A Genetic Cause of Alzheimer’s? How Research at Vanderbilt May Help a Superhero
Eric Sha | February 1, 2023
Many of us know a family member, friend, or colleague that has Alzheimer’s disease. Alzheimer’s disease is a neurodegenerative disorder that impacts millions of people around the world and is the 6th leading cause of death among adults in the U.S. Its patients are subjected to a slow, painful decline. Unfortunately, there are currently very limited treatments for the disease, so finding new treatments to help Alzheimer’s patients is crucial.
What causes Alzheimer’s? Despite decades of research on Alzheimer’s, scientists have not reached a consensus on the cause of the disease. However, there are a variety of factors that could lead to the development of Alzheimers, including genetics, lifestyle, and environment. Recently, Chris Hemsworth, the star of “Thor”, learned about one of these factors when he discovered that he has a genetic variant that increases his risk for Alzheimer’s. Interestingly, this particular gene was also the subject of a research study at Vanderbilt.
Thor and Alzheimer’s
Last month, Hemsworth announced that he was taking a break from acting after his diagnosis. He has a genetic variant of the fat metabolism protein apolipoprotein E (APOE-e4), which is known to be the strongest genetic risk factor for Alzheimer’s disease, contributing to impaired cognition in older adults. A recent study by researchers at Vanderbilt sheds light on this protein and its link to Alzheimer’s. As part of the Vanderbilt Memory and Aging Project, Drs. Mabel Seto, Timothy Hohman, and colleagues identified genes that modify the association between APOE-e4 and cognitive performance.
Image (left): Chris Hemsworth has two copies of APOE-e4, making him 8-12 times more likely to develop Alzheimer’s (Gage Skidmore, CC BY-SA 3.0 <https://creativecommons.org/licenses/by-sa/3.0>, via Wikimedia Commons).
APOE-e4 and Alzheimer’s
APOE-e4 is associated with both an increased risk for Alzheimer’s and with the development of the disease at an earlier age. Approximately 15-25% of the general population carries at least one allele for APOE-e4, increasing the risk of developing Alzheimer’s by two to threefold. Around 2% of the general population, including Hemsworth, carry both copies of APOE-e4, increasing the risk of developing Alzheimer’s by eight to twelvefold. However, not all people carrying APOE-e4 develop Alzheimer’s, suggesting that the existence of the protein itself doesn’t cause Alzheihmer’s. Thus, finding out which genes contribute to the neurodegenerative effects of APOE-e4 is an important step towards developing interventions that can treat or prevent Alzheimer’s.
The impact of specific genes on APOE-e4 and cognitive decline
In the paper by Drs. Mabel Seto, Timothy Hohman, and colleagues, which was published in the October 2022 issue of Neurobiology of Aging, the team used RNA sequencing to identify specific genes that modify the association between APOE-e4 and cognitive performance. One gene identified was RNASE6, an important gene in the innate immune system. RNASE6 was associated with worse memory among the APOE-e4 carriers in the study, indicating that the gene likely plays a role in the cognitive decline associated with APOE-e4. They also found that RNASE6 had a similar effect in the brain’s prefrontal cortex, and that RNASE6 also impacts brain tissue.
Combined with previous studies that found RNASE6 was associated with neuroinflammation, the study’s results suggest that there is an association between RNASE6 and the progression of Alzheimer’s. This exciting discovery could lead to the future development of therapeutics that can target these genes with the goal of delaying or preventing development of Alzheimer’s.
C, Rupp, B. ,. Peters-Libeu. English: Obtained from RCSB PDB. 11 July 2001. RCSB Protein Data Bank, Wikimedia Commons, https://commons.wikimedia.org/wiki/File:A_22K_fragment_of_APOE4_(APOE4)_(IB68).jpg.
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Seto, Mabel, et al. “RNASE6 Is a Novel Modifier of APOE-Ε4 Effects on Cognition.” Neurobiology of Aging, vol. 118, Oct. 2022, pp. 66–76. PubMed, https://doi.org/10.1016/j.neurobiolaging.2022.06.011.
Skidmore, Gage. English: Chris Hemsworth Speaking at the 2019 San Diego Comic-Con International in San Diego, California. 20 July 2019. Own work, Wikimedia Commons, https://commons.wikimedia.org/wiki/File:Chris_Hemsworth_by_Gage_Skidmore_2_(cropped).jpg.
“The Role of Genes in Your Alzheimer’s Risk.” Mayo Clinic, https://www.mayoclinic.org/diseases-conditions/alzheimers-disease/in-depth/alzheimers-genes/art-20046552. Accessed 4 Dec. 2022.