Prioritizing Modifiable Risk Factors for Dementia Prevention across the Spectrum of Genetic Susceptibility: A
Fei Tian1, Jinde Zhao1, Lan Chen1
1Joint International Research Laboratory of Environment and Health, Ministry of Education, Department of Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, China.
Annals of Neurology
|October 14, 2025
Summary
Dementia risk factors like social contact and diabetes are most impactful in individuals with lower genetic predisposition. Personalized prevention strategies considering genetic background are crucial for effective dementia risk reduction.
Area of Science:
- Neuroscience
- Genetics
- Public Health
Background:
- Dementia is a growing public health concern with identified modifiable risk factors.
- The interplay between genetic predisposition and the impact of these risk factors on dementia development is not fully understood.
Purpose of the Study:
- To investigate how modifiable risk factors for dementia vary in importance across different genetic risk profiles.
- To assess the population-attributable fractions (PAFs) of these risk factors in relation to genetic predisposition.
Main Methods:
- Utilized data from 182,473 dementia-free individuals in the UK Biobank cohort.
- Calculated hazard ratios (HRs) and PAFs for 11 modifiable risk factors (e.g., social contact, diabetes, education).
- Analyzed risk factor associations across genetic groups defined by APOE genotypes and a polygenic-risk score (PRS).
Main Results:
- Low social contact, diabetes, and abdominal obesity were key dementia risk factors, particularly in individuals with low genetic risk (APOE ε2ε2/ε2ε3).
- Abdominal obesity had the highest PAF (13.68-15.73%) in low genetic risk groups.
- Less education and hypertension were significant contributors in high genetic risk groups (high APOE and high PRS).
Conclusions:
- Dementia prevention strategies should be personalized, considering an individual's genetic background.
- Tailored interventions based on genetic predisposition can enhance the effectiveness of dementia prevention efforts.
- Metabolic risk factors showed a decreased overall population-attributable fraction with increasing genetic risk.
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