Association of Lifestyle and Genetic Risk With Incidence of Dementia
Open accessAbstract
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.
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Modifiable lifestyle factors such as physical activity, diet, sleep, and social engagement influence neurodegeneration risk.
“While aging remains the primary non-modifiable risk factor, accumulating evidence highlights the role of modifiable lifestyle factors-such as physical activity, diet, sleep, and social engagement -in influencing neurodegeneration risk [2,3].”
From What Are the Key Biological Pathways Through Which Lifestyle Factors Influence Neurodegeneration? (2025) · cites this paper as [3]
The Healthy Lifestyle Score section includes physical activity and diet, and the Discussion reports that a favorable lifestyle was associated with lower incident dementia risk. The paper’s score does not include sleep or social engagement, and its findings concern dementia incidence rather than neurodegeneration risk broadly. (LLM, conf=0.88)
Experimental — accuracy not yet measuredHealthy lifestyles, such as regular physical activity and healthy diet, are associated with weight loss and reduced risk of dementia by 0.68 times.
“Therefore, healthy lifestyles, such as regular physical activity and healthy diet, are associated with weigh loss and reduced the risk of dementia by 0.68 times.375,376”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [376]
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“A higher healthy diet score has been shown to be associated with a lower risk of dementia [23].”
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What Are the Key Biological Pathways Through Which Lifestyle Factors Influence Neurodegeneration?
Su, Z. (2025) · Theoretical and Natural Science · doi:10.54254/2753-8818/2025.au25765
- Authors
- Lourida, I., Hannon, E., Littlejohns, T. J., Langa, K. M., Hyppönen, E., Kuzma, E., & Llewellyn, D. J.
- Affiliations
- University of Exeter (GB)
- University of Oxford (GB)
- University of Michigan (US)
- University of South Australia (AU)
- University of Exeter Medical School, Exeter, United Kingdom
- Corresponding author
- Llewellyn, David J.
- ORCID
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2019-08-06
- Volume
- 322
- Issue
- 5
- Pages
- 430
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- PMC
- PMC6628594
- OpenAlex
- W2960583731
- Cited by
- 881
- References
- 35
- Citations by year
- 2026: 116 · 2025: 162 · 2024: 174 · 2023: 134 · 2022: 122 · 2021: 94 · 2020: 61 · 2019: 17
- FWCI
- 59.15
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- other-oa
- Locations
- JAMA (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Figshare (submittedVersion)
- Open Research Exeter (University of Exeter) (submittedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- Alzheimer's Association
- Alan Turing Institute (TU/ASG/R-SPEH-118)
- National Institute for Health and Care Research
- Department of Health and Social Care
- University of Oxford
- James Tudor Foundation
- National Institutes of Health
- Medical Research Council (MC_PC_17228)
- Engineering and Physical Sciences Research Council (EP/N510129/1)
- National Health and Medical Research Council (1157281)
- National Institute on Aging (RF1AG055654)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Risk Factors
- Keywords
- dementia, polygenic risk score, healthy lifestyle, genetic risk, lifestyle modification, physical activity, diet, alcohol consumption, smoking, older adults, dementia incidence, gene-environment interaction, UK Biobank
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