Association of Lifestyle and Genetic Risk With Incidence of Dementia
Question Is a healthy lifestyle associated with lower risk of dementia, regardless of genetic risk?
Findings In this retrospective cohort study that included 196 383 participants of European ancestry aged at least 60 years without dementia at baseline, participants with a high genetic risk and unfavorable lifestyle score had a statistically significant hazard ratio for incident all-cause dementia of 2.83 compared with participants with a low genetic risk and favorable lifestyle score. A favorable lifestyle was associated with a lower risk of dementia and there was no significant interaction between genetic risk and healthy lifestyle.
Meaning A healthy lifestyle was associated with lower risk of dementia among participants with low or high genetic risk.
Importance Genetic factors increase risk of dementia, but the extent to which this can be offset by lifestyle factors is unknown.
Objective To investigate whether a healthy lifestyle is associated with lower risk of dementia regardless of genetic risk.
Design, Setting, and Participants A retrospective cohort study that included adults of European ancestry aged at least 60 years without cognitive impairment or dementia at baseline. Participants joined the UK Biobank study from 2006 to 2010 and were followed up until 2016 or 2017.
Exposures A polygenic risk score for dementia with low (lowest quintile), intermediate (quintiles 2 to 4), and high (highest quintile) risk categories and a weighted healthy lifestyle score, including no current smoking, regular physical activity, healthy diet, and moderate alcohol consumption, categorized into favorable, intermediate, and unfavorable lifestyles.
Main Outcomes and Measures Incident all-cause dementia, ascertained through hospital inpatient and death records.
Results A total of 196 383 individuals (mean [SD] age, 64.1 [2.9] years; 52.7% were women) were followed up for 1 545 433 person-years (median [interquartile range] follow-up, 8.0 [7.4-8.6] years). Overall, 68.1% of participants followed a favorable lifestyle, 23.6% followed an intermediate lifestyle, and 8.2% followed an unfavorable lifestyle. Twenty percent had high polygenic risk scores, 60% had intermediate risk scores, and 20% had low risk scores. Of the participants with high genetic risk, 1.23% (95% CI, 1.13%-1.35%) developed dementia compared with 0.63% (95% CI, 0.56%-0.71%) of the participants with low genetic risk (adjusted hazard ratio, 1.91 [95% CI, 1.64-2.23]). Of the participants with a high genetic risk and unfavorable lifestyle, 1.78% (95% CI, 1.38%-2.28%) developed dementia compared with 0.56% (95% CI, 0.48%-0.66%) of participants with low genetic risk and favorable lifestyle (hazard ratio, 2.83 [95% CI, 2.09-3.83]). There was no significant interaction between genetic risk and lifestyle factors (P = .99). 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 (hazard ratio, 0.68 [95% CI, 0.51-0.90]).
Conclusions and Relevance Among older adults without cognitive impairment or dementia, both an unfavorable lifestyle and high genetic risk were significantly associated with higher dementia risk. A favorable lifestyle was associated with a lower dementia risk among participants with high genetic risk.
Both genetic and lifestyle factors play a role in determining individual risk of Alzheimer disease and other dementia subtypes.1 Mutations in the amyloid precursor protein (APP; OMIM:104760), presenilin 1 (PSEN1; OMIM:104311), and presenilin 2 (PSEN2; OMIM:600759) genes can cause early-onset Alzheimer disease, although this accounts for a small percentage of cases.2 Most dementia cases occur sporadically in older adults in whom multiple genes influence risk. The ε4 allele of the apolipoprotein E gene (APOE; OMIM:107741) is known to increase the risk of Alzheimer disease.3,4 A meta-analysis of genome-wide association studies identified additional loci associated with the risk of late-onset Alzheimer disease in participants of European ancestry.3 Polygenic risk scores combining multiple risk alleles for Alzheimer disease are predictive of incident all-cause dementia and provide a quantitative measure of genetic dementia risk.5,6
There is considerable evidence that individuals who avoid smoking tobacco, are physically active, drink alcohol in moderation, and have a healthy diet have a lower dementia risk.7–10 Studies have combined lifestyle factors to create a composite lifestyle score to investigate the relationship between lifestyle factors and other health conditions, such as cardiovascular disease and diabetes.11,12 It is possible that genetic risk can be offset by lifestyle factors. Studies that examined whether the risk reduction associated with adherence to a healthy lifestyle varied on the basis of APOE ε4 allele haplotype have yielded inconsistent results; however, statistical power was limited in these studies and other genetic factors were not incorporated.13,14
The purpose of this study was to use data from a large population-based cohort to investigate the hypothesis that adherence to a healthy lifestyle may offset genetic risk for dementia.