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The genetic factors of Alzheimer’s disease
In EA patient autopsies, neurofibrillar ovillus formed by TAU protein pads inside neurons are observed, giving rise to an insoluble ball. Tau is phosphoryila in critical places of its structure and loses its stabilizing microtubules function, accumulating and causing neuronal death. The CSF, being in contact with the extracellular space of the brain, constitutes an ideal sample to evaluate the biochemical activity of the brain and, therefore, of the changes in the same that take place in dementia. It presents, however, the inconvenience of extracting by lumbar puncture, an invasive method, although it presents few complications (1-2). The alteration of these biomarkers in cerebrospinal fluid (CSF) has been associated in numerous studies at an increased rate of progress to EA in patients with mild cognitive impairment and correlates with loss of evidence evidence by magnetic resonance in regions of the medial temporal lobe typicallyAffected by the EA as the hypothalamus and the enterorrinal cortex, before the dementia is manifested clinically (2, 9).
Recent studies have evaluated the sensitivity and specificity of CSF markers to differentiate the values of Alzheimer’s patients from the controls. The total tau protein demonstrated an average sensitivity of 81% and an average specificity of 91%. In addition, combining beta-amyloid measures 42 and Tau in the CSF improved the diagnostic potential of markers. The phospho-tau/beta-amyloid ratio 42 was superior in diagnostic power to any of the isolated measures in the differentiation of patient controls, obtaining a sensitivity of 86% and a specificity of 97%. When the two beta-amyloid biomarkers and phosphorylated tau proteins are positively measured, the probability of EA development from a slight cognitive deterioration increases (5, 10).
However, a recent meta -analysis leads to being cautious with the results present in current literature. The methods are considered to be very heterogeneous and insufficient studies to establish these parameters as a unique diagnostic element in the usual clinical practice, although we are approaching obtain).
Apolipoprotein E4 (APOE4)
Recently it has been related as a genetic risk factor for Alzheimer’s disease the apolipoprotein E (APOE) gene, which has 3 common alleles: APOE2, APOE3 and APOE4, the most important risk factor being the APOE4, being the most important risk factor. Between 60 and 80% of EA patients have at least one APOE4 allele, which is associated with serious risk, APOE3 is associated with an intermediate risk, and APOE2 with the least risk of suffering from the disease (12).
This is due to the fact that a greater number of senile plates have been observed in the brains of patients of 2 alleles APOE4, while the possession of the APOE2 allele decreased the presence of these plates. The amino acids that mark the differences between the APOE variants are in positions 112 and 158 (see Table 1: Amino acids of the apolipoproteins). In APOE4, the arginine of position 112 has two key properties: it allows the interaction of protein domains and reduces its stability. As a consequence, a partially folded structure will be established, which will be important because reactive intermediaries are related to different pathophysiological processes (12).
With age, neurons must be remodeled and repaired to maintain synaptic connections;APOE participates in these processes in the different cell types of the central nervous system (CNS) including astrocytes and some neurons. APOE2 and 3 forms are more effective in normal maintenance and repair of cells that APOE4 due to its different characteristics. Neurons synthesize APOE in response to damage, but APOE4 is more susceptible to proteolysis by a protease, making the fragments generated toxic to neurons, since it induces changes in the synthesis and elimination of the beta-amyloid peptide andAppearance of neurofibrillary structures similar to ovillus. In turn, these fragments stimulate the phosphorylation of the Tau protein, which also contribute to said ovillar formation. Neurotoxicity is related to the ability of APOE fragments to penetrate the plasma membrane and enter the cytosol and interact with cytoskeleton and mitochondria, causing functional alterations (12).
Therefore expressed, the APOE4 can currently serve us for EA’s early detection, as well as a direct approach to this protein to avoid neurodegenerative changes, by drugs that correct the structure and block the harmful action of APOE. The efforts and advances in research are aimed on this line.
Genes and mutations that can be detected in dementia
The genetic factors that are related to the family Alzheimer’s dementia of early onset, is linked to the 1,14,21 chromosomes;While late starting forms are linked to chromosomes 12 and 19. Sick individuals without family history of disease, in most of these, cannot be explained from the genetic point of view, although hypotheses have been indicated that pose the action of toxic or unidentified infectious agents that affect genetic aspects and theirpossible mutations. Among these genes are those of the presenilines-1 and 2, and that of the APOE4, of which we have previously spoken. (13)
The existence of a locus has been demonstrated on chromosome 14 (14q 24.3) In a group of families with Alzheimer’s disease in an early phase (EAFP). In this chromosome the gene called S 182 was isolated, which encodes the synthesis of presenilin-1. At least 4 different mutations have been found in the preseniline-1 gene, which is a change of amino acids, whose alteration represents about 30-50 % of the cases of EAFP (14).
The preseniline-1 gene is expressed in different regions of the brain, in the skeletal muscle, in the kidney, in the pancreas, in the placenta and in the heart and it is believed that it can have an important role in the apoptosis process. Most mutations are linked to exon 5 and exon 8. The effects on the presenilin-1 gene, in both axons, show a significant difference with respect to the age of the beginning of the disease (14).
The preseniline 2 (PS -2) gene also contains 10 exons, and has 67 % homology with respect to the amino acid sequence of the preseniline -1, and, therefore, presents homology in function. It is thought that the mutations of this gene can cause an increase in apoptosis and as a consequence to accelerate the neurodegenerative process. In families with EAF that present mutations in the preseniline-1 gene, the average age of start is much earlier (45 years, range between 29 and 62 years) than families with mutations in the preseniline-2 mutations (52 years, rangebetween 40 and 88 years) (14).
Beta-amyloid 42, TAU and phospho-tau neurodegeneration biomarkers, and plasma t-tau are strongly associated with Alzheimer’s disease and mild cognitive deterioration in numerous studies. The genetic screening can also contribute to the diagnosis, since two APOE4 alleles are associated with a higher risk of dementia development being the most susceptible to proteolysis patient, and the toxic generated fragments for neurons, induce changes in the synthesis and elimination of the elimination of theBeta-amyloid peptide and appearance of neurofibrillary structures similar to ovillus.
However, heterogeneity and insufficient amount of research to date lead to a state of uncertainty regarding the value of these tests in the preclinical stage. Special attention should be paid to the risk of excessive diagnosis of dementia in daily practice. In this sense, we must treat EA as a multifactorial disease derived from heterogeneous etiologies and whose pathophysiological mechanisms are not yet established with certainty. A combinatorial approach of biomarkers, images and fluids integrated with genetic screening and cognitive impairment tests will be required. In addition, it will be necessary to establish standards for the collection of samples and the unified calibration of instruments to avoid variability and establish more specific parameters. Together, the results lead us to think that research is increasing.