Nearly Everyone with Duplicated APOE4 Gene will Develop Alzheimer's, Study Suggests

Researchers at the Sant Pau Research Institute have made a significant discovery regarding the APOE4 gene and its connection to Alzheimer's disease. Their findings, published in Nature Medicine, show that over 95 percent of individuals aged 65 and older who have two copies of the APOE4 gene display biological signs of Alzheimer's in their brains or biomarkers in their cerebrospinal fluid and PET scans.

“These data represent a reconceptualization of the disease or what it means to be homozygous for the APOE4 gene,” said the study’s lead, Juan Fortea, MD, PhD, who is also the Director of the Memory Unit at the Neurology Service of Sant Pau. “This gene has been known for over 30 years, and it was known to be associated with a higher risk of developing Alzheimer's disease. But now we know that virtually all individuals with this duplicated gene develop Alzheimer's biology.”

According to Dr. Fortea, these results are significant because about two to three percent of the population has the duplicated APOE4 gene. The study also concluded that these individuals develop Alzheimer's at an earlier age compared to those with other variants of the gene, suggesting that having two copies of APOE4 could represent a distinct genetic form of the disease.

The research evaluated clinical, pathological, and biomarker data from a large sample, including 3,297 brain donors and over 10,000 individuals with Alzheimer's disease biomarkers. The results highlighted that virtually all APOE4 homozygotes showed Alzheimer's pathology and had higher levels of disease-associated biomarkers by age 55 compared to those with the APOE3 gene. By age 65, more than 95 percent exhibited abnormal amyloid levels in their cerebrospinal fluid, and 75 percent had positive amyloid scans.

Alberto Lleó, MD, PhD, also from the Sant Pau Research Institute, pointed out the potential applications of these findings. "The data clearly show that having two copies of the APOE4 gene not only increases the risk but also anticipates the onset of Alzheimer's, reinforcing the need for specific preventive strategies,” he explained.

According to the researchers, the study marks a significant step forward in understanding Alzheimer's disease and could lead to more tailored approaches to prevention and treatment for those most at risk.