Mutation vs. Mutation
A Colombian grandmother with a gene for early dementia has changed our understanding of Alzheimer's disease
Recently, a 73-year-old resident of Colombia, who has a rare genetic mutation transmitted from generation to generation, came to the attention of doctors studying Alzheimer's disease. Its carriers begin to show signs of mental disorder at an early age (on average at 45-50 years).
Despite the heavy genetic "inheritance", the woman, however, is in her right mind and firm memory. The results of her examination can become a starting point for the development of a new direction of treatment and prevention of this severe neurodegenerative disease.
Article by Arboleda-Velasquez et al. Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report published in the journal Nature Medicine.
The most common cause of early familial Alzheimer's disease is the E280A mutation in the gene encoding the presenilin 1 protein. Most carriers of this mutation live in Colombia, in a historically isolated mountainous region in the Andes. All these people belong to the same family, which traces its lineage back to a married couple from the Basque region of Spain, who settled in Colombia in the early 1700s.
According to researchers, among the currently living 5,000 representatives of this genus, one in five carries the E280A mutation. Usually, in these people, already in the third decade of life, memory deficiency begins to manifest itself, fluency of speech is lost; later, other progressive cognitive impairments appear, and by the age of 50 dementia develops. In these families, it is not uncommon for elderly parents to be forced to take care of their 40-year-old children who have fallen into "childhood".
The attention of scientists was attracted by a representative of this genus, who, being a carrier of the mutation, lived to 73 years and retained her sanity.
The most surprising thing is that the study of the brain of this woman, conducted using positron emission tomography, revealed an unusually large number of amyloid plaques (deposits of pathological, incorrectly folded beta-amyloid protein), the formation of which is considered as one of the main causes of the development of Alzheimer's disease. At the same time, no signs of significant damage to neurons were observed. In addition, she had few deposits of another pathological protein – tau, which also serve as a sign of Alzheimer's disease.
But two copies of the mutant variant of the APOE gene were found in the woman at once. In total, this gene has three variants: one of them reduces the risk of developing Alzheimer's disease, the other, on the contrary, increases (about half of these patients have at least one copy of this variant). This woman was found to have a third, usually "neutral" variant, but supplemented with another mutation of the same gene – APOE3 Christchurch (APOE3ch). At the same time, the protective effect, apparently, is given by the presence of two copies of APOE3ch in the genotype - several people of the Colombian genus with one copy of this gene developed Alzheimer's disease early.
It is known that the protein encoded by the APOE gene is able to bind to molecules on the cell surface that are actively involved in various intercellular and intermolecular interactions, and can contribute to the penetration of toxic tau protein into them. According to scientists, in this case, resistance to the development of Alzheimer's disease is associated with the APOE3ch mutation, which disrupts this binding, as a result of which the accumulation of tau protein does not occur.
If this is indeed the case, then the reproduction of this process using molecular inhibitors of the APOE gene (protein) or by editing the APOE gene can be used for the prevention and treatment of Alzheimer's disease.
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