If you carry this specific genetic variant, your risk of developing Alzheimer's significantly increases.
In a groundbreaking revelation, a team of scientists have uncovered a previously unacknowledged genetic cause of Alzheimer's. In a study released on Monday, these researchers found substantial evidence to suggest that individuals born with two copies of a genetic variation linked to Alzheimer's risk are practically predetermined to develop this neurodegenerative disorder as they age. A hefty 2% of the general population might share this mutation, pointing towards a larger-than-assumed genetic risk of Alzheimer's.
Alzheimer's, the most prevalent form of dementia, currently affects approximately 7 million Americans. It’s a multifaceted condition with a myriad of potential risk factors, including age, cardiovascular disease, and genetics. While some rare mutations almost invariably cause younger-than-average individuals to develop Alzheimer's, other mutations raise the risk of the classic form of the disease, which typically appears post age 65. One such mutation affects the apolipoprotein E gene, commonly known as APOE, and is christened APOE4.
Approximately a quarter of the population carries at least one copy of APOE4, and this variant is a key focus in Alzheimer’s risk research by scientists. However, many studies neglect to distinguish between people having one or both copies of the gene. Some research has proposed that APOE4 homozygotes, or double-carriers, face a far higher risk of Alzheimer's than others.
An extensive group of researchers from Spain and the US took up the challenge. To settle the debate, they delved into brain donor data from the National Alzheimer's Coordinating Center (NACC), as well as data from five other large-scale studies that tracked people's biomarkers linked to Alzheimer's, including their APOE4 status. In total, their analysis comprised over 13,000 individuals.
In the NACC data, the researchers found that nearly everyone with two APOE4 genes showed signs of medium to high levels of brain changes associated with Alzheimer's at the time of their demise. This was only true for 50% of those with APOE3, the most common APOE variant, which isn't associated with Alzheimer's risk. In the biomarker data, the team discovered that almost everyone with two APOE4 copies had abnormal levels of amyloid beta in their spinal fluid, a potential early indication of the disease, by age 65. By age 80, almost 90% of these carriers presented all the biomarkers related to amyloid and tau, another prominent protein in Alzheimer's, that the researchers could track.
While not every individual with these changes will display the clinical symptoms of Alzheimer's before death, the findings, published on Monday in the journal Nature Medicine, demonstrate almost-complete penetrance, according to the authors— the odds of a genetic mutation causing a particular trait. People with two APOE4 genes appear close to certain to develop the initial signs of Alzheimer's by their mid-60s. Given such certainty, it's more accurate to label this mutation as representing a distinct, "genetic form" of Alzheimer's, the researchers claim. They also acknowledge that 2% of the population is estimated to have two APOE4 copies, which would render this form of Alzheimer's one of the most widespread diseases linked to a single gene.
These findings, pending confirmation by others, could bring significant alterations to how we study Alzheimer's. The broader definition of genetic Alzheimer's should encompass the APOE4 form, regarded as generally causing Alzheimer's at an older age than other genetic causes. Given the elevated risk associated with double APOE4 copies, future studies should separate double carriers from single copy carriers, the researchers propose. Simply possessing knowledge about this heightened risk should aid scientists in better understanding how Alzheimer's evolves, potentially leading to more effective treatments for it in the future.
"In summary, our study offers compelling evidence to propose that APOE4 homozygotes [i.e., individuals with two APOE4 alleles, or copies] represent a distinct, genetically determined form of [Alzheimer's disease], which has important implications for public health, genetic counseling of carriers, and future research directions," they wrote.
Key insights:
- Carrying two copies of the APOE4 gene significantly increases the risk of developing late-onset Alzheimer's compared to those with one copy or no copies of the APOE4 allele.
- APOE4 carriers experience a higher rate of cognitive decline compared to non-carriers once diagnosed with Alzheimer's.
- APOE4 carriers demonstrate increased amyloid deposition, tau pathology, and neuroinflammation, contributing to the neurodegenerative processes in Alzheimer's disease.
- The recognition of the APOE4 mutation as a distinct genetic form of Alzheimer's disease has spurred the development of precision medicine approaches and targeted therapeutics for APOE4 carriers.
- Current and future research efforts should consider the unique pathophysiological features of APOE4 carriers and leverage these insights to develop effective treatment strategies for Alzheimer's disease.
- The groundbreaking revelation suggests that individuals born with two copies of the APOE4 genetic variation, a key focus in Alzheimer's risk research by scientists, are practically predetermined to develop a distinctive genetic form of Alzheimer's as they age.
- According to the researchers, over 2% of the population might carry two APOE4 copies, implying that this form of Alzheimer's could be one of the most widespread diseases linked to a single gene.
- Future studies should separate double APOE4 carriers from single copy carriers, as the elevated risk associated with double APOE4 copies could aid scientists in better understanding how Alzheimer's evolves, potentially leading to more effective treatments in the future.
- The findings, if confirmed, could lead to the broader definition of genetic Alzheimer's encompassing the APOE4 form, which is generally causing Alzheimer's at an older age than other genetic causes. This recognition has spurred the development of precision medicine approaches and targeted therapeutics for APOE4 carriers.
