In my previous column, I dealt in general with Alzheimer’s disease and the growing problem it is becoming for our aging population. Today I want to discuss in a little more detail exactly what we know about what happens inside the brain as the disease progresses.
Research in this field is rapidly advancing and will hopefully lead to more successful treatments and possibly a cure for this devastating illness.
We have already established that Alzheimer’s seems to be the result of problems in the way the brain processes proteins, and there are two types of toxic proteins that build up in the brains of people with the disease. These are tau proteins and amyloid peptide fragments.
Tau proteins make up the neurofibrillary tangles found throughout the brains of demented individuals. Tau is a substance that binds to another protein named tubulin in the formation of these tangles.
Neurofibrillary tangles are not only found in the brains of Alzheimer’s patients; they are also found in high concentrations among those with the disease and they seem to correlate with the severity of the dementia. The more advanced the disease, the more tangles of tau are found.
Tangles of tau proteins are known to cause some types of dementia and their role in Ahlzeimer’s is under debate. All of the confirmed Alzheimer’s genes so far influence the life cycle of the Abeta peptide, which therefore is thought by some to be more significant in causing Alzheimer’s than the tau protein.
Amyloid plaques, found between the cells in the brain and discussed in last week’s column, are made up of Abeta amyloid peptides. These are short chains of 42 amino acids and are thought to be extremely important in the development of Alzheimer’s.
Although these plaques are not exclusive to Alzheimer’s disease, they are usually extensive in the hippocampus and cerebral cortex of Alzheimer’s patients.
Abeta amyloid peptides are formed from a longer protein called the amyloid precursor protein (APP). Research over the past decade has discovered that abnormal processing of APP can cause the disease. Abeta peptides can accumulate if there is too much production or too little clearance.
Recent genetic research has also discovered that some families with hereditary Alzheimer’s have mutated versions of two genes (presenilin 1 and 2). These genes have a role in cutting the APP gene.
When mutations exist, they cause an increase in production of amyloid peptides. The more peptides exist, the more likely it is that plaques will form. There are over 150 different genetic mutations that are already known to cause the disease with certainty.
Although this research into mutations in APP and presenilin genes has shed light on Alzheimer’s, these mutations only account for 5 per cent of all Alzheimer’s. Clearly, more information is needed.
Another gene called the APOE gene seems to be important in Alzheimer’s. This gene plays a key role in cholesterol metabolism.
Several forms of the APOE gene exist and one of them appears to be very common among Alzheimer’s patients. In fact, roughly 25 per cent of people with the disease have this version of the APOE gene. This is a susceptibility gene and is neither necessary nor sufficient for the disease on its own.
Another gene of recent interest is responsible for the insulin degradation enzyme (IDE) and is found on chromosome 10. It is involved in breaking down insulin as well as Abeta peptides.
This may account for the association between diabetes and Alzheimer’s disease. Type 2 diabetics have a two-fold increase in Alzheimer’s disease and those with Alzheimer’s disease have a two-fold increase in type 2 diabetes.
There are many other genes under investigation and as they are confirmed they will lead to a greater understanding of the mechanisms involved. This will in turn lead to rational development of treatments. This is one of the most exciting areas of molecular genetic research and has the potential for immense practical payoff in the not-too-distant future.
Dr. Latimer is president of Okanagan Clinical Trials and a Kelowna psychiatrist.