The Search for Alzheimer’s Causes and Risk Factors
While scientists know Alzheimer's disease involves progressive brain cell failure, the reason cells fail isn't clear. Like other chronic conditions, experts believe that Alzheimer's develops as a complex result of multiple factors rather than any one overriding cause. Both age and genetics have been identified as risk factors, but many questions still remain. The discovery of additional risk factors will deepen our understanding of why Alzheimer's develops in some people and not others.
Although Alzheimer's is not a normal part of growing older, the greatest risk factor for the disease is increasing age. After age 65, the risk of Alzheimer's doubles every five years. After age 85, the risk reaches nearly 50 percent.
Family history and Alzheimer's
Another Alzheimer's risk factor is family history. Research has shown that those who have a parent, brother, sister or child with Alzheimer's are more likely to develop the disease. The risk increases if more than one family member has the illness. When diseases tend to run in families, either heredity (genetics) or environmental factors or both may play a role.
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 Alzheimer's genes in both categories.
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 strongest impact on risk. APOE-e4 is one of three common forms of the APOE gene; the others are APOE-e2 and APOE-e3.
Everyone inherits a copy of some form of APOE from each parent. Those who inherit one copy of APOE-e4 have an increased risk of developing Alzheimer's. Those who inherit two copies 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. Scientists estimate that APOE-e4 is implicated in about 20 percent to 25 percent of Alzheimer's cases.
In 2003, the Alzheimer's Association partnered with the National Institute on Aging to begin recruiting participants for the National Alzheimer's Disease Genetics Study, a federal initiative to collect and bank blood samples from families with several members who developed Alzheimer's disease late in life. The goal is to identify additional Alzheimer's risk genes. The study continues to seek participants.
Deterministic genes directly cause a disease, 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 less than 5 percent of Alzheimer's cases, cause familial early-onset forms in which symptoms usually develop between a person's early 40s and mid-50s.
Although the genes that cause "familial Alzheimer's" are rare, their discovery has provided important clues that help our understanding of Alzheimer's. All of these genes affect processing or production 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. Several drugs now in development target beta-amyloid as a potential strategy to stop Alzheimer's disease or significantly slow its progression.
Two international investigations are under way to gain further insight into Alzheimer's disease by studying individuals with deterministic Alzheimer's genes: (1) The Dominantly Inherited Alzheimer Network (DIAN), funded by the National Institute on Aging (NIA), includes 10 flagship research centers in the United States, the United Kingdom and Australia. (2) 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. Learn more on our Treatment Horizon page.
Genetic tests are available for both APOE-e4 and the rare genes that directly cause Alzheimer's. However, health professionals do not currently recommend routine genetic testing for Alzheimer's disease. Testing for APOE-e4 is sometimes included as a part of research studies.
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A closer look at genes linked to Alzheimer's
The 23 human chromosome pairs contain all of the 30,000 genes that code the biological blueprint for a human being. This interactive illustration highlights the chromosomes containing each of the three genes that cause familial Alzheimer's and the gene with the greatest impact on Alzheimer's risk.
Roll your mouse over the colored text below to highlight interactive features in the image.
Presenilin-1 (PS-1), identified in 1992, is the second gene with mutations found to cause inherited Alzheimer's. Variations in this gene are the most common cause of inherited Alzheimer's.
Presenilin-2 (PS-2), discovered 1993, is the third gene with mutations found to cause inherited Alzheimer's.
Apolipoprotein E-e4 (APOE4), discovered in 1993, is the first gene variation found to increase risk of Alzheimer's and remains the risk gene with the greatest known impact. Having this mutation, however, does not mean that a person will develop the disease.
Catalyst for progress
Scientists have developed animal models of Alzheimer's by genetically engineering mice to carry the human genes that cause rare inherited forms of the disease. These mice provide an invaluable means for researchers to study potential new treatments and approaches to prevention. In 1987, The Alzheimer's Association funded the proof-of-concept work that laid the foundation for developing future Alzheimer's mouse models. In 2002, the Association funded development of a "triple-transgenic" mouse, widely considered the best animal model currently available. Learn more about our commitment to research.