Pathophysiology in Alzheimer’s Disease

 by Hamish Orr

What is Alzheimer’s Disease? 

Alzheimer’s is a neurodegenerative disease which currently has no cure. Alzheimer’s is the most common cause of dementia, being the cause of approximately 70% of cases. It is characterised by loss of memory. The disease progresses from forgetting short term, recent events to forgetting names and places before forgetting more important things like long term memories, language and motor skills and loss of memory of close family members' names. There are other symptoms such as reduced direction in life, mood swings. The cause of death is often pneumonia due to the loss of the ability to swallow causing food to enter the lungs, leading to infections. 

Pathophysiology 

Alzheimer’s in the most simple terms is caused by loss and damage to the neurons (nerve cells) and synapses (connections between neurons). When there is a loss of a large enough number of neurons and synapses within the brain there is increased atrophy which leads to the destruction of areas of the brain such as the parietal lobe, temporal lobe and most noticeably the frontal cortex, responsible for a variety of brain functions. There are two key pathologies which are known to be clear causes of Alzheimer’s disease, plaques and tangles (αβ-plaques and neurofibrillary tangles.) 

What are Aβ-Plaques (Amyloid Plaques)? 

In the cell membranes of neurons within the brain there are proteins called Amyloid Precursor Proteins, (APP) where one end of the protein is inside the cell and another is outside the cell. It is understood that the purpose of the protein is to help the neuron grow and repair itself. Proteins within cells are used often and need to be broken down and recycled so that they can continue to work efficiently. The APP protein is broken down by enzymes called α-Secretase and γ-secretase which cut the protein into parts which are soluble and can be dissolved and removed by the body. However, sometimes an enzyme called β-Secretase is combined with α-secretase leading to the formation of an insoluble protein piece called amyloid Beta which are chemically ‘sticky’ to each other and clump together to form plaques. The plaques are lumps of these monomers which build up increasingly over time. When these plaques are in the way of neurons they can prevent signalling between neurons impairing many brain functions. Furthermore the plaques can trigger an immune response which can cause inflammation which could potentially lead to damage to surrounding brain structures and neurons. 

Amyloid plaques can further build up on the blood vessels of the brain, leading to a condition called amyloid angiopathy increasing the risk of rupture of blood vessels in the brain leading to possibilities of strokes.

What are neurofibrillary tangles? 

Neurofibrillary tangles are a problem with the internal structure of the neurons. Neurons are held together by a network of microtubules which are responsible for the movement of substances through the cell. The microtubules are held together within the cell by a protein called Tau. It is thought that the buildup of plaques outside the cell leads to the activity of enzymes inside the cells, including the activity of kinase. Kinase is an enzyme that transfers phosphate groups to the Tau proteins within the microtubules that are within the cells. The addition of the phosphate group to the tau protein causes it to detach from the microtubules and clump up in the cells and get tangled. This leads to the development of neurofibrillary tangles. This leads to the weakening of signalling and transport via the microtubules of the neuron cells. This failure of the cell to function will often lead to a programmed cell death, called apoptosis. This causes atrophy of the brain and shrinking of the gyri, which are the ridges of the brain and the sulci, the gaps between ridges can get larger. This atrophy can also lead to an increase in the size of the fluid filled ventricles of the brain. 

Causes and Types of Alzheimer’s

Sporadic Alzheimer’s 

Sporadic Alzheimer’s is also known as late onset and doesn't have a clear known cause. IT is responsible for most cases and is linked to age with over 50% of 85 year olds having sporadic Alzheimer’s disease compared to 1% of 60-65 year olds. 

Although an exact cause isn’t known the environmental factors in conjunction with other risk factors such as specific gene alleles could lead to the development of Alzheimer’s disease. The e4 allele apolipoprotein E (APoE-e4) has been linked to increased risk of Alzheimer’s. The risk is even higher when two alleles of the gene are inherited. The apolipoprotein E is responsible for the breakdown of beta amyloid but the e4 allele is deemed to be less effective in doing so. This means that there is a higher risk of developing beta amyloid plaques and the problems associated with them. 

Familial Alzheimer’s 

Familial Alzheimer’s disease is also known as early onset Alzheimer’s and is due to a dominant gene speeding up the progression of the disease. There are many genes that could be responsible. PSEN-1 (chromosome 14) and PSEN-2 genes (chromosome 1) have been linked to early onset Alzheimer’s. The genes are responsible for producing subunits of the gamma secretase and change where on the APP protein the enzyme will act. This can lead to less soluble pieces of APP being produced and also leads to the formation of aβ-plaques. 

Trisomy 21 in Alzheimer’s

Also known as Down Syndrome, Trisomy 21 involves an extra chromosome 21. As the APP gene is located on chromosome 21 there is an increase in the amount of APP expression. This can lead to an increase in the amount of amyloid plaques building up leading to Familial Alzheimer’s disease often by age 40. 

Management

There is very little that can be done about Alzheimer’s and there are some drugs that are available but none of them are able to halt the progression of the disease.