Title: New Study Redefines Alzheimer’s as Genetic Form for Carriers of Two APOE4 Gene Copies
A groundbreaking study published in Nature Medicine could redefine Alzheimer’s disease for people carrying two copies of the APOE4 gene. The research suggests that these individuals are virtually guaranteed to develop the condition and face symptoms at an earlier age, effectively classifying them as having a new genetic form of the disease.
Previous studies have shown that people with two copies of the APOE4 gene variant have a significantly higher risk of developing Alzheimer’s compared to those with the most common version of the APOE gene, known as APOE3. About 2% to 3% of the general population, or 15% of people with Alzheimer’s, have two copies of the APOE4 variant.
Researchers from the University of Wisconsin’s Alzheimer’s Disease Research Center and the University of Barcelona analyzed more than 3,000 donated brains from the U.S. National Alzheimer’s Coordinating Center, along with biological and clinical data on more than 10,000 individuals from three countries.
Key findings include:
1. By age 65, at least 95% of people with two copies of APOE4 have abnormal levels of an Alzheimer’s-related protein called beta amyloid in their spinal fluid, and 75% have positive brain scans for amyloid.
2. Nearly all APOE4 homozygotes have higher levels of amyloid at age 65 than people who do not carry the risk variant.
3. APOE4 homozygotes meet the three main criteria for being a genetic disease: nearly everyone with these two variants has Alzheimer’s biology, they develop symptoms at about the same rate, and clinical and biological changes occur in a predictable sequence.
Implications for Alzheimer’s Treatment
The findings have several implications for Alzheimer’s research and treatment:
1. The recently approved Alzheimer’s treatment Leqembi from Eisai and Biogen may affect patients with two copies of the APOE4 variant differently. Clinical trials have shown higher rates of brain bleeding and swelling associated with the treatment for these patients.
2. Dr. Reisa Sperling, an Alzheimer’s researcher at Mass General Brigham, suggests that APOE4 homozygotes should be treated at a younger age due to their high likelihood of rapid progression to impairment.
3. Dr. Samuel Gandy, an Alzheimer’s researcher at Mount Sinai in New York, emphasizes the need for enrolling APOE4 homozygotes into trials designed to prevent the disease before they develop symptoms.
The new designation for Alzheimer’s that develops later in life would not replace other genetic forms, such as Autosomal-dominant Alzheimer’s Disease, which is caused by mutations in three different genes, and Down syndrome. However, it is crucial to note that the study mainly involved people of European ancestry, and more research is required to determine the implications of APOE4 for people of African descent.
This study highlights the significance of genetics in understanding the development and risk assessment of Alzheimer’s disease and could potentially impact clinical trial design and treatment development for those carrying two copies of the APOE4 gene variant.