Grand Rounds

Does a Healthy Lifestyle Decrease Risk of Dementia Even in Those with High Genetic Risk?

BACKGROUND AND PURPOSE:

Genetics and lifestyle are both important in determining individual risk of Alzheimer’s or other forms of dementia
Previous studies have provided evidence that individuals with a healthy lifestyle are at a lower dementia risk
- It is possible that a healthy lifestyle may be able to offset genetic risk of dementia
Lourida et al. (JAMA, 2019) examined whether a healthy lifestyle could decrease risk of dementia, even in those with a significant genetic predisposition

Retrospective cohort study
Participants enrolled in the UK Biobank
- European ancestry | ≥60 years | No evidence of cognitive impairment or dementia at baseline | Genetic information available
- Exposures based on polygenic risk score and lifestyle score
Polygenic risk score for dementia: Load of common genetic variants associated with Alzheimer disease and dementia risk
- Low (lowest quintile)
- Intermediate (quintiles 2 to 4)
- High (highest quintile)
Healthy lifestyle score based on 4 dementia risk factors
- Healthy behaviors score 1 point each each: No smoking | Regular physical activity | Diet (4 of 7 cardiometabolic health food groups) | Moderate alcohol consumption
- Favorable (3 or 4 healthy factors)
- Intermediate (2 healthy factors)
- Unfavorable (0 or 1 healthy factors)
Lifestyle was ‘weighted’, adjusting for age, sex, education and socioeconomic status etc.
Primary outcome
- Incident all-cause dementia

196,383 individuals | 1,545,433 person-years
- Mean (SD) age: 64.1 (2.9) years
- 52.7% were women
- Median follow-up: 8.0 (IQR 7.4 to 8.6) years
Lifestyle
- Favorable lifestyle: 68.1% | Intermediate lifestyle: 23.6% | Unfavorable lifestyle: 8.2%
Polygenic risk scores
- High risk score: 20% | Intermediate risk score: 60% | Low risk score: 20%
Risk for developing dementia
- High genetic risk: 1.23% (95% CI, 1.13% to 1.35%)
- Low genetic risk: 0.63% (95% CI, 0.56% to 0.71%)
- adjusted hazard ratio (HR): 1.91 (95% CI, 1.64 to 2.23)
Risk for developing dementia when taking in to account both genetic risk and lifestyle
- High genetic risk and unfavorable lifestyle: 1.78% (95% CI, 1.38% to 2.28%)
- Low genetic risk and favorable lifestyle: 0.56% (95% CI, 0.48% to 0.66%)
- HR: 2.83 (95% CI, 2.09 to 3.83)
Risk for developing dementia in high risk group but with differing lifestyle scores
- High genetic risk and favorable lifestyle: 1.13% (95% CI, 1.01% to 1.26%)
- High risk and unfavorable lifestyle: 1.78% (95% CI, 1.38% to 2.28%)
- HR: 0.68 (95% CI, 0.51 to 0.90)
Genetic factors and lifestyle were not related and appeared to confer independent risk (p = 0.99)

A healthy lifestyle can significantly reduce risk for dementia even in those at risk due to genetic background
There is potential to prevent 1 case of dementia for every 121 individuals if lifestyle was improved from unfavorable to favorable
High genetic risk and unfavorable lifestyle was associated with a higher risk of dementia
Having a favorable lifestyle was associated with a lower risk of dementia even among participants with a high genetic risk

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