The Alzheimer's Brain

Alzheimer's disease is a degenerative disease of the brain. Understanding how the anatomy of the Alzheimer's differs from a normal brain gives us insight. It can help us cope better with the changes that happen to our loved ones as a result of this debilitating disease.

In Alzheimer's disease, the appearance of the Alzheimer's affected brain is very different to a normal brain. The cerebral cortex atrophies. That means that this area of the brain shrinks and this shrinkage is dramatically different from the cerebral cortex of a normal brain. The cerebral cortex is the outer surface of the brain. It is responsible for all intellectual functioning. There are two major changes that can be observed in the brain at autopsy:

• The amount of brain substance in the folds of the brain (the gyri) is decreased
• The spaces in the folds of the brain (the sulci) are grossly enlarged.

Microscopically there are a number of changes in the brain too.

The two major findings in the Alzheimer's brain are amyloid plaques and neurofibrillary tangles. Amyloid plaques are found outside the neurons, neurofibrillary plaques are found inside the neurons. Neurons are the nerve cells within the brain.

Plaques and tangles are found in the brains of people without Alzheimer's. It is the gross amounts of them that are significant in Alzheimer's disease.

Amyloid plaques are mostly made up of a protein called B-amyloid protein which is itself part of a much larger protein called APP (amyloid precursor protein). These are amino acids.

We do not know what APP does. But we do know that APP is made in the cell, transported to the cell membrane and later broken down. Two major pathways are involved in breakdown of APP (amyloid precursor protein). One pathway is normal and causes no problem. The second results in the changes seen in Alzheimer's and in some of the other dementias.

In the second breakdown pathway APP is split by enzymes B-secretase (B=beta) then y-secretase (y=gamma). Some of the fragments (called peptides) that result stick together and form a short chain called an oligomer. Oligomers are also known as ADDL, amyloid-beta derived diffusible ligands. Oligomers of amyloid beta 42 have been shown to cause problems in the communication between neurons. Amyloid beta 42 also produces tiny fibers, or fibrils. When they stick together they form amyloid plaque. Some of these plaques can insert themselves into the membrane of the neuron cell causing substances outside the cell to leak into it, causing further damage. This damage results in a buildup of Amyloid beta 42 peptides leading to neuron dysfunction and death.​

The second major finding in the Alzheimer's brain are neurofibrillary tangles. Neurofibrillary tangles are composed of a protein called tau protein. Tau proteins play a crucial role in the structure of the neuron. In people with Alzheimer's tau proteins cause abnormality through overactive enzymes resulting in the formation of neurofibrillary tangles. Neurofibrillary tangles result in the death of the cells.

The role of amyloid plaques and neurofibrillary tangles on the functioning of the brain is by no means fully understood. Most people with Alzheimer's disease show evidence of both plaques and tangles, but a small number of people with Alzheimer's only have plaques and some have only neurofibrillary tangles.
People with plaque only Alzheimer's show a slower rate of deterioration during their lives. People with neurofibrillary tangles are more likely to be diagnosed with frontotemporal dementia.

Research into Alzheimer's disease is finding out more and more about the anatomy and physiology of the brain. As we understand more about the role of plaques and tangles observed in the Alzheimer's brain the closer we get to a significant breakthrough and a cure for Alzheimer's disease.