Alzheimer’s disease (AD) is a devastating condition, and while most cases are not directly inherited, a small percentage, less than 5%, are caused by specific genetic mutations passed down within families. This Familial form of AD, known as early-onset familial Alzheimer’s disease (EOFAD), typically manifests much earlier in life, often before the age of 65, and sometimes as early as a person’s 30s or 40s.
Three genes have been directly linked to EOFAD. Mutations in these genes are the primary cause of this familial form of Alzheimer’s:
- Presenilin 1 (PSEN1): Located on chromosome 14, mutations in PSEN1 are the most common cause of familial Alzheimer’s.
- Presenilin 2 (PSEN2): Found on chromosome 1, PSEN2 mutations are another, though less frequent, cause of EOFAD.
- Amyloid Precursor Protein (APP): Situated on chromosome 21, mutations in the APP gene are also associated with early-onset familial Alzheimer’s.
Inheritance of these EOFAD genes follows an autosomal dominant pattern. This means that if a parent carries a mutation in one of these genes, there is a 50% chance that each of their children will inherit the same mutation. For individuals with a family history of early-onset Alzheimer’s, genetic testing is available to detect these specific gene mutations and understand their familial risk.
It’s important to distinguish EOFAD from the more common forms of Alzheimer’s. Beyond these causative genes, other genetic variations can influence an individual’s susceptibility to developing Alzheimer’s disease, although they do not directly cause the familial form. A prominent example is the apolipoprotein E (APOE) gene.
The APOE gene has different forms, or alleles: APOE ε2, APOE ε3, and APOE ε4. Each of these forms has a different impact on Alzheimer’s risk. APOE ε2 is associated with a reduced risk of AD, APOE ε3 is considered neutral in terms of risk, and APOE ε4 is linked to an increased risk. Everyone inherits two copies of the APOE gene, one from each parent.
Approximately 25% of the population carries one copy of APOE ε4 (heterozygous), and about 1% has two copies (homozygous). Having one copy of APOE ε4 can increase the risk of developing AD by about 3 times, while having two copies can increase the risk by 8 to 10 times compared to those without the APOE ε4 allele. It is crucial to understand that APOE ε4 is a risk factor, not a direct cause of Alzheimer’s. Many people with APOE ε4 will never develop Alzheimer’s, and conversely, people without APOE ε4 can still develop the disease.
The development of Alzheimer’s is complex and influenced by a combination of genetic, lifestyle, and environmental factors. Currently, there is no preventative treatment for Alzheimer’s. Therefore, routine presymptomatic genetic testing for APOE, particularly in the absence of familial early-onset AD, is generally not recommended. Focus remains on understanding the multifaceted nature of Alzheimer’s and advancing research towards effective treatments and preventative strategies, especially for those with a familial predisposition.
