Alzheimer’s disease is a progressive and irreversible neurodegenerative disease of the brain that mainly affects people over 65 years of age. It is the number one cause of dementia. It most commonly presents with the symptoms of memory loss (initially short-term memory loss).
The main goal of the current treatment regimen is to slow down the rate of progression of the disease and improve the memory impairment. Although such measures are only temporary, they play a vital role in the quality of life of a person who is suffering from Alzheimer’s disease.
At present, approved treatment is available that targets the disease pathology, ic h means that at present, there is no cure for the disease. However, scientists are constantly on the lookout for new drugs that affect the disease pathology, possibly reversing it or curing the patient. But why can’t we find a cure for Alzheimer’s disease yet? To understand the answer to this question, it is important to have some knowledge about the basic pathology of the disease. Let’s cover some basic background information on Alzheimer’s first.
Which area of the brain is affected first in Alzheimer’s disease?
In the brain, the first area to be affected by Alzheimer’s disease is the entorhinal cortex. The torhinal cortex plays a vital role in the maintenance of a person’s memory and navigational abilities. More specifically, in Alzheimer’s disease, the lateral entorhinal cortex seems to be affected first by Alzheimer’s. As the disease progresses further, more areas of the brain get damaged, and ultimately, this leads to global neurological dysfunction.
How does the brain get damaged in Alzheimer’s disease?
For most cases (95% to 98%), the exact cause is unknown! We can only move forward based on some hypotheses about the disease’s pathology that we have postulated based on current information and research. In the rest of the cases, a genetic defect can be identified, which can be attributed to the development of Alzheimer’s disease.
So, what are the possible causes of Alzheimer’s disease?
1. Genetic defects
Alzheimer’s disease can be broken down into two main typeslate-onsetet Alzheimer’s disease and early-onset Alzheimer’s disease. The late-onset AD is the most common, and it affects people aged over 65. There are genetic components associated with both of these types of Alzheimer’s disease. Late-onsetAlzheimer’s disease
This is the most common type of Alzheimer’s disease. We still have not determined the exact cause, but scientists have developed several solid hypotheses. It is usually said that the cause of this variant of Alzheimer’s disease is multifactorial, which means that this disease develops as a result of the combined effect of a person’s genetics, environmental, nd lifestyle factors.
Scientists have so far identified one possible genetic variation,,,,chif present in, iincreases the possibility and risk of a person developing Late onset Alzheimer’s disease – the Apolipoprotein E (APOEgene, which is located on chromosome 19.
The APOE gene is responsible for the production of a type of protein called Apolipoprotein E. This protein is one of the major transport proteins for cholesterol, fat-soluble vitamins, and other types of fat in the lymphatic system and blood.
There are three main varieties of this protein:
- APOE ε2: This is the least common variant, and the presence of this protein may actually provide some protection against Alzheimer’s disease.
- APOE ε3: This variety is the most common, and the presence of this variety neither increases nor decreases the risk of developing Alzheimer’s disease.
- APOEε4: This variety is associated with an increased risk of developing Alzheimer’s disease.
What is important to remember is that the presence of APOE ε2 or APOE ε3 does not mean that a person will not develop Alzheimer’s disease. Similarly, the presence of APOEε4 does not guarantee the development of Alzheimer’s disease.
How does the APOE protein cause Alzheimer’s disease?
One of the major ways Alzheimer’s disease develops is by the deposition of Amyloid proteins, which are abnormalities in the nerve cells that ultimately destroy the nerve cells. The deposition of amyloid plaques in the brain is one of the characteristic findings in Alzheimer’s disease. The APOE protein helps in the breakdown of these abnormal amyloid proteins. However, the APOEε4 variant is less efficient at breaking down these proteins, which makes individuals having the APOEε4 variant more susceptible to developing Alzheimer’s disease.
Early-onset Alzheimer’s disease
This variety of Alzheimer’s disease occurs in people aged 30 to 60 years and represents around 5% of all Alzheimer’s cases. In the majority of cases, a familial inherited change in one of three particular chromosomes leads to the disease, which is called the Early Onset Familial Alzheimer’s disease. The three chromosomes that are changed are chromosomes 1, 14, and 21. Specific inherited defects in any one of these three chromosomes lead to Alzheimer’s disease.
Mutated genes in these three chromosomes are responsible for the production of three different types of proteins:
- Mutated genes in chromosome 1 produce the protein Presenilin 2
- Mutated genes in chromosome 14 produce the protein Presenilin 1
- Mutated genes in chromosome 21 produce the protein Amyloid precursor protein
These mutated genes and the abnormal proteins produced by them ultimately lead to an increased production of abnormal amyloid proteins, which get deposited in the nerve cells, particularly neurons, and ultimately cause Alzheimer’s disease. As discussed in Late Onset Alzheimer’s disease, the deposition of amyloid plaques in the brain is one of the characteristic findings of Alzheimer’s disease.
It is interesting to note here that 50% people with Down’s syndrome eventually develop Alzheimer’s disease at an early age of 40 years. The rest developAlzheimer’s as they age around 65 years. Down syndrome has an extra copy of chromosome 21. Scientists are still researching the link between Down’s syndrome and Alzheimer’s disease, but one possible explanation is that the presence of an extra copy of chromosome 2,1which produces amyloid precursor protein,, i n leads to increased production and deposition of amyloid plaques in the brain, which causes the early onset of Alzheimer’s.
2. Deficiency of acetylcholine
Acetylcholine is a neurotransmitter that is responsible for the maintenance of intact memory and learning. In Alzheimer’s disease, the cholinergic hypothesis states that there is reduced synthesis of acetylcholine, leading to impaired memory and learning.
3. Amyloid protein deposition ithe n the brain
The amyloid hypothesis suggests that the deposition of abnormal amyloid proteins in the brain is the main reason behind the development of the disease. Indeed, the presence of beta amyloid plaques is one of the characteristic findings of Alzheimer’s disease. These beta amyloid proteins are produced in excess (a few possible explanations for the increased production of amyloid proteins have already been discussed above) and damage nerve cells, which ultimately leads to the development of Alzheimer’s disease.
4. Abnormal Tau protein
Tau proteins are normal components of nerve cells, particularly neurons, and Alzheimer’s disease is said to develop when these tau proteins become defective. Indeed, the presence of large numbers of abnormal tau proteins, also known as Neurofibrillary tangles, is the other characteristic finding of Alzheimer’s disease. Let’s discuss TaungTau proteins and how they lead to Alzheimer’s disease.
What are Tau proteins?
Tau proteins are important structural proteins of microtubules. Microtubules are important components of all cells in the body. Tau proteins are mostly found in the neurons, and their main function is to stabilize the microtubules. When tau proteins become defective, they cannot function properly and cannot stabilize the microtubules, which leads to the development of neurodegenerative diseases like Alzheimer’s disease and Parkinson’s disease.
How do tau proteins get defective in Alzheimer’s disease and other neurodegenerative diseases?
The tau hypothesis states that abnormal or excessive phosphorylation of tau proteins causes them to clump together into an insoluble mass of proteins called Neurofibrillary tangles, which are also known as paired helical filaments. The presence of neurofibrillary tangles is one of the main hallmarks of Alzheimer’s disease.
Scientists do not know the exact pathology behind the formation of neurofibrillary tangles, but some causes are:
- Mutated Tau protein
- Trauma to the brain
- Aluminium
Infographic showing the causes of Alzheimer’s disease
Now that we have some basic understanding of Alzheimer’s disease, let’s move on to the next section.
Why can’t we find the cure for Alzheimer’s yet?
The basic problem lies in the fact that Alzheimer’s disease is a multi-factorial disease. It is a combination of genetics, environmental health, and lifestyle choices. To put things into a broader perspective, let’s think about AIDS for a while. Acquired Immune Deficiency Syndrome or AIDS is a disease that is caused by the Human Immunodeficiency Virus or HIV. Even though there is a clear correlation between the disease and the causative factor, we still have not found a cure for AIDS. But since the link between AIDS and HIV is simpler, we have been able to progress much further in terms of knowledge and finding an actual cure for HIV than we have forAlzheimer’s.
Can genetic tests predict Alzheimer’s disease?
There are some genetic tests available that can predict the chances of the development of Alzheimer’s in a person who is related by birth to someone (positive family history) suffering from the disease. Such tests are not recommended for everyone because they are not always accurate. The presence of a genetic risk factor does not mean that the person will always develop the disease (as explained earlier in this article). Moreover, we have no way to prevent the disease, unlike, for example, breast or ovarian can, where genetic testing in a person with a positive family history allows that person to take some preventive measureslike susurgeryr chemoprevention.
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