— The Thor actor recently learned about his genetic predisposition
Michele R. Berman, MD
December 1, 2022
Australian actor Chris Hemsworth, best known for his role as Thor in the Marvel Universe, revealed he is at increased risk of developing Alzheimer’s disease due to a genetic predisposition. Hemsworth learned this while filming a new National Geographic series, “Limitless.”
The docuseries has Hemsworth participate in extreme activities in an attempt to push back on the natural decline that comes with age. As part of this process, he underwent a battery of genetic tests.
Hemsworth has two copies of the gene APOE4, one from each parent. Numerous studies have linked this genetic trait with an increased risk of Alzheimer’s. According to the NIH, approximately 25% of the population carry one copy of the gene, but only 2-3% carry two copies. Having at least one APOE4 gene increases your risk of developing Alzheimer’s disease two- to threefold. If you have two APOE4 genes, your risk is even higher, approximately eight- to twelve-fold.
To Hemsworth, the test result wasn’t a total surprise: his grandfather has Alzheimer’s disease. Although hearing this news was originally unsettling, he is trying to use the knowledge to his advantage. In an interview in Vanity Fair, he said:
“If I didn’t know this [Alzheimer’s] information, I wouldn’t have made the changes I made. I just wasn’t aware of any of it, so now I feel thankful that I have in my arsenal the sort of tools to best prepare myself and prevent things happening in that way.”
Performing in this series has helped Hemsworth put his life goals into perspective. “It really triggered something in me to want to take some time off. And since we finished the show, I’ve been completing the things I was already contracted to do. Now when I finish this tour this week, I’m going home and I’m going to have a good chunk of time off and just simplify. Be with the kids, be with my wife,” he said.
The APOE gene
The APOE gene codes for the glycoprotein apolipoprotein E (ApoE). This protein combines with lipids to form lipoproteins which package cholesterol and other fats and carry them through the bloodstream and cerebrospinal fluid.
ApoE interacts significantly with the low-density lipoprotein receptor (LDLR), which is essential for the normal catabolism of triglyceride-rich lipoproteins. In peripheral tissues, ApoE is primarily produced by the liver and macrophages, and mediates cholesterol metabolism. In the central nervous system, ApoE is mainly produced by astrocytes and transports cholesterol to neurons via ApoE receptors, which are members of the LDLR gene family. ApoE is the principal cholesterol carrier in the brain and is necessary for cholesterol transportation from astrocytes to neurons.
The APOE gene is mapped to chromosome 19. Each person inherits two APOE alleles, one from each biological parent. The gene is polymorphic with three main alleles: APOE4, APOE3, and APOE2. The APOE3 allele is the most common (78% globally), followed by APOE4 (14%) and APOE2 (8%). Although these three forms differ from each other by a single amino acid substitution, the changes have profound effects at the structural and functional level.
For example, APOE4 increases risk for Alzheimer’s disease and is also associated with an earlier Alzheimer’s onset. APOE2 may provide some protection against Alzheimer’s. APOE3 is believed to play a neutral role in the disease, neither decreasing nor increasing risk.
APOE and Alzheimer’s
The association of Alzheimer’s disease and the APOE4 allele has been known since 1993 when a group at Duke University studied 234 people from 42 families afflicted with late-onset Alzheimer’s. By age 80, almost all those in the study who had two copies of the APOE4 gene developed the disease. Since that time, numerous studies have strengthened that association.
Researchers are trying to determine the mechanisms by which APOE4 can lead to the development of Alzheimer’s disease. Some believe that structure of APOE4 makes it more likely to bind to β-amyloid (Aβ) peptides.
According to a review by Liu et al., “ApoE–lipoproteins bind to several cell-surface receptors to deliver lipids and also to hydrophobic amyloid-β (Aβ) peptide, which is thought to initiate toxic events that lead to synaptic dysfunction and neurodegeneration in Alzheimer’s disease. Apo isoforms differentially regulate Aβ aggregation and clearance in the brain, and have distinct functions in regulating brain lipid transport, glucose metabolism, neuronal signaling, neuroinflammation, and mitochondrial function.”
Accumulation of abnormal triglycerides in astrocytes may be another important factor. A group, led by Li-Huei Tsai, MD, PhD, and Susan Lindquist, PhD, created stem cells from people carrying APOE3 or APOE4 alleles. These stem cells were then coaxed into becoming astrocytes and were used to study how APOE4 astrocytes processed lipids compared to the APOE3 astrocytes. The APOE4 astrocytes accumulated triglycerides which have many more unsaturated fatty acid chains than normal. In addition, lipid buildup in the APOE4 astrocytes was much greater than in APOE3 astrocytes. Their findings were similar when stem cells were coaxed into becoming microglia.
Yet another group, Montagne et al., suggested that having the APOE4 allele may lead to accelerated breakdown of the blood brain barrier and the degeneration of the brain capillary pericytes which maintain its integrity. Their study showed that APOE4 carriers were distinguished from non-carriers by blood-brain barrier breakdown in the hippocampus and medial temporal lobe. “This finding is apparent in cognitively unimpaired APOE4 carriers, more severe in those with cognitive impairment, but not related to cerebrospinal fluid or positron emission tomography measurements of Alzheimer’s amyloid-β or tau pathology,” they wrote.
Inheriting an APOE4 allele does not ensure that a person will develop Alzheimer’s; it only increases the risk. Some people with an APOE4 allele never get the disease, while others who develop Alzheimer’s don’t carry any APOE4 alleles.
APOE and Other Conditions
APOE and age-related hearing loss
The presence of an APOE4 allele also increases the risk of age-related hearing loss. A study from the Netherlands by Kurniawan et al. measured hearing loss by pure-tone audiometry in 435 85-year-olds. They found that those with the APOE-ε4/ε4 genotype had the highest levels of hearing loss (n=6; 56.1 dB), those with the APOE-ε3/ε4 or ε2/ε4 genotype (n=89) had intermediate levels of hearing loss (51.0 dB), and those without the APOE4 allele (n=340) had the lowest levels of hearing loss.
APOE and age-related macular degeneration
Age-related macular degeneration (AMD) is the most common cause of blindness in the elderly. It is caused by neuroepithelial degeneration in the macula. Klaver et al. conducted a genetic-association study looking at APOE alleles and AMD. Unlike other disease states, the APOE4 allele was associated with a decreased risk while the APOE2 allele was associated with a slightly increased risk of AMD.
Lewy body dementia
Lewy body dementia is characterized by intellectual decline, visual hallucinations, sudden changes in attention and mood; and movement problems characteristic of Parkinson disease such as rigidity of limbs, tremors, and impaired balance and coordination.
People who inherit one copy of the APOE4 allele have an increased chance of developing dementia with Lewy bodies. It is unclear how the APOE4 allele contributes to the development of this condition. It is thought that the ApoE produced from the APOE4 allele may disrupt the transport of alpha-synuclein into and out of cells. When alpha-synuclein is trapped inside or outside of cells, it accumulates in clusters, creating Lewy bodies. Accumulation of these clusters throughout the brain impairs neuron function and ultimately causes cell death.
APOE alleles have been shown to influence the risk of cardiovascular disease. Although APOE has been recognized as important in the suppression of atherosclerosis, this may not be the case for all APOE alleles. People who carry at least one copy of the APOE4 allele have an increased chance of developing atherosclerosis.
The APOE2 allele has been shown to greatly increase the risk of a rare condition called hyperlipoproteinemia type III. Most people with this disorder have two copies of the APOE2 allele, leading researchers to conclude that APOE2 plays a critical role in the development of the condition. Hyperlipoproteinemia type III is characterized by increased blood levels of cholesterol, triglycerides, and beta-very low-density lipoproteins (beta-VLDLs), which carry cholesterol and lipoproteins in the bloodstream. A buildup of cholesterol and other fatty materials can lead to the formation of small, yellow skin growths called xanthomas and the development of atherosclerosis.
Michele R. Berman, MD, is a pediatrician-turned-medical journalist. She trained at Johns Hopkins, Washington University in St. Louis, and St. Louis Children’s Hospital. Her mission is both journalistic and educational: to report on common diseases affecting uncommon people and summarize the evidence-based medicine behind the headlines.