A new study published in the journal Nature Medicine has shed light on the genetic component of Alzheimer's disease, suggesting that it may be inherited more frequently than previously believed. The research suggests that Alzheimer's disease linked to a specific gene, called APOE4, should be considered a distinct, inherited form of the disease, requiring different approaches to testing and treatment.

Traditionally, Alzheimer's disease has been categorized as either sporadic or familial. The majority of cases are considered sporadic, developing later in life. Familial cases, caused by mutations in three genes, are known to be rare, accounting for approximately 2% of all Alzheimer's diagnoses.

However, this new study challenges the existing understanding by asserting that 1 in 6 cases of Alzheimer's could be considered inherited or familial. The revised assessment of inherited risk is attributed to a better understanding of the role played by a fourth gene responsible for producing a lipid-carrying protein called apolipoprotein E (APOE). APOE is involved in transporting cholesterol throughout the body and brain and is thought to play a role in the formation and removal of beta amyloid plaques, a hallmark of Alzheimer's.

The study compared individuals with two copies of the APOE4 gene to those with other forms of the APOE gene, as well as individuals with other inherited forms of Alzheimer's disease such as early-onset autosomal dominant Alzheimer's disease (ADAD) and Down syndrome-associated Alzheimer's disease (DSAD). The analysis involved data from nearly 3,300 brains stored at the National Alzheimer's Coordinating Center and information from 10,000 participants in five clinical trials.

The findings revealed that individuals with two copies of the APOE4 gene were more likely to develop the biological changes associated with Alzheimer's disease, similar to those with other genetic forms of the disease. Remarkably, nearly 95% of the participants with two copies of APOE4 demonstrated the biological markers of Alzheimer's disease by the time they reached 82 years old.

The study authors argue that having two copies of the APOE4 gene should be considered a genetic form of the disease, rather than just a risk factor. Individuals with two copies of APOE4 also displayed earlier onset of symptoms, developing Alzheimer's approximately 10 years earlier than those with other forms of the APOE gene. The build-up of beta amyloid and tau proteins in their brains followed a similar trajectory as observed in people with other inherited forms of the disease.

The implications of classifying APOE4 as an inherited form of Alzheimer's are significant. It suggests that a larger proportion of Alzheimer's cases is caused by genetic factors than previously understood. Previously, only gene changes associated with early-onset forms of Alzheimer's and Down's syndrome were recognized to contribute to the disease. However, individuals with two copies of the APOE4 gene make up approximately 15% of diagnosed Alzheimer's cases, or 1 in 7 cases.

Experts now highlight the need for personalized treatment and precision medicine, acknowledging that Alzheimer's should not be treated as a single entity. The study emphasizes the importance of genetic testing for APOE4, which could change the diagnostic and treatment approach for individuals carrying the gene. While APOE testing is currently not recommended as a routine part of Alzheimer's diagnosis, the study authors suggest that this stance may need to be revisited.

This groundbreaking research provides valuable insights into the genetic underpinnings of Alzheimer's disease, paving the way for improved understanding, early detection, and personalized interventions for those at increased genetic risk.