Is Alzheimer's Genetic?

Family history is not necessary for an individual to develop Alzheimer's. However, research shows that those who have a parent or sibling living with Alzheimer's are more likely to develop the disease than those who do not have a first-degree relative with Alzheimer's. Those who have more than one first-degree relative with Alzheimer's are at an even higher risk. When diseases like Alzheimer's and other dementias tend to run in families, either genetics (inherited factors) or modifiable factors such as sleep, smoking habits, hypertension or diabetes can further increase risk.

• Genetics and Alzheimer's
• Beta-amyloid and treatments

Genetics and Alzheimer's

There are two categories of genes that influence whether a person develops a disease: (1) risk genes and (2) deterministic genes. Researchers have identified hereditary Alzheimer's genes in both categories.

• More than 100 risk genes are suspected to confer greater susceptibility for developing late-onset (age 65 or older) Alzheimer's, the most common form of the disease. Risk genes increase the likelihood of developing a disease but do not guarantee it will happen. Researchers have found several genes that increase the risk of Alzheimer's. APOE-e4 is the first risk gene identified and remains the gene with the strongest impact on risk for some populations. Testing positive for APOE-e4 may not mean the same for Alzheimer's risk across all racial and ethnic groups. Researchers estimate that between 40-65% of people diagnosed with Alzheimer's have the APOE-e4 gene.
• APOE-e4 is one of three common forms of the APOE gene; the others are APOE-e2 and APOE-e3. We all inherit a copy of some form of APOE from each parent. Those who inherit one copy of APOE-e4 from their mother or father have an increased risk of developing Alzheimer's. Those who inherit two copies from their mother and father have an even higher risk, but not a certainty. In addition to raising risk, APOE-e4 may tend to make symptoms appear at a younger age than usual, which adds to the complexity of understanding how APOE may contribute to a person's risk.
• However, there are several variations in the inheritance of APOE-e4 that need to be considered to determine an individual's risk. The risk for Alzheimer's from APOE-e4 can vary across populations. For example, in general, Europeans can have a higher risk than individuals that have some African ancestry such as African Americans and Caribbean Hispanic individuals. Some African countries have the lowest reported risk due to APOE-e4. Many people in the United States have ancestors from several population backgrounds and have inherited DNA from multiple ancestries.
• An estimated 20-30% of individuals in the United States have one or two copies of APOE-e4; approximately 2% of the U.S. population has two copies of APOE-e4.
• Unlike risk genes, deterministic genes directly cause a disease, virtually guaranteeing that anyone who inherits one will develop a disorder. Scientists have found rare genes that cause Alzheimer's in only a few hundred extended families worldwide. These genes, which are estimated to account for 1% or less of Alzheimer's cases, cause familial early-onset forms in which symptoms usually develop between a person's early 40s and mid-50s. The vast majority of individuals living with Alzheimer's have late-onset disease, occurring at age 65 or later.

Two international networks have been developed to gain further insight into Alzheimer's disease by identifying individuals with deterministic Alzheimer's genes who are willing to participate in research. The Dominantly Inherited Alzheimer Network (DIAN), funded by the Alzheimer's Association, the National Institute on Aging (NIA) and others, includes nearly 40 research institutes in North America, Australia, Europe and South America. The Alzheimer's Prevention Initiative (API) focuses on an extended family in Antioquia, Colombia in South America. At 5,000 members, this is the world's largest family in which a gene that causes Alzheimer's has been identified. API collaborators include DIAN.
 

Beta-amyloid and treatments

Many of the risk genes and deterministic genes affect processing or production and clearance of beta-amyloid, the protein fragment that is the main component of plaques. Beta-amyloid is a prime suspect in decline and death of brain cells. Three treatments, aducanumab (Aduhelm®), donanemab (Kisunla™) and lecanemab (Leqembi®), have demonstrated that removing amyloid from the brain is reasonably likely to reduce cognitive and functional decline in people living with early Alzheimer’s. (Aducanumab will be discontinued on Nov. 1, 2024. Please connect with your provider on treatment options.) Several other amyloid-targeting therapies are also in development.