A recent analysis led by researchers at University College London (UCL) indicates that variants of the APOE gene may contribute to a substantial majority of Alzheimer's disease cases and a significant portion of all dementia cases. The study, published in the journal npj Dementia, suggests that 72% to 93% of Alzheimer's disease cases and approximately 45% of all dementia cases might not occur without the influence of the APOE gene's ε3 and ε4 alleles. These estimates are higher than previous findings due to the inclusion of the ε3 variant, which was often considered neutral in prior analyses, as a risk factor when compared to the ε2 variant.
Main Findings
The analysis focused on the APOE gene, which has three common variants: ε2, ε3, and ε4. Traditionally, individuals inheriting two copies of the ε4 variant have been associated with a high risk of Alzheimer's disease, while the ε3 variant was largely considered neutral, and ε2 protective. The new findings propose that both ε3 and ε4 variants increase the risk of Alzheimer's disease when compared to carrying two copies of the ε2 variant.
Dr. Dylan Williams, a genetic epidemiologist at UCL, noted that the contribution of both ε3 and ε4 variants suggests a broader role for APOE in Alzheimer's disease. The study estimated that between 72% and 93% of Alzheimer's cases and approximately 45% of all dementia cases could be linked to these APOE variants. The variation in estimates between studies was attributed to differences in how Alzheimer's and dementia were defined and measured.
Methodology
The study involved a comprehensive analysis of the proportion of Alzheimer's and dementia cases attributable to common variations in APOE. Researchers utilized data from four extensive studies, comprising over 450,000 participants of European ancestry. For the first time in such an analysis, a rare group of individuals with two copies of the ε2 variant was used as a low-risk baseline, enabling a more precise assessment of the relative risks posed by ε3 and ε4.
Implications for Research and Treatment
The findings highlight the APOE gene and the protein it produces as a significant target for drug development aimed at preventing or treating dementia. Researchers suggest that interventions targeting these variants could have considerable potential. Future research could explore approaches such as gene editing, gene therapy, or conventional drugs that target the molecular pathways between the gene and the disease.
Dr. Sheona Scales, Director of Research at Alzheimer's Research UK, acknowledged the significance of evidence suggesting ε3 contributes to Alzheimer's risk. She also noted that few current clinical trials directly target the APOE gene, underscoring the importance of further research into how ε3 and ε4 influence risk and their potential as therapeutic targets.
Broader Context and Contributing Factors
While the APOE gene is identified as a major factor, Alzheimer's and other dementias are complex conditions not solely caused by this gene. Even individuals with the highest-risk combination (two copies of ε4) have a lifetime risk of Alzheimer's estimated below 70%. Complex interactions with other genetic and environmental factors are at play. Dr. Williams emphasized that most individuals with ε3 and ε4 variants do not develop dementia in a typical lifetime.
Other research suggests that approximately half of dementia incidence could be prevented or delayed by addressing modifiable risk factors such as social isolation, high cholesterol, smoking, obesity, diabetes, and high blood pressure. Strategies related to APOE are considered one approach among many to reduce disease occurrence.
Potential Mechanisms
Previous studies indicate that the ε4 variant may increase dementia risk through several mechanisms, including being less effective at clearing harmful amyloid-beta proteins, disrupting fat and energy processing in brain cells, and promoting inflammation. These changes can gradually damage neurons, potentially making the brain more vulnerable. Further research is needed to fully understand why the ε3 variant increases dementia risk relative to ε2.
Challenges and Expert Perspectives
Modifying the APOE gene presents challenges, as it plays a critical role in cholesterol and fat transport. Researchers note that complete elimination of its function could lead to adverse effects, and future therapies, such as gene editing or dampening activity, are not immediate or without risk. Additionally, the study noted that over 99% of the study population carried either the ε3 or ε4 variant, suggesting that preventing Alzheimer's through such means would involve treating nearly the entire population.
Expert responses to the study varied. Professor Tim Frayling of the University of Geneva commented on the study's claims, noting that approximately 99.4% of individuals carry the Apoe3 or Apoe4 variants. He offered an analogy, stating that most road traffic deaths would not occur without cars. Conversely, 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.
Current Alzheimer's drugs, designed to remove toxic proteins from the brain, have offered limited benefits and have been rejected for widespread use by the UK’s National Institute for Health and Care Excellence (NICE). Due to the complexity of Alzheimer's risk, APOE testing is not available on the NHS for risk assessment. Individuals concerned about dementia risk are advised to consult their general practitioner.
Funding and Collaborations
This study was conducted by researchers at UCL and the University of Eastern Finland. It received funding from organizations including Alzheimer's Research UK and the Medical Research Council, among others.