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Alzheimers disease
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Introduction

Alzheimer’s disease (AD) is the commonest form of dementia among older people. There are about 600,000 sufferers of AD in the UK and it is the fourth most common cause of death. It is named after Dr. Alois Alzheimer, a German doctor who observed abnormal clumps, now known as Amyloid plaques and bundles of tangled fibres, now known as Neurofibrillary tangles in the brain of a woman who had died of an unusual mental illness. These two pathological features are now considered to be diagnostic markers for AD. They are found in large numbers in parts of the brain that control thought, memory, and language, such as the cortex and hippocampus, where they are believed to be responsible for the death of nerve cells, hence its classification as a neurodegenerative disease. Other areas of the brain such as those important for controlling movement are less affected and, therefore, Alzheimer patients do not have difficulties in walking, at least in the early stages of disease. The death of nerve cells inevitably leads to a shrinkage of the affected parts of the brain.

Brain sections showing plaques (top left) amd tangles (top right). The bottom figure contrasts the appearance of a section of normal brain (bottom left) with that from an Alzheimer brain (bottom right)

As with many neurodegenerative diseases, there are sporadic and familial forms of the disease. The sporadic form is the form most commonly seen in the elderly and affects approximately 10% of those above the age of 60. The familial form has a much earlier onset and is more aggressive. It has an identical pathology to the sporadic form of the disease and can occur in individuals as young as 25 years old. Genetics research has linked the familial form to mutations in any of 3 genes for, amyloid precursor protein (APP), Presenilin 1 and Presenilin 2. Together, mutations in these three genes account for up to 50% of familial cases, suggesting the involvment of, as yet, unknown genes. Individuals with Down's syndrome, which is caused by the individual having 3 copies of chromosome 21 (trisomy 21), develop typical Alzheimer’s disease pathology and this is the same chromosome on which the APP gene resides.

The sporadic, late-onset form is now known to be genetically-linked, but in contrast to familial AD the genetic link is not strong. Genes increase risk of late onset AD but do not cause it. Only one such gene is known with any confidence APOE . However there are likely to be many other susceptibilty genes. The AlzGene database hosted at the Alzforum website is an excellent source of up to date information on genes assocaited with AD. It is important to identify the genes involved in the disease process because knowledge of the function of the normal and mutated genes will lead to a better understanding of the disease processes and will suggest possible therapies.

As well as genetic factors there are environmental susceptibility factors. Diabetes is one, head injury and vascular disease are likely to be others. Education may be protective.

The core of amyloid plaques contains several proteins, the principal one being a small peptide known as amyloid ß-peptide (Aß), which is cleaved from a larger molecule, APP by particular enzymes known as secretases. Therefore, abnormal metabolism of APP can lead to excessive production of Aß and this is believed to be a primary event that triggers Alzheimer’s disease, although the mechanism is not yet understood. Investigating how Aß is produced and how Aß leads to nerve cell death are important areas of research.

Neurofibrillary tangles are comprised of bundles of filaments twisted about each other in pairs (paired helical filaments or PHF). PHF are composed of a protein called tau, which is a normal protein present in all nerve cells and functions to stablise normal fibrous structures known as microtubules.

Links

Alzheimer's Society

Alzheimer Research Forum

CNR Newsletter (formerly Alzheimers disease newsletter

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