Early-onset Alzheimer´s disease - APP, PSEN1 or PSEN2 genes.

Alzheimer´s disease is a central neurodegenerative disorder that primarily affects cholinergic neurons in the hippocampus, the neurocortical association area, and other limbic structures. Neuropathologic changes include cortical atrophy, extracellular neuritic plaques, interneuronal neurofibrillary tangles, and amyloid deposits in the walls of cerebral arteries. It is characterized by a progressive loss of cognitive function that includes recent memory, abstract reasoning, the ability to concentrate, visual perception and spatio-temporal function. Over time, patients are unable to work and need continuous supervision. In the final phase of the disease, most patients develop rigidity, mutism, and incontinence. Affected individuals usually survive 8 to 10 years after the onset of symptoms, but the course of the disease can range from 1 to 25 years. Death is usually caused by pneumonia, malnutrition, or general body wasting.

Alzheimer´s disease can be classified as early-onset or late-onset. Signs and symptoms of the early form appear before the age of 65, while the late-onset form appears after the age of 65. The early-onset form is much less common than the late-onset form, accounting for less than 5% of all cases of Alzheimer´s disease.

Most cases of early-onset Alzheimer´s disease are due to genetic mutations in one of three genes: APP, PSEN1, or PSEN2. When any of these genes is altered, large amounts of a peptide fragment called β-amyloid are produced that is toxic to the brain. This peptide can accumulate in the brain forming amyloid plaques, characteristic of Alzheimer´s disease. The accumulation of β-amyloid and toxic plaques can lead to nerve cell death and the progressive signs and symptoms of this disease.

The APP gene, located on the long arm of chromosome 21 (21q21.3), encodes a protein called amyloid precursor protein. This protein is found in many tissues and organs, including the central nervous system. Although little is known about the function of amyloid precursor protein, it is thought that it may bind to other proteins on the cell surface or help cells attach to each other. In the brain, it likely helps direct the migration of neurons early in development. Amyloid precursor protein is cleaved by enzymes to create peptides, some of which are released outside the cell. Two of these fragments are called soluble amyloid precursor protein (SAPP) and β-amyloid peptide. SAPP is believed to have growth-promoting properties and may play a role in the formation of neurons in the brain, both before and after birth. The SAPP peptide can also control the function of certain other proteins by inhibiting their activity. β-amyloid is also likely to be involved in the plasticity of neurons.

More than 50 different mutations in the APP gene have been identified that can cause early-onset Alzheimer´s disease. These mutations are responsible for less than 10% of all cases of early-onset Alzheimer´s disease. The most common APP genetic mutation replaces the aminoacid valine with the aminoacid isoleucine at position 717 of the protein (Val717Ile or V717I). Mutations in the APP gene can lead to an increased amount of amyloid-β peptide or a longer form of the peptide. When these protein fragments are released from the cell, they can accumulate in brain clusters and form amyloid plaques, characteristic of Alzheimer´s disease.

Some evidence indicates that people with Down syndrome are at increased risk of developing Alzheimer´s disease. Down syndrome, a disease characterized by mental retardation and other health problems, occurs when a person is born with an extra copy of chromosome 21 in every cell. As a result, people with Down syndrome have three copies of many genes in each cell, including the APP gene, instead of the normal two copies. Although the connection between Down syndrome and Alzheimer´s disease is unclear, excess β-amyloid peptide-encoding cells may explain the increased risk.

The PSEN1 genes, located on the long arm of chromosome 14 (14q24.3) and PSEN2, located on the long arm of chromosome 1 (1q42.13), encode the proteins presenilin 1 and presenilin 2, respectively. These proteins carry out the main function of the γ-secretase complex, which is to cleave other proteins into peptides (proteolysis). The γ-secretase complex is located in the membrane surrounding cells, where it cleaves many transmembrane proteins. This cleavage is an important step in several chemical signaling pathways that transmit signals from outside the cell to the nucleus. One of these pathways, known as Notch signaling, is essential for the normal maturation and division of hair follicle cells and other types of skin cells. Notch signaling is also involved in the normal function of the immune system. In addition, the γ-secretase complex plays a role in amyloid precursor protein (APP) processing, described above.

More than 150 PSEN1 gene mutations have been identified in patients with early-onset Alzheimer´s disease. Mutations in the PSEN1 gene are the most common cause of early-onset Alzheimer´s disease, accounting for up to 70% of cases. Almost all mutations in the PSEN1 gene change nucleotides in a particular segment of the PSEN1 gene. These mutations result in the coding of an altered presenilin 1 protein that interferes with the function of the γ-secretase complex, impairing APP processing and causing overproduction of a longer version of the toxic β-amyloid peptide. Copies of this protein fragment stick together and accumulate in the brain, forming amyloid plaques.

Eleven mutations in the PSEN2 gene associated with early-onset Alzheimer´s disease have been described. Mutations in this gene are responsible for 5% of all cases of early-onset disease. Two of the most common PSEN2 mutations change amino acids that are used to code for presenilin 2. One mutation replaces the aminoacid asparagine with the amino acid isoleucine at position 141 (Asn141Ile or N141I). The other mutation changes the aminoacid methionine to the aminoacid valine at position 239 (Met239Val or M239V). These mutations appear to disrupt amyloid precursor protein processing, leading to overproduction of β-amyloid peptide. This protein fragment can accumulate in the brain and form amyloid plaques.

Early-onset Alzheimer´s disease is inherited in an autosomal dominant pattern, which means that one copy of the altered gene in each cell is sufficient to cause the disease. In most cases, an affected person inherits the altered gene from an affected parent.

Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with Early-Onset Alzheimer disease, by means of the complete PCR amplification of the exons of the APP, PSEN1 y PSEN2 genes, respectively, and their subsequent sequencing. In the first place, the complete study of the PSEN1 gene is recommended, where most of the mutations accumulate. If this result is negative, we recommend proceeding to the study of exons of the APP gene and, later, of the PSEN2 gene can be studied.

Recommended samples: non-coagulated blood obtained with EDTA for separation of blood leucocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).