Genetic Variant Linked with Alzheimer's Risk May Actually Lead to Its Own Form of the Disease

While most cases of Alzheimer’s aren’t directly caused by genes, there are certain genetic factors that are known to increase a person’s risk. One is the APOE4 genetic variant; an estimated 40% to 65% of Alzheimer’s patients carry at least one copy. A new study suggests that this variant may not just be a risk factor, though. It could lead to its own form of Alzheimer’s.

Research recently published in the journal Nature Medicine involved the study of more than 3,000 donated brains and data on more than 10,000 participants in clinical studies. The goal was to see how having inherited two copies of the APOE4 genetic variant impacted Alzheimer’s risk… and whether this was actually a genetically determined form of the disease.

The findings showed that, by age 55, nearly all participants with two APOE4 genes had Alzheimer’s pathology and higher levels of biomarkers than those with the more common APOE3 gene, which isn’t linked with risk of disease. Ten years later, once they’d reached 65, more than 95% of patients with two APOE4 genes had Alzheimer’s pathology in their brains or biomarkers in their cerebrospinal fluid and PET scans. The average age of symptom onset for this group was also age 65, years sooner than those with other APOE variants.

The researchers say this suggests that having two APOE4 genes – known as being an APOE4 homozygote - is actually its own version of Alzheimer’s, genetically determined.

Dr. Juan Fortea, lead researcher and Director of the Memory Unit of the Neurology Service at the Hospital of Sant Pau in Barcelona, explains, "These data represent a reconceptualization of the disease or what it means to be homozygous for the APOE4 gene. 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. This is important because they represent between 2 and 3% of the population.”

The findings may also be significant in another way, as, currently, no more than 1% of Alzheimer’s cases are thought to be directly caused by genes, and those impact early-onset cases.

However, researchers do point out that not everyone with two APOE4 genes develops the disease, and learning why could be helpful. They also say that more research is needed into APOE4 carriers of African heritage, as the risk doesn’t seem to be as pronounced in this group.

The findings do suggest, though, that prevention strategies and targeted treatment may be helpful for dual carriers of this genetic variant. Currently, they make up about 15% of Alzheimer’s patients.

Dr. Víctor Montal, study co-author who is now studying the molecular structure of the APOE gene at the Barcelona Supercomputing Center, says, “The findings emphasize the importance of monitoring APOE4 homozygotes from an early age for preventive interventions.”