Alzheimer disease: genetics

Introduction
Scientists believe that many factors influence when Alzheimer disease begins and how it progresses. The more they study this devastating disease, the more they realize that genes play an important role.

The genetics of disease
Some diseases are caused by a genetic mutation, or permanent change in one or more specific genes. If a person inherits from a parent a genetic mutation that causes a certain disease, then he or she will usually get the disease. Sickle cell anemia, cystic fibrosis, and early-onset familial Alzheimer disease are examples of inherited genetic disorders.

In other diseases, a genetic variant may occur. A single gene can have many variants. Sometimes, this difference in a gene can cause a disease directly. More often, a variant plays a role in increasing or decreasing a person's risk of developing a disease or condition. When a genetic variant increases disease risk but does not directly cause a disease, it is called a genetic risk factor.

Identifying genetic variants may help researchers find the most effective ways to treat or prevent diseases such as Alzheimer disease in an individual. This approach, called precision medicine, takes into account individual variability in genes, environment, and lifestyle for each person.

Alzheimer disease genetics
Alzheimer disease is an irreversible, progressive brain disease. It is characterized by the development of amyloid plaques and neurofibrillary tangles, the loss of connections between nerve cells, or neurons, in the brain, and the death of these nerve cells. There are two types of Alzheimer disease—early-onset and late-onset. Both types have a genetic component.

Early-onset Alzheimer disease. Early-onset Alzheimer disease occurs in people age 30 to 60. It is rare, representing less than 5 percent of all people who have Early-onset Alzheimer disease occurs in people age 30 to 60 and represents less than 5 percent of all people with Alzheimer disease. Most cases are caused by an inherited change in one of three genes, resulting in a typle known as early-onset familial Alzheimer disease, or FAD. For others, the disease appears to develop without any specific, known cause.

A child whose biological mother or father carries a genetic mutation for early-onset familial Alzheimer disease has a 50/50 chance of inheriting that mutation. If the mutation is in fact inherited, the child has a very strong probability of developing early-onset familial Alzheimer disease.

Early-onset familial Alzheimer disease is caused by any one of a number of different single-gene mutations on chromosomes 21, 14, and 1. Each of these mutations causes abnormal proteins to be formed. Mutations on chromosome 21 cause the formation of abnormal amyloid precursor protein (APP). A mutation on chromosome 14 causes abnormal presenilin 1 to be made, and a mutation on chromosome 1 leads to abnormal presenilin 2.

Each of these mutations plays a role in the breakdown of APP, a protein whose precise function is not yet fully understood. This breakdown is part of a process that generates harmful forms of amyloid plaques, a hallmark of the disease.

Critical research findings about early-onset Alzheimer disease have helped identify key steps in the formation of brain abnormalities typical of the more common late-onset form of Alzheimer disease. Genetics studies have helped explain why the disease develops in people at various ages.

NIA-supported scientists are continuing research into early-onset disease through the Dominantly Inherited Alzheimer Network (DIAN), an international partnership to study families with early-onset familial Alzheimer disease. By observing the Alzheimer disease-related brain changes that occur in these families long before symptoms of memory loss or cognitive issues appear, scientists hope to gain insight into how and why the disease develops in both its early- and late-onset forms.

Late-onset Alzheimer disease. Most people with Alzheimer disease have the late-onset form of the disease, in which symptoms become apparent in the mid-60s and later. The causes of late-onset Alzheimer disease are not yet completely understood, but they likely include a combination of genetic, environmental, and lifestyle factors that affect a person's risk for developing the disease.

Researchers have not found a specific gene that directly causes the late-onset form of the disease. However, one genetic risk factor—having one form of the apolipoprotein E (APOE) gene on chromosome 19—does increase a person's risk. APOE comes in several different forms, or alleles:

• APOE e2 is relatively rare and may provide some protection against the disease. If Alzheimer disease does occur in a person with this allele, it develops later in life than it would in someone with the APOE e4 gene.
• APOE e3 is the most common allele. Researchers think it plays a neutral role in Alzheimer disease—neither decreasing nor increasing risk.
• APOE e4 increases risk for Alzheimer disease and is also associated with an earlier age of disease onset. A person has zero, one, or two APOE ε4 alleles. Having more APOE ε4 alleles increases the risk of developing Alzheimer disease.

APOE ε4 is called a risk-factor gene because it increases a person's risk of developing the disease. However, inheriting an APOE ε4 allele does not mean that a person will definitely develop Alzheimer disease. Some people with an APOE ε4 allele never get the disease, and others who develop Alzheimer disease do not have any APOE ε4 alleles.

Using a relatively new approach called genome-wide association study (GWAS), researchers have identified a number of regions of interest in the genome (an organism's complete set of DNA, including all of its genes) that may increase a person's risk for late-onset Alzheimer disease to varying degrees. By 2015, they had confirmed 33 regions of interest in the Alzheimer disease genome.

A method called whole genome sequencing determines the complete DNA sequence of a person's genome at a single time. Another method called whole exome sequencing looks at the parts of the genome that directly code for the proteins. Using these two approaches, researchers can identify new genes that contribute to or protect against disease risk. Recent discoveries have led to new insights about biological pathways involved in Alzheimer disease and may one day lead to effective interventions.

Genetic testing
A blood test can identify which APOE alleles a person has, but results cannot predict who will or will not develop Alzheimer disease. It is unlikely that genetic testing will ever be able to predict the disease with 100 percent accuracy, researchers believe, because too many other factors may influence its development and progression.

Currently, APOE testing is used in research settings to identify study participants who may have an increased risk of developing Alzheimer disease. This knowledge helps scientists look for early brain changes in participants and compare the effectiveness of treatments for people with different APOE profiles. Most researchers believe that APOE testing is useful for studying Alzheimer disease risk in large groups of people but not for determining any one person's risk.

Genetic testing is used by researchers conducting clinical trials and by physicians to help diagnose early-onset Alzheimer disease. However, genetic testing is not otherwise recommended.

Major Alzheimer disease genetics research efforts underway
The National Institute on Aging supports several major genetics research programs.

• The Alzheimer's Disease Sequencing Project (ADSP) is an innovative collaboration between NIA and the National Human Genome Research Institute, both part of NIH. The first phase of the project determined the order of all 3 billion letters in the individual genomes of 580 participants. It also generated whole exome sequencing data for an additional 11,000 volunteers.
• The Alzheimer's Disease Genetics Consortium is a collaborative effort to collect and analyze genetic data from thousands of families around the world to identify genes associated with an increased risk of developing late-onset Alzheimer disease.
• The Late-Onset Alzheimer's Disease Genetics Study is gathering and analyzing genetic and other information from 1,500 or more families in the United States with two or more members who have late-onset Alzheimer disease.
• The International Genomic Alzheimer's Project (IGAP) is comprised of four consortia in the United States and Europe that have been working together since 2011 on genome-wide association studies (GWAS) involving thousands of DNA samples and shared data sets. In a study of more than 74,000 individuals, IGAP recently reported the identification of 19 novel regions of interest that are associated with the disease.
• The Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) is a national genetics data repository that gives investigators access to data to study the genetics of late-onset Alzheimer disease.
• The National Cell Repository for Alzheimer's Disease (NCRAD) is a national resource that helps researchers find genes that increase the risk of Alzheimer disease by providing biological samples and data.

Volunteers are critical to Alzheimer disease genetics research. The more genetic information that researchers can gather and analyze from individuals and families—both healthy volunteers and those who may be at risk—the more clues they will have for finding additional risk-factor genes.

To learn more about Alzheimer disease genetics studies, contact NCRAD toll-free at 1-800-526-2839 or visit https://ncrad.iu.edu.

To learn more about volunteering for Alzheimer disease clinical trials and studies, visit www.nia.nih.gov/alzheimers/volunteer.

For more information
Alzheimer's Disease Education and Referral (ADEAR) Center
1-800-438-4380
https://www.nia.nih.gov/alzheimers

Alzheimer's Association
1-800-272-3900
1-866-403-3073 (TDD/toll-free)
www.alz.org

Alzheimer's Foundation of America
1-866-232-8484 (toll-free)
www.alzfdn.org

National Library of Medicine
National Center for Biotechnology Information
www.ncbi.nlm.nih.gov

Additional information is available from the National Human Genome Research Institute (NHGRI), part of the NIH. Visit the NHGRI website at www.genome.gov.

This information was developed by the Alzheimer's Disease Education and Referral (ADEAR) Center, National Institute on Aging.

Alzheimer's Disease Education and Referral (ADEAR) Center, National Institute on Aging. Alzheimer's Disease Genetics Fact Sheet. Available at:https://www.nia.nih.gov/health/alzheimers-disease-genetics-fact-sheet. Accessed March 30, 2023.

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