Scientists have proposed a new classification for Alzheimer’s patients, suggesting that genetics could be a cause, rather than just a risk factor, for some cases of the disease. The study, published in the journal Nature Medicine, focuses on a gene variant called APOE4. Inheriting one copy of the APOE4 gene increases the risk of developing Alzheimer’s, while two copies greatly increase the risk. The researchers found that almost all patients with two copies of APOE4 developed the biological pathology of Alzheimer’s, leading them to propose that it should be considered a cause, not just a risk factor.
The findings redefine the understanding of Alzheimer’s genetics and could broaden the scope of efforts to develop treatments, including gene therapy. The new classification would make this type of Alzheimer’s one of the most common genetic disorders in the world. It is estimated that 15 to 20 percent of people with Alzheimer’s dementia have two copies of APOE4. This reclassification could also affect the design of clinical trials and pave the way for earlier diagnosis before symptoms of cognitive decline appear.
Clinical Implications and Treatment Considerations
Patients with two copies of APOE4, known as APOE4 homozygotes, face higher safety risks from anti-amyloid drugs, such as Leqembi. The Food and Drug Administration has required a black-box warning on the label of Leqembi, stating that the medication can cause serious and life-threatening events for people with two copies of APOE4. Some treatment centers have chosen not to offer the drug to these patients due to the heightened risks.
Classifying patients with two copies of APOE4 as having a distinct genetic form of Alzheimer’s could have significant implications for the development of safer and more effective treatments. It could also add urgency to current efforts to prevent cognitive decline in individuals who do not yet have symptoms. Researchers are exploring gene editing and gene therapy approaches to transform APOE4 into a variant called APOE2, which appears to protect against Alzheimer’s.
Shifting Understanding of Genetic Risks and Disease Forms
The new classification proposed in the study challenges the traditional understanding of genetic risks for Alzheimer’s. Currently, less than 2 percent of cases are considered genetically caused.
However, recognizing APOE4 as a distinct genetic form of the disease would suggest that a larger proportion of cases are categorized as genetically determined. This would necessitate personalized treatment approaches and precision medicine for different forms of the disease.
The findings also have implications for disease risk assessment and clinical trials. APOE4 homozygotes have a significantly higher risk of developing Alzheimer’s and exhibit similar clinical and biological changes as other inherited forms of the disease. This emphasizes the need to include these individuals in trials at younger ages and earlier stages of pathology.
Ethical and Medical Considerations in Diagnosis and Testing
The reclassification of APOE4 as a distinct genetic form of Alzheimer’s raises questions about whether individuals should undergo genetic testing to determine their APOE status. Currently, genetic testing for APOE4 is not recommended as a routine part of diagnosis. However, if treatments specifically targeting this genetic form of the disease become available, testing guidelines and the communication of results may need to be reconsidered.
There are ethical considerations surrounding the decision to undergo genetic testing, as it can cause anxiety for individuals who have a high risk of developing Alzheimer’s. Further research is needed to assess the benefits and potential harm associated with genetic testing for APOE4. It is crucial to balance the need for early diagnosis with the emotional well-being of the patients.
The study findings suggest a genetic cause for Alzheimer’s and call for a reevaluation of treatment approaches. Recognizing APOE4 as a distinct genetic form of the disease could have significant implications for diagnosis, treatment, and clinical trial design. Precision medicine and personalized treatment plans are critical for addressing different forms of Alzheimer’s. However, ethical considerations must be taken into account when determining the role of genetic testing and the communication of results to patients.