were:

• 2.05 vs 3.64 for dementia
• 1.2 vs 2.8 for stroke
• 4.46 vs 7.34 for late-life depression

The 21-point Brain Care Score measures modifiable risk factors related to age-related brain diseases, with higher scores indicating better brain care. It assesses blood pressure, hemoglobin A1C levels, cholesterol levels, body mass index, weekly diet, alcohol consumption, smoking habits, aerobic activity, sleep habits, stress levels, social relationships, and feelings of meaning or purpose in life.

Earlier research suggested the tool was effective in capturing risk of stroke, dementia, and late-life depression in a large population. However, "we had not previously examined whether people with a high genetic risk for these conditions could still benefit from healthy lifestyle choices like a good diet, exercise, sleep, and social interactions, in addition to control of blood pressure, cholesterol, and blood sugar," Anderson said.

"This study reinforces the idea that your genetics do not make you predestined to certain outcomes," he told MedPage Today.

"Controlling risk factors can go a long way toward promoting healthy aging even if your genetics are working against you," he added. "This is true for stroke and dementia, where previous studies have also supported this concept using different tools to capture modifiable risk factors, but also for late-life depression, which shares risk factors with both stroke and dementia."

The analysis included 368,340 U.K. Biobank participants. Median age was 58 years, and 46.3% were men.

Genetic risk was assessed using polygenic risk scores for stroke and depression; for dementia, APOE status was used. The APOE4 allele is the strongest risk factor gene of Alzheimer's disease and "polygenic risk scores for Alzheimer's disease are not substantially more predictive than APOE status alone," the researchers noted.

Most participants (59.7%) had wild-type genetic risk for dementia; these were APOE3 homozygotes. High genetic risk for dementia included APOE4 homozygotes and people who carried APOE4/APOE3 alleles; this applied to 27% of the study population.

For all three outcomes -- dementia, stroke, and late-life depression -- the median follow-up was 12.5 years. During follow-up, 9,361 stroke events, 6,959 new cases of dementia, and 14,371 new cases of late-life depression emerged.

The data in this study "provide some context for important discussion on the ethics of genetic data release because there is clear benefit to proactive risk management regardless of an individual's inborn disease risk," Anderson and co-authors wrote.

"These results are particularly important now that direct-to-consumer companies are returning polygenic risk data to their customers," they pointed out. "Along these lines, our results support the notion that genetic predisposition can be counterbalanced by lifestyle and health behavior modifications."

This was an observational analysis, and relationships between Brain Care Scores and outcomes are not causal, the researchers emphasized. The study design also limited the ability to assess the independence of components within the Brain Care Score. Future research may clarify the effect of changes in baseline Brain Care Scores over time, Anderson and co-authors noted.

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