New Study Helps Explain Alzheimer’s Genetic Risk

Brains

Editor’s note: Pending an FDA decision, 23andMe no longer offers new customers access to health reports referred to in this post. Customers who purchased prior to November 22, 2013 will still be able to see their health reports, but those who purchased after that time will not. Those customers will have access to ancestry information as well as access to their uninterpreted raw data.

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.

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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 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.


  • Greg Gaither

    Is there any indication that treating people with one or both APOE4 alleles before AD symptoms occur may be an effective preventative therapy? If so, when could/should this treatment commence?

    • http://23andMe.com Robin Smith

      Hi Greg,

      No, there have not been any studies looking at the effectiveness of levetiracetam in people with APOE e4. It’s important to note that the drug has not been approved by the FDA for the treatment of Alzheimer’s. If you’d like to learn more about the future of Alzheimer’s treatment, follow this link:
      http://www.alz.org/research/science/alzheimers_treatment_horizon.asp

      Robin Smith

  • darkeyes

    The data is incomplete, since relevant TOMM40 data is not tested, and I am wondering if it should. I don’t think it should, unless a good preventive pharmaceutical becomes available. People with the long or very long TOMM40 poly-T intron have a higher risk for Alzheimer’s as well. The long version (not short or very long) is often associated with APO e4- in Europeans (due to “linkage disequilibrium”), but not in all Africans or even some Japanese people. It appears that APO e3/e3s and APO e3/e4s have a higher risk of Alzheimer’s if they have long or very long allele(s) of TOMM 40. Again, this test is not done by 23 and Me.

    There is no preventive pharmaceutical as yet, although clinical trials are ongoing on various meds. I advise a healthy lifestyle, such as regular exercise and a Mediterranean-type diet. Avoid smoking and obesity.

    Have a good rest of the weekend!

  • darkeyes

    By the way, as I’ve stated, some African Americans with E4 are protected to some extent by having the short version of the TOMM40 allele. At least that’s what it looks like so far. This other SNP described above may or may not be as important. I believe, based on what I have read, and I have worked with people with dementia throughout my career (hence my interest) that lifestyle and lack of ACCESS to healthcare may play an important role in African Americans having a higher risk of Alzheimer’s. Look at it this way – less access to healthful foods such as fresh fruits and vegetables, less exercise opportunities, and less access to a doctor really can increase one’s risk of dementia, especially multi-infarct or Alzheimer’s. Consider this when you look at individual SNPs. There is a more important reason for the “increased risk of Alzheimer’s” in certain minorities, I believe.

  • Jeremiah

    what is rs2248663? is it a gene or a protein? and how is it increases the risk of having a early onset of Alzheimer’s disease?

    • ScottH

      Jeremiah, Thanks for the note. No rs2248663 is not a gene. It marks a single location within a specific gene. It’s what’s called a single nucleotide polymorphism, or SNP, and it marks a single base pair of DNA. The variation at that location is what is associated with Alzheimer’s. In this case have a C genotype at that location is associated with a lower age of onset for Alzheimer’s in people who do not have the APOE4 variant. 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.

      • Jeremiah

        Thanks for replying, if i understand it correctly, you mean that the no rs2248663 is a genetic marker which present in the RNF219 gene and where if at that location there is a C present, meaning, they will have an early-onset of Alzheimer’s disease and RNF219 gene is associated with the production of beta amyloid.

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