The PSEN1 gene is a significant factor in a rare form of Alzheimer’s disease that appears at an earlier age than is typical for the condition. While the gene plays a role in healthy cellular processes, specific alterations within it are connected to an inherited form of early-onset Alzheimer’s. Understanding this gene provides insight into the underlying mechanisms of this particular type of neurodegenerative disorder.
The Normal Function of the PSEN1 Gene
The PSEN1 gene provides instructions for creating a protein called presenilin-1. Presenilin-1 is a component of the gamma-secretase complex. Gamma-secretase functions somewhat like a pair of molecular scissors within cells. It is a membrane-embedded aspartyl protease complex that cleaves various proteins as part of routine cellular maintenance and signaling pathways.
One of its normal activities involves processing the amyloid precursor protein (APP), among other substrates like the Notch receptor. Presenilin-1 also participates in processes beyond APP cleavage, including Notch signaling, beta-cadherin processing, and calcium metabolism.
How Mutations Cause Familial Alzheimer’s Disease
Familial Alzheimer’s Disease (FAD) is an inherited condition often caused by PSEN1 gene mutations. Mutations in PSEN1 disrupt the normal function of the gamma-secretase complex, altering how it processes the amyloid precursor protein (APP). Instead of cleaving APP in the usual way, these mutations lead to the overproduction of a specific, longer protein fragment called amyloid-beta 42 (Aβ42).
Aβ42 is prone to clumping, forming amyloid plaques in the brain, a defining feature of Alzheimer’s. Over 300 different mutations have been identified in the PSEN1 gene, with most increasing the Aβ42 to Aβ40 ratio. These PSEN1 mutations are inherited in an autosomal dominant pattern, meaning that a person needs to inherit only one copy of the altered gene from a parent to develop the disease.
Clinical Characteristics of PSEN1-Related Alzheimer’s
Alzheimer’s disease caused by PSEN1 mutations manifests at a younger age than sporadic Alzheimer’s. Individuals often begin showing symptoms in their 30s, 40s, or 50s, though onset can occasionally occur in their 20s. This early onset is a distinguishing feature, with mutations in PSEN1 accounting for a significant portion, ranging from 30% to 70%, of early-onset familial Alzheimer’s disease cases.
Disease progression is often more rapid and aggressive than in late-onset Alzheimer’s. While memory loss is a common symptom, other neurological issues can be more prominent or appear earlier in the disease course. These can include muscle twitches (myoclonus), seizures, and language difficulties. Some mutations may also lead to atypical symptoms such as spasticity.
Genetic Testing and Counseling Considerations
Genetic testing for PSEN1 mutations is considered for individuals with a strong family history of early-onset Alzheimer’s, especially if symptoms appeared before age 65. This testing is not routinely recommended for the general population or for those with late-onset Alzheimer’s, as PSEN1 mutations are specific to the inherited, early-onset form. If a pathogenic variant has been identified in an affected family member, predictive testing for asymptomatic adults at risk becomes an option.
Genetic counseling is important before and after PSEN1 testing. Counseling helps individuals and their families understand the implications of the test results, including the 50% chance of inheriting the mutation if a parent carries it. Genetic counselors explain the potential medical, emotional, and social consequences of learning one’s genetic status, which can be profound for individuals and their families.