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Corresponding author: Milena Draganova-Filipova ( milena_draganovafilipova@abv.bg ) © 2022 Milena Draganova-Filipova, Vanina Bojilova, Plamen Zagorchev.
This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Citation:
Draganova-Filipova M, Bojilova V, Zagorchev P (2022) Alzheimer’s disease: the hypotheses, known and unknown connections between uv-radiation, mtdna haplotypes and life span – a review. Folia Medica 64(6): 878-883. https://doi.org/10.3897/folmed.64.e68268
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Alzheimer’s disease (AD) is the most common neurodegenerative disease with controversial etiology. One theory claims that AD is due to brain aging affecting mainly the functions of mitochondria, therefore, the factors leading to mitochondrial ageing should lead to the development of Alzheimer’s disease. Another theory is that different mitochondrial DNA haplogroups can be predisposition for the onset of the condition. Here we focused on the possible connection between AD and UV radiation using the data on the monthly UV index in Europe, its correlation with mortality rate due to AD and mitochondrial DNA haplogroups distribution. If a link between the two theories is proved, it will mean that UV radiation is a risk factor not only for skin cancer but also for a large group of neurodegenerative diseases amongst which is the Alzheimer’s disease.
Alzheimer’s disease, life-span, mtDNA haplotypes, UV-radiation
Along with Parkinson’s disease, Alzheimer’s disease (AD) is the most common neurodegenerative disease. With millions of people suffering from Alzheimer’s disease across the globe, the prognosis for the future development of AD is for the number of patients to increase. At the same time, little is clear about the origins and the development of this disease.
There are two theories we are going to discuss in this review. The first one looks at the Alzheimer’s disease as a hereditary condition. It has been established that in a small proportion of all cases of Alzheimer’s dementia, AD is hereditary. Most of the genes that cause Alzheimer’s disease have already been studied. The second theory proposes that Alzheimer’s disease develops due to brain aging.
In most patients with Alzheimer’s dementia, the pathogenesis is due to brain aging. Oxidative stress and mitochondrial dysfunction are the major factors behind developing Alzheimer’s dementia.[
Oxidative damage leads to deletion in mitochondrial DNA (mtDNA), but the mechanism is under-researched. Oftentimes, point mutations and rearrangements are discovered. There are mutant copies of mtDNA within the cell and their number must reach a certain threshold before clinical symptoms and cell death become visible.[
The process of cell aging was first described by Harman fifty years ago. He suggested that cell aging was due to the production of reactive oxygen species.[
The main reason why mitochondria generate reactive oxygen species is the respiratory chain. In the respiratory chain, which consists of sites I to IV, energy is produced from two stable molecules – reduced nicotinamide adenine dinucleotide (NADH) and semiquinone flavin adenine dinucleotide (FADH). Site I contains flavin mononucleotide (FMN), which is responsible for the release of reactive oxygen species.[
An increase in oxygen consumption does not increase the production of reactive oxygen species but reduces it. The only instance when increased oxygen consumption increases the levels of reactive oxygen species is when there are a greater number of mitochondria.[
With aging, changes occur in the mitochondria. An example of such alteration is the oxidation of mtDNA. Oxidative damage can be explained by the lack of histone protection, its close proximity to reactive oxygen species, and the few repair mechanisms.[
Mitochondria are exceptional because they have their own DNA in the form of a circular, double-stranded molecule. [
In a study from 1994, Corral-Debrinski et al.[
We can hypothesize as to whether some people are genetically more prone to developing Alzheimer’s disease because of their mtDNA. Studies have long taken interest in the mtDNA haplogroups. Initially discovered to allow us to follow human migration back to the mitochondrial Eve, today they can be connected to a number of illnesses. This hypothesis stands some ground when it comes to Alzheimer’s disease. Van der Walt and colleagues[
The hypothesis that mtDNA is a risk factor for the development of Alzheimer’s disease is unproven. The results from different tests and experiments are inconsistent to support an unequivocal conclusion. Mitochondrial dysfunction certainly causes the overproduction of reactive oxygen species. An experiment in which mtDNA was taken from a person with Alzheimer’s disease and was then transferred to a cell with no mtDNA showed that the host cell began generating reactive oxygen species. The enzymes that should have neutralized the species appeared heavily reduced. The suggestion that mtDNA haplogroups may be a predisposition to Alzheimer’s disease spurs from the knowledge that a risk factor in the pathogenesis is allele e4 of apolipoprotein E.[
Research on brain tissue from a patient with Alzheimer’s disease shows abnormalities in the structure of the functioning mitochondria called ‘giant’ mitochondria.[
In countries with a high mortality rate, haplogroup J, which is considered by some studies to be over-represented in patients with Alzheimer’s disease, is indeed highly represented where it is one out of the three most common haplogroups.[
There is evidence that the HV cluster is also connected to Alzheimer’s disease development, regardless of sex. Table
A recent study of groups in the Polish population found that haplogroup H was another risk factor. It is believed that haplogroup H and, in particular, some of its subdivisions like H3, H4, H5 and H6 are associated with coupled oxidative phosphorylation. It follows that they should lead to an increased production of reactive oxygen species.
In summary, even small risk factors affecting mtDNA and haplogroups could have a pathogenic effect. It is true that some genetic abnormalities could resemble early aging[
mtDNA haplogroups by frequency in some European states. Countries below the bold line are among the countries with the lowest mortality rate from AD in the world
HV | H | H5 | J | U | |
Finland | 0 | 36.3 | 23 | 5.9 | 0.8 |
Sweden | 0.5 | 45.8 | 2.2 | 7.7 | 2.8 |
Switzerland | 0.4 | 47.9 | 4.4 | 11.5 | 0.4 |
Spain | 0.7 | 44.1 | 2.6 | 6.6 | 1.8 |
France | 2 | 44.3 | 3.1 | 7.7 | 1.4 |
UK | 0 | 44.7 | 4.1 | 11.5 | 2.7 |
Italy | 2.9 | 40.2 | 3.9 | 8.1 | 2.7 |
Germany | 0.5 | 44.8 | 4.8 | 9 | 0.8 |
Poland | 1 | 43.9 | 4.5 | 7.9 | 1.4 |
Czech Republic | 1.7 | 40.2 | 4 | 10 | 0.6 |
Bulgaria | 3.8 | 41.9 | 3.2 | 7.7 | 2.5 |
North Macedonia | 0 | 45 | 4 | 7.5 | 2 |
Bosnia and Herzegovina | 1.1 | 45.8 | 5.6 | 8.3 | 1.1 |
Globally, Alzheimer’s disease affects about 3% of adults 60 and older, yet its etiology is still a mystery. In addition to the ones we analyzed, there may be other factors involved as well. Both of the hypotheses in the present article are still not proven. However, they pose important issues regarding the causes of Alzheimer’s dementia, its risk factors, and methods for delaying or perhaps preventing the start of this degenerative disease. Studies on the causes of this illness will continue to focus on such issues.
The study is sponsored by Bulgarian National Science Fund, Project DN11-15/2017.
Competing Interests
The authors have declared that no competing interests exist.
Author contributions
M.D-F. and P.Z. conceived of the presented idea. M.D-F. and V.B. wrote the manuscript. All authors discussed and commented on the manuscript.