Alzheimer’s diseaseAPOE, APP, PSEN1 and PSEN2 genes

Alzheimer's disease is a central neurodegenerative disorder that especially affects the cholinergic neurons of the hippocampus, the area of ​​neurocortical association and other limbic structures. The neuropathological changes that this pathology includes are cortical atrophy, extracellular neuritic plaques, interneuronal neurofibrillary tangles (NFTs) and amyloid deposits in the walls of the cerebral arteries. It is characterized by a progressive loss of cognitive function that involves recent memory, abstract reasoning, ability to concentrate, visual perception and spacetime function. Over time, patients can’t work and need continuous supervision. In the final phase of this disease, most patients develop stiffness, mutism and incontinence. In general, affected people survive 8 to 10 years after the onset of symptoms, but the course of the disease can vary 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 emerges after the age of 65. The early onset form is much less frequent than the late onset form, and represents less than 5% of all cases diagnosed with Alzheimer's.

Most cases of early-onset Alzheimer's disease are due to genetic mutations in one of the three genes described: APP (amyloid beta precursor protein), PSEN1 (presenilin 1) or PSEN2 (presenilin 2). When any of these genes is altered, large amounts of a peptide fragment called β-amyloid are produced. This peptide is toxic to the brain, where can accumulate forming amyloid plaques, typical findings of this pathology. The accumulation of β-amyloid and toxic plaques can lead to the death of nerve cells.

The APP gene is located on the long arm of chromosome 21 (21q21.3) and 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 this protein, it is believed that it can bind to other proteins on the cell surface or help cells bind to each other. It is likely that in the brain it helps direct the migration of neurons at the beginning of development. The 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, from Soluble Amyloid Precursor Protein) and β-amyloid peptide. It is believed that sAPP has properties that promote growth and may play a role in the formation of neurons in the brain, both before and after birth. In addition, the sAPP peptide can also control the function of other proteins, inhibiting their activity. It is also likely that β-amyloid participates in the plasticity of neurons.

On the one hand, more than 50 different mutations in the APP gene that can cause early-onset Alzheimer's disease have been identified. These mutations are responsible for less than 10% of cases of early Alzheimer's. The most frequent genetic mutation in APP replaces the amino acid valine with the amino acid isoleucine at position 717 of the protein (Val717Ile or V717I). Mutations in the APP gene may result in an increase in the amount of the β-amyloid peptide or a longer form of the peptide. When these protein fragments are released from the cell, they can accumulate in brain groups and form the characteristic amyloid plaques of Alzheimer's disease.

Some evidence indicates that people with Down’s syndrome have an increased risk of developing Alzheimer's disease. Down’s syndrome is a disease characterized by mental retardation and other health problems, which occurs when a person is born with an extra copy of chromosome 21 in each cell. As a result, people with Down’s syndrome have three copies of many genes in each cell, including the APP gene, instead of the two normal copies. Although the connection between Down’s syndrome and Alzheimer's disease has not been clarified, excess coding of the β-amyloid peptide in cells may explain the increased risk.

The PSEN1 gene, which are located on the long arm of chromosome 14 (14q24.3), and the PSEN2 gene, 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 that surrounds 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 its nucleus. One of these pathways, known as Notch signaling, is essential for 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 participates in the processing of the amyloid precursor protein (APP), described above.

In patients with early-onset Alzheimer's disease, more than 150 mutations in the PSEN1 gene have been identified. These mutations are the most frequent cause of the early form of Alzheimer's, and represent up to 70% of cases. Almost all mutations in PSEN1 change nucleotides in a certain segment of the gene. These mutations result in the coding of an altered form of the presenilin 1 protein, which interferes with the function of the γ-secretase complex, altering the processing of APP and thus resulting in the overproduction of a longer version of the toxic peptide β- amyloid. Copies of this protein fragment bind and accumulate in the brain, forming amyloid plaques.

Finally, 11 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 of the disease. Two of the most frequent PSEN2 mutations change amino acids that are used to encode presenilin 2. A mutation replaces the amino acid asparagine with the amino acid isoleucine at position 141 (Asn141Ile or N141I). The other mutation changes the amino acid methionine to the amino acid valine at position 239 (Met239Val or M239V). These mutations appear to interrupt the processing of the amyloid precursor protein, which causes an overproduction of β-amyloid peptide. This protein fragment can accumulate in the brain and also form amyloid plaques.

The causes of late-onset Alzheimer's disease have not been demonstrated, but they have been linked to variations in one or more genes in combination with lifestyle and environmental factors. A variant of the APOE gene (apolipoprotein E), located on the long arm of chromosome 19 (19q13.32), known as the ε4 allele, has a strong relationship with the development of the disease, especially when it is in homozygosis (the two alleles of a gene are identical). Therefore, the ε4 version of the APOE gene increases an individual's risk of developing late-onset Alzheimer's disease. However, this same ε4 APOE allele may also be associated with an earlier onset of memory loss and other symptoms. It is unknown how the ε4 APOE allele is related to the risk of Alzheimer's disease, but it is considered that this allele is associated with the presence of a greater number of amyloid plaques in the brain tissue of affected people. An accumulation of beta amyloid peptide and toxic amyloid plaques can cause the death of neurons and the progressive signs and symptoms of this pathology.

Early-onset Alzheimer's disease is inherited with an autosomal dominant pattern, that is, a copy of the altered gene in each cell is sufficient to express the disease. In most cases, an affected person inherits the altered gene from an affected parent. On the other hand, the inheritance pattern of late Alzheimer's form is uncertain. People who inherit a copy of the ε4 APOE allele are more likely to develop the disease; the risk is even greater in individuals who inherit two copies of this allele. It is important to keep in mind that people with the ε4 APOE allele inherit an increased risk of developing Alzheimer's disease, not the disease itself.

Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with Early Onset Familiar Alzheimer Disease, by means of the complete PCR amplification of the exons of the APP, PSEN1, PSEN2 and APOE genes, respectively, and their subsequent sequencing.

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).