Genetics is the study of traits and characteristics passed from one generation to the next through genes inherited by each of our biological parents. A gene is a segment of DNA that provides instructions through the coding of proteins to specify our physical and biological traits.
In addition to our genes, lifestyle and environmental factors play critical roles in a person’s development and overall health.
GENETIC VARIATIONS
A genetic disease results from changes in an individual’s DNA sequence referred to as genetic mutations or variants. Some changes are inherited and present at birth. Some occur during a person’s lifetime. Most genetic variants have little to no effect on protein production. Some genetic variants code a protein to improve its function. However, sometimes, the change alters the instructions so that the resulting protein is damaged (or not made at all), which has serious consequences for our health.
SPORADIC ALZHEIMER’S DISEASE
Most cases of Alzheimer’s disease are sporadic, meaning they occur at random without a clear pattern of inheritance. Sporadic Alzheimer’s does not have a single genetic cause but is a product of the complex interactions between genetics, lifestyle, and environmental influences. Sporadic cases of Alzheimer’s disease usually occur in individuals aged 65 years or older.
THE APOE GENE
Researchers have identified a number of genes that increase the risk of developing Alzheimer’s disease. The apolipoprotein E gene, APOE, has the most significant influence for risk of sporadic Alzheimer’s disease. Everyone has two copies of the APOE gene, inherited from their parents, and there are three predominant forms, or alleles, of APOE.
- APOE2 is a protective allele. People with APOE2 are less likely to develop sporadic Alzheimer’s disease; if they do, it usually occurs later in life.
- APOE3 is the most common form of the gene. It is a neutral allele because it neither increases nor decreases a person’s risk.
- APOE4 is the strongest genetic risk factor for sporadic Alzheimer’s disease. According to the Mayo Clinic, having a single copy of APOE4 doubles or triples the risk of developing Alzheimer’s disease; having two copies increases your risk by eight to twelvefold.
Having one or two copies of APOE4 does not guarantee that a person will develop Alzheimer’s disease. It indicates an elevated risk compared to the general population. It is possible to be an APOE4 carrier and never develop the disease.
OTHER SPORADIC ALZHEIMER’S DISEASE GENETIC RISK FACTORS
APOE4 is not the only sporadic Alzheimer’s disease risk factor; however, it is by far the most significant one. By scanning and comparing the DNA (genome) of people with and without Alzheimer’s disease, scientists have identified other genetic differences that may be associated with a higher risk of developing sporadic Alzheimer’s disease. These include genetic variations in the ABCA7, TREM2, SORL1, and CD33 genes, among others. Through the detailed analysis of sporadic Alzheimer’s disease genomes, scientists are obtaining a clearer picture of the genetic blueprint of Alzheimer’s disease.
Recognizing the importance of understanding the genetic differences associated with Alzheimer’s disease, Cure Alzheimer’s Fund launched the Alzheimer’s Genome Project in 2005. By analyzing the complete genetic makeup of individuals from families with a history of sporadic Alzheimer’s disease, the project seeks to uncover the full range of genetic variants that increase susceptibility to sporadic Alzheimer’s disease and those that might protect against it. This undertaking has been fruitful and has led to the identifying several genes beyond the well-known APOE4 risk allele. The discoveries made through the Alzheimer’s Genome Project hold the promise of leading to breakthroughs in how we approach the prevention, diagnosis, and treatment of Alzheimer’s disease, moving towards more tailored and effective interventions and therapies.
AUTOSOMAL DOMINANT (INHERITED) ALZHEIMER’S DISEASE
Unlike sporadic Alzheimer’s disease, autosomal dominant Alzheimer’s disease is the result of a genetic mutation and follows a direct inheritance pattern through families. Individuals with this form of Alzheimer’s disease have a mutation in one of three genes: amyloid precursor protein (APP), presenilin 1 (PSEN1), or presenilin 2 (PSEN2). A person with autosomal dominant Alzheimer’s disease inherited it from a biological parent and has a 50/50 chance of passing it to their offspring. Mutations in these genes are dominant, meaning only one damaged copy is necessary to cause the disease. This form of Alzheimer’s disease accounts for less than 1% of all cases. The onset of autosomal dominant Alzheimer’s disease is usually much earlier than the sporadic form of Alzheimer’s disease, with symptoms often developing between 30-50 years of age. (MedlinePlus, National Library of Medicine.)
ALZHEIMER’S DISEASE AND DOWN SYNDROME
Down syndrome is a genetic condition caused by an extra copy of chromosome 21. People with Down syndrome are at an increased risk of developing Alzheimer’s disease because chromosome 21 contains the APP gene, which is responsible for the production of amyloid-beta. Having three copies of the APP gene (versus two) means that people with Down syndrome overproduce amyloid-beta, which can lead to amyloid plaques, a hallmark of Alzheimer’s disease. Roughly half of all people with Down syndrome will eventually develop dementia due to Alzheimer’s disease.
While there are more than 70 genes associated with an increased risk of developing Alzheimer’s disease, it is important to understand that increased risk is not a guarantee of developing the disease. As our understanding of the genetics of Alzheimer’s disease increases, so will the opportunities for determining future methods of disease intervention and prevention.