Genetics and Lifestyle: A New Picture of Alzheimer's Risk
Two independent research studies, alongside a new model of genetic contribution, have examined the relationship between the APOE gene, modifiable lifestyle factors, and the risk of developing Alzheimer's disease and other forms of dementia. The findings detail the influence of specific genetic variants and the potential limits of lifestyle intervention.
🧬 Part I: The True Weight of Genetics
New analysis suggests the contribution of the APOE gene to Alzheimer's may be larger than previously understood.
A new analysis led by researchers at University College London (UCL) and published in npj Dementia has modeled the contribution of common variations in the APOE gene to dementia risk. The study analyzed data from over 450,000 participants across four large studies.
The APOE gene has three common variants (alleles): ε2, ε3, and ε4. Individuals inherit two copies of the gene. The ε4 variant has long been recognized as a major genetic risk factor for Alzheimer's disease. The ε2 variant is associated with a lower risk.
This new analysis found that, compared to the ε2 variant, the more common ε3 and ε4 variants are both associated with an increased risk of Alzheimer's disease. The researchers estimated that 72% to 93% of Alzheimer's disease cases might not occur without the contribution of these two variants. The analysis also estimated that approximately 45% of all dementia cases would likely not arise without their influence. These estimates are higher than previous calculations because the study accounted for the contribution of the ε3 variant, which was previously considered neutral in terms of risk.
Dr. Dylan Williams (UCL Division of Psychiatry) stated that the findings suggest the APOE gene's contribution to Alzheimer's disease may be larger than previously understood.
🧘 Part II: Where Lifestyle Helps—and Where It Hits a Wall
Managing lifestyle risks may help reduce dementia risk for individuals with one or no APOE ε4 alleles, but new approaches may be needed for those with two copies.
A separate study by Kyushu University and RIKEN, published on May 21 in Alzheimer's & Dementia, examined whether favorable modifiable risk factors (mRF) can lower dementia risk in individuals with different APOE ε4 genetic backgrounds.
Modifiable risk factors include health conditions and behaviors such as blood pressure control and physical activity. Researchers analyzed data from 9,605 Japanese adults aged 65 and older. Participants' APOE ε4 genotypes and mRF scores were assessed.
The study confirmed that dementia risk increased with the number of APOE ε4 alleles an individual carried.
- Individuals with two copies (homozygotes) had a more than 10-fold higher risk than non-carriers.
- Among those with one or no APOE ε4 alleles, a lower mRF score (indicating more favorable lifestyle and health factors) was associated with a significantly lower risk of dementia.
However, among individuals with two copies of the APOE ε4 allele, no significant difference in dementia risk was observed based on their mRF scores. Brain MRI scans showed that lower mRF scores were linked to less brain atrophy and fewer white matter lesions in individuals with one or no APOE ε4 alleles. This association was not observed in those with two APOE ε4 alleles, who had greater brain atrophy more broadly.
Professor Toshiharu Ninomiya from Kyushu University stated that managing lifestyle risks may help reduce dementia risk for individuals with one or no APOE ε4 alleles, but that new approaches may be needed for those with two copies.
🔬 Part III: Implications for Research and Treatment
Both studies have implications for future research and treatment development.
Regarding the UCL analysis, the researchers stated that the APOE gene and the protein it produces represent a significant target for drug development. Potential approaches for reducing risk conferred by the ε3 and ε4 variants include gene editing, gene therapy, or drugs targeting the molecular pathway between the gene and the disease. Dr. Williams noted that the extent to which APOE has been researched as a drug target may not be proportionate to its full importance.
Dr. Sheona Scales, Director of Research at Alzheimer’s Research UK (which funded the UCL study), commented that despite the known link between APOE and Alzheimer's, few current clinical trials target this gene, underscoring the importance of further research.
Experts not involved in the UCL study offered varied responses.
- Professor Tim Frayling of the University of Geneva offered a comparison, stating the claim about APOE's role is analogous to saying most road traffic deaths would not occur without cars. He also noted that approximately 99.4% of individuals carry the ε3 or ε4 variants.
- Professor Tara Spires-Jones of the University of Edinburgh stated that understanding genetic risk factors like APOE is crucial for developing effective treatments and prevention strategies.
📚 Context and Complexity
Both studies and the accompanying analysis acknowledge that Alzheimer's disease and other dementias are complex conditions with multiple contributing factors.
- The UCL study notes that even individuals with two copies of the ε4 variant have a lifetime risk of Alzheimer's estimated below 70%.
- The UCL study also states that complex interactions with other genetic and environmental factors are at play, and that other research suggests approximately half of dementia incidence could be prevented or delayed by addressing modifiable risk factors.
- The Kyushu University study demonstrates the interaction but also the limitations of lifestyle modification for individuals with the highest genetic risk (two APOE ε4 alleles).
- Dr. Scales noted that not all individuals with these APOE gene variations develop dementia.
Previous research suggests the ε4 variant may increase dementia risk by being less effective at clearing harmful amyloid-beta proteins, disrupting fat and energy processing in brain cells, and promoting inflammation. The mechanisms by which the ε3 variant increases risk relative to the ε2 variant require further investigation.
Alzheimer's disease affects over 40 million people globally. The Kyushu University study was published in Alzheimer's & Dementia, and the UCL analysis was published in npj Dementia. The UCL study was conducted by researchers at UCL and the University of Eastern Finland, with funding from Alzheimer's Research UK and the Medical Research Council.