ApoE research is not just about its three main alleles. You may have heard the words Christchurch and Jacksonville in connection with ApoE, but did you know that well over 100 variants have been described, some of them in association with Alzheimer's disease? This week, Alzforum's curators formally introduce to the Alzheimer's disease research community the newest member of our family of genetic variant datasets. It includes detailed information on the clinical phenotypes and molecular effects of 137 APOE genetic variants, 39 of them studied in a neurological context. Peruse the collection here.

  • Alzforum launches APOE genetic variant dataset.
  • The collection includes 137 variants with neurological and non-neurological data.
  • [Editor's note: With this story, Alzforum is reporting on the work of our own curators.]

APOE caught the attention of the AD field in the early 1990s, when linkage studies of multiple affected families uncovered a disease-associated locus on chromosome 19. Shortly after, geneticists pinpointed the APOE4 allele as the likely culprit and discovered that the APOE2 allele was protective. Since then, most research on the connection between AD and APOE has focused on these two common alleles, particularly APOE4.

However, other APOE variants, many of them rare, are also proving relevant to AD. APOE2 has been joined by R154S (Christchurch), V254E (a.k.a. Jacksonville), and R269G, for example, as variants that appear to confer protection against AD, at least in some individuals. Additional variants, such as E98Nfs and others marked in yellow in the new dataset, shed light on the effects of knocking out APOE. Still others, such as the common polymorphisms c.-286T>G (a.k.a. rs405509 or -219T/G) and c.-558A>T (a.k.a. rs449647 or -491A/T) offer clues to how ApoE gene expression is regulated.

As with other datasets in the Alzforum Mutations database, the APOE collection is set up so users can read about individual variants by clicking on the amino acids in the protein diagram or on the “Additional Variants” box in the lower-left-hand corner. For example, clicking on the circle corresponding to amino acid R154 reveals links to R154Afs, R154C, R154H, and R154S (Christchurch). Highlighted variants (dark blue) have been examined in three or more publications and/or were deemed to be of particular interest by Alzforum curators.

Radio buttons at the top of the interactive diagram allow users to view either all variants at once, variants studied in a neurological context, or variants studied in a non-neurological context. The table below the diagram lists the corresponding variants based on the selected filter. Clicking on a link for a specific variant, the user can then read a summary of the data reported for that variant, including neurological findings, as well as observations related to lipid metabolism, cardiovascular disease, and kidney disorders.

Alzforum asked several experts, in and outside of the field of neuroscience, to test-drive a beta version of the APOE resource. “I’ve been nerding out on the ApoE website,” wrote Lance Johnson at the University of Kentucky in Lexington in an email to Alzforum, adding, “What an incredible resource! I can’t wait to share it with my trainees and colleagues.” Michael Belloy at Stanford University agreed, “I believe this is really a wonderful reference that you have put together; there are many variants listed here I wasn’t specifically aware of.”

We loved the praise, but the resource has limitations, too. With individual genetic variants serving as its main building blocks, the dataset understates the field's emerging appreciation that many phenotypes are determined by groups of variants acting together. Indeed, as described in the APOE4 summary page, the risk of AD conferred by this allele is modified by several other genetic variants. While not fully addressing this issue, a few pages in the APOE dataset depart from the general format of parsing information into individual variants. For example, users interested in what happens when APOE4 and APOE2 co-exist in the same person can check out the APOE2/4 entry.

Lastly, users can learn about the APOE region, a segment of DNA with several genes including APOE that are involved in biological pathways implicated in AD pathology. As you explore the collection, let us know what you think at mutations@alzforum.org.—Marina Chicurel


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Mutation Interactive Images Citations

  1. APOE

Mutations Citations

  1. APOE C130R (ApoE4)
  2. APOE R176C (ApoE2)
  3. APOE R154S (Christchurch)
  4. APOE V254E
  5. APOE R269G
  6. APOE E98Nfs
  7. APOE c.-286T>G (rs405509)
  8. APOE c.-558A>T (rs449647)
  9. APOE R154Afs
  10. APOE R154C
  11. APOE R154H
  12. APOE [R176C];[C130R] (ApoE2/4)
  13. APOE Region

Other Citations

  1. Mutations database

Further Reading

No Available Further Reading