With dementia cases expected to nearly triple worldwide by 2050, researchers are increasingly focused on identifying ways to prevent or delay the disease. While lifestyle and health-related factors, such as blood pressure control and physical activity, influence dementia risk, genetics also play a major role. Currently, it is unclear whether maintaining a favorable lifestyle reduces dementia risk equally across different genetic backgrounds.
A new study led by Kyushu University and RIKEN, published May 21 in Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring, examines whether favorable modifiable risk factors (mRF)—behaviors or conditions that people can change or control—can lower dementia risk even among individuals with high genetic susceptibility.
To explore this, the researchers analyzed data from 9,605 community-dwelling Japanese adults ages 65 and older. They determined each participant’s APOE ?4 genotype, a primary genetic risk factor for Alzheimer’s disease, and calculated the mRF score based on lifestyle and health-related factors. This allowed the team to evaluate how genetic predisposition and lifestyle choices jointly influence dementia risk.
The results showed that dementia risk rose progressively with the number of APOE ?4 alleles. Because humans inherit one allele of each gene from each parent, a person can carry zero, one or two APOE ?4 alleles. Individuals carrying two alleles, known as homozygotes, had more than 10 times the dementia risk of noncarriers.
Notably, among individuals with one or no APOE ?4 alleles, maintaining a healthier profile with lower mRF scores was linked to a significantly lower risk of dementia. In contrast, among individuals with two APOE ?4 alleles, dementia risk did not differ significantly between those with lower and higher mRF scores.
Brain MRI scans supported these findings. Among those with one or no alleles of the gene, lower mRF scores were associated with less brain atrophy and fewer white matter lesions—areas of damaged tissue in the brain linked to cognitive decline and dementia. In contrast, individuals with two alleles of the gene exhibited greater brain atrophy and more extensive tissue damage regardless of their lifestyle profile.
These findings suggest that maintaining favorable lifestyle and health conditions can effectively mitigate dementia risk, even among individuals carrying a single APOE ?4 allele. This underscores the importance of population-based prevention strategies focused on managing vascular and lifestyle risk factors.
“Among individuals carrying one APOE ?4 allele, as in those carrying no APOE ?4 alleles, favorable management of risk factors may help reduce the risk of dementia,” says Professor Toshiharu Ninomiya from Kyushu University’s Faculty of Medical Sciences, who led the study.
“On the other hand, for individuals carrying two APOE ?4 alleles, earlier intervention as well as new preventive or therapeutic approaches beyond lifestyle and health management may warrant consideration.”
More information
Masaya Kumamoto et al, APOE ?4, modifiable risk factors, and dementia in community?based older Japanese adults, Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring (2026). DOI: 10.1002/dad2.70371
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