Editor’s note: Pending an FDA decision, 23andMe no longer offers new customers access to health reports referred to in this post. Customers who received their health information prior to November 22, 2013 will still be able to see their health reports, but those who purchased after that time will only have access to ancestry information as well as access to their uninterpreted raw data. These new customers may receive health reports in the future dependent on FDA marketing authorization.
Robin Smith, Health Content Scientist
A report published this month in the journal Nature describes a breakthrough in scientists’ understanding of Alzheimer’s Disease. Researchers from Columbia University dissected the relationship between a genetic risk factor in the APOE gene and the formation of protein plaques, a classical feature of Alzheimer’s disease pathology.
Late-onset Alzheimer’s Disease risk is thought to be influenced by a range of genetic factors, each contributing a small effect. The lone exception is the ε4 variant of the APOE gene, which is present in 15-40 percent of people, depending on their ancestry, and associated with a high risk for Alzheimer’s. Scientists originally found this association with Alzheimer’s in people of European descent. Recent studies, now included in 23andMe’s Alzheimer’s Disease report, have shown that the ε4 variant is also linked to higher risk in other ethnicities. It is important to note, however, that ε4 is only one indicator of Alzheimer’s risk. Most people with ε4 do not get the disease.
A hallmark of Alzheimer’s disease is the formation of protein deposits, or plaques, in various regions of the brain. The plaques are mostly made up of a substance called beta amyloid, which is created when the protein APP is broken down. Researchers think that the accumulation of beta-amyloid interferes with neuron-to-neuron communication and leads to the degeneration of neurons.
The relationship between the APOE ε4 variant and beta amyloid has historically been murky. The Columbia study reconciles these two pieces of the puzzle. The authors used a new approach to find a genetic signature in healthy ε4 carriers before the onset of Alzheimer’s. Many of the genes that form that signature are also important for beta-amyloid production.
When the authors of the study treated brain cells with ε4 protein, but not other variants of APOE, they observed an increase in the amount of beta amyloid produced. Two key genes in their pre-Alzheimer’s signature, RNF219 and SV2A, were key to this process. The drug levetiracetam (sold under the trade name Keppra), which is already approved by the FDA to treat people with epilepsy, prevented beta amyloid production by interfering with SV2A. This result is consistent with a previous finding that levetiracetam could improve cognition in people with “amnestic mild cognitive impairment”, sometimes thought of as a pre-Alzheimer’s state.
The Columbia study also found that a SNP in the RNF219 gene is associated with features of Alzheimer’s in people without ε4. Having one or more copies of a C at rs2248663 in people without ε4 was linked to lower age of onset and more plaques. People with African ancestry are far more likely to have a C at this position, which could help explain in part why African Americans are more likely to develop Alzheimer’s than people of European descent.