Alzheimer's disease is a distressing condition that affects 1% of the population over the age of 60. The condition causes dementia, which describes a group of symptoms caused by disease of the brain.
Dementia
Degeneration of the nerve cells (neurons) in areas of the brain, whether caused by lack of oxygen or unnecessary metabolites, leads to loss of function in that area.
Depending on the region affected, the symptoms can range from confusuion and mood swings to loss of memory, concentration and ability to communicate.
Causes of dementia include vascular disorders such as stroke, protein bundles called Lewy bodies forming within the neurons, alcohol abuse and infectious diseases such as CJD. The leading cause of dementia however, accounting for up to 70% of all cases, is Alzheimers disease.
The Pathophysiology of Alzheimers disease
Although the pathophysiology is not fully understood, neurologists believe that the disease is due to degeneration of neurons in the cerebral cortex and associated areas of the brain. The cerebral cortex is the whitish folded surface of the brain responsible for higher functions such as sensation and movement.
The loss of many nerve fibres from within this area causes the brain to appear smaller and with deeper folds.
The hippocampus, the key area of the cerebral cortex involved in memory formation, is thought to be worst affected by Alzheimers disease.
What Causes Alzheimers disease?
The neuron degeneration that occurs in Alzheimer's is caused by two main characteristic developments within the brain:
Beta-amyloid Plaques
Also known as senile plaques, beta-amyloid plaques are formed from a sticky substance called beta-amyloid peptide, produced in the brain by the cleavage of Amyloid Precursor Protein (APP).
Beta-amyloid peptide is harmless in the brain at low amounts and when in its diffuse form. When its levels become higher, it may form plaques within the brain, which will eventually trigger an immune reaction. The resulting inflammatory response involves the release of free radicals, which cause brain-cell death.
Normally present in neural membranes, APP is thought to have a role in stabilising contact between synapses, the junctions between nerve cells. Some people produce too much APP and are therefore prone to excessive amounts of beta-amyloid peptide.
People with Downs Syndrome, for example, have 3 copies of chromosome 23 instead of 2, and it is here that the gene for APP is found, so they tend to produce too much APP and are usually victims of the disease by the age of forty.
In other cases of Alzheimers, beta-amyloid peptide is produced in normal amounts but is transported differently. On chromosome 19 we all have a gene for Apolipoprotein E (ApoE), of which there are various forms. People with type 4 (ApoE4) on both copies of chromosome 19 are 8 times more likely to develop AD than those with type 2 or type 3. This is because ApoE4 protein binds beta-amyloid peptide and promotes its aggregation, leading to the formation of senile plaques much more readily than either of the other two forms.
Neurofibrillary Tangles
Nerve cells communicate across synaptic junctions with each other by secreting substances called neurotransmitters, which are transported out of the cell through tiny channels known as microtubules.
The assembly and stability of these tubules are dependent on various proteins, the most important of these being tau protein. Activation of proteins in biological systems is achieved via a process called phosphorylation. Abnormal phosphorylation of tau protein leads to the formation of abnormal filaments in place of microtubules, thus the neuron is unable to transport its neurotransmitter and so communication between membranes breaks down.
Age-related genetic mutations account for less than 5% of all cases. In most circumstances, it is simply the predetermined genetic make-up acquired by the process of ageing that leads to the scenarios described above.
Proteins are normally degraded and replenished regularly to ensure correct function, while long-lived insoluble proteins such as collagen, are not renewed in such a way and so are left open to a pathological process called glycation. This occurs when sugars in the system cross-link the protein molecules, causing them to become even more insoluble. In the case of collagen this causes tissues to become fibrous and less elastic with age. Glycation is the second most significant cause of aging, after free-radical production.
Proteins such as tau and aggregated beta-amyloid are prone to glycation, causing them to be more abundant in their insoluble forms, cumulatively leading to Alzheimers.
Secondary to this, glycated proteins also bind metals such as iron and copper more readily, causing the production of hydroxyl free radicals. Lipid peroxidation then follows, the resulting products of which affect the cellular transport of ions and glucose, ultimately causing degeneration of the neuron.
03/06/2009