Alzheimer’s Disease and the hope of a therapy

This essay was written by Nigel Birdsall and was first published in the 1997 Mill Hill Essays.

Far Longer than Forever

Far longer than forever,
Cross the distance we’re apart,
Feelings of warmth and comfort
Etched your image in my heart.

Far longer than forever,
Beyond the journey’s end,
I’ll think of you with fondness,
My special caring friend.

Nothing’s a greater challenge
Than the present endeavor,
To remember you past memory
Far longer than forever….

Tim Brennan 1997

This poem was written by a person with Alzheimer’s Disease. This disease is a brain disorder which is characterised by its insidious onset, a progressive and irreversible loss of memory which, together with increasing confusion, personality changes and dementia, leads eventually to a childlike helplessness. The author is at the point of progression of the disease where he is still very much aware of himself and his failing abilities. He writes in a note accompanying the poem:

“I can no longer perform math properly or handwrite or tie my shoes. Getting dressed is tiring. At times, it is difficult to think and then speak properly. Alzheimer’s Disease is a subtraction process. We may forget your name and who we are and what we are doing. Yet, we remember love. Love seems to be the most basic and primary essential.”

It is important to realise that, despite the mental problems, an Alzheimer patient can still retain emotions. A recent quotation from Ronald Reagan’s son also illustrates this point:

“These days because of the Alzheimer’s, he doesn’t always know my name when I come to visit him, but he knows who I am. I’m the person who gives him a hug”

Alzheimer’s sufferers can also retain some surprisingly high level functions. For example, my wife’s mother could still readily play the piano and accompany her young grandchildren’s singing, despite having Alzheimer’s Disease of such severity that she could not string together two intelligible words.

Dementia in general is associated with an intellectual deterioration in an adult which is severe enough to interfere with both their work and their social skills. The changes in mental processes not only involve disturbances in memory but also in perception, the ability to learn, to solve problems and to think abstractly and make judgements. Senile dementia is simply dementia in the aging adult. This may be a consequence of Alzheimer’s Disease but there may be other explanations, for example the effects of several small strokes.

The duration of the disease is long, often five to ten years from diagnosis, and sufferers may spend the last five or more of those years under close care at home or in a nursing home. Individuals who are well looked after may survive physically even if they have a total loss of mental processes. Death often results from other diseases – for example, heart disease, cancer, stroke or pneumonia. The decrease in life expectancy associated with Alzheimer’s Disease makes it the fourth or fifth leading cause of death.

Alzheimer’s Disease predominantly affects older people; it is estimated that it afflicts one in twenty of the population over sixty-five. The incidence rises with advancing age such that about one in five of people over seventy-five and almost half of those over eighty-five are affected to some extent. For unknown reasons women appear to be affected more than men. This is not due to their increased life expectancy. No statistics however can describe the gradual inevitable decline endured by the patient nor the stress and suffering experienced by the family and the carers.

Is it Alzheimer’s or is it something else? As people grow older, their memory becomes less good and they may worry that they have Alzheimer’s Disease. In many instances, this may just be ‘benign forgetfulness’ or age-associated memory impairment. Older people also learn less rapidly than younger people. If a young and an old person are both told the same story, immediately afterwards, the younger person will recall more details. However, after half an hour, the younger person and a healthy older person will both be able to recall most of the facts that they had learned originally. In other words older people learn more slowly but do not forget that much more. Alzheimer’s Disease limits the amount of information one can learn but, even more so, it drastically affects the information that can be recalled even after a short period of time. Depression in the elderly can also give rise to memory problems and some of the symptoms of Alzheimer’s Disease; these symptoms however are often abolished by the use of antidepressants.

The diagnosis of Alzheimer’s Disease in a living person is not easy. It relies on the detailed observation and measurement over time of the progressive and irreversible loss of mental and physical faculties. It is estimated that a positive diagnosis of Alzheimer’s Disease is accurate in nine out of ten cases but up to four out of ten Alzheimer cases are not recognised because the clinical diagnosis is confounded by the presence of the frequent additional neurological or other problems found in the elderly. This means that there is a relatively low probability of a misdiagnosis of Alzheimer’s Disease but many cases of Alzheimer’s are missed.

The definitive diagnosis of Alzheimer’s Disease is by an examination of the brain after death. In 1907 a German neurologist, Alois Alzheimer, after whom the disease was named, looked under the microscope at the nerve cells of the brain of a fifty-six year old woman who had died after several years of progressive mental decline. He discovered tangles of fibres, likened to knotted ropes, which were not found in normal nerve cells. In addition, clusters of nerves in the brain seemed to be dying and to be surrounded by piles of debris forming characteristic “plaques”.

Alzheimer originally thought that the presence of plaques and tangles in the brain were only characteristic of a dementia that starts relatively early in life. However it has been found subsequently that high levels of these markers are present in Alzheimer’s Disease of all ages and the severity of the dementia has been correlated with the density of the tangles and plaques. It is also now known that plaques and tangles are found in the normal aged brain but at much lower levels than found in an Alzheimer’s brain of the same age. As found in Alzheimer’s patients, these levels increase in the normal aging brain. It is therefore possible for, say, a normal eighty-five year old to have a level of plaques and tangles which, in a fifty-five year old, would be diagnostic of Alzheimer’s Disease. It seems that the Alzheimer’s pathology is not just the simple consequence of an acceleration of a normal aging process.

Plaques and tangles are also found in the brains of people with Down’s Syndrome who live to be forty or fifty years old. People with this syndrome have a characteristic appearance and a special form of mental retardation and are born with three and not the normal two copies of chromosome twenty-one in their cells. In times past they only used to live to age thirty or so, but nowadays many live longer and almost all of this group develop Alzheimer’s Disease.

Boxers can suffer irreversible brain damage due to blows to the head. At least one in ten – some studies claim over half – eventually develop the ‘punch-drunk syndrome’, a dementia which is associated with slurred speech, poor memory and coordination, and the characteristic plaques and tangles of Alzheimer’s Disease in their brains. Last year it was also reported that autopsies of two young boxers who died in the ring revealed tangles, but not plaques, in their brains. Other forms of head injury have been shown to lead to plaque formation within days. It is not known whether the effects of such traumas would have led to Alzheimer’s Disease. It is evident however that, in some instances, there can be a rapid development of plaques and tangles in the brain, in contrast to the very slow buildup in Alzheimer’s Disease.

What are the risk factors for Alzheimer’s Disease? Down’s Syndrome has been mentioned but the main risk factor, over which we have no control, is age; the older we get, the greater the chance of Alzheimer’s but it should be emphasised that this disease is not inevitable in old age. A second risk factor is being female, although this factor could well become less important in the future with the increasing use of post-menopausal estrogen replacement therapy since there is some evidence that estrogen may delay the onset of the disease.

Genetic factors can also play a role. Having a close relative with Alzheimer’s Disease increases the risk. This is especially true for identical twins where the unaffected twin has an even chance of developing the disease. In the case of first degree relatives, that is parents, children or siblings, the risk is considerably reduced but nevertheless is present. One study has shown that a person aged eighty with no parent who had Alzheimer’s Disease has about a one in ten chance of being afflicted. This risk increased to one in three if one parent had the disease and to one in two if both were affected.

In addition to the Down’s Syndrome/chromosome twenty-one linkage, mutations on this chromosome can lead to an inherited form of Alzheimer’s Disease. Mutations in a gene called presenilin-1 on chromosome fourteen also appear to be very important in a rare hereditary form of early onset Alzheimer’s Disease.

In contrast, epidemiological studies have shown that Cherokee Indians may have a genetic resistance to the disease. Of more general relevance, several epidemiological comparison studies have shown that people with a history of smoking have a lower incidence of Alzheimer’s Disease than nonsmokers. These findings have led to speculation that smoking somehow protects against Alzheimer’s Disease. However the very high risk of cancer and heart disease associated with smoking means that it cannot be advocated as a means of preventing Alzheimer’s Disease and furthermore, smoking, as a means of potentially slowing down existing Alzheimer’s Disease, could be dangerous simply on the grounds of the potential fire hazard caused by the forgetfulness. It has also been observed that there is a lowered incidence of Alzheimer’s Disease in people with severe arthritis. This has been linked to the long term use of medicines called nonsteroidal anti-inflammatory drugs. Ibuprofen and possibly aspirin appear to be effective but these drugs can also have other side effects in long-term use.

There is also considerable evidence that the possession of a gene for a particular form of a protein called Apolipoprotein-E (ApoE) increases one’s risk of developing Alzheimer’s Disease late in life. This protein is involved in the metabolism of cholesterol and there can be three forms of ApoE, each coded by different genes known as E2, E3 and E4. Everyone has a combination of two of these genes. Having one E4 gene in combination with either E2 or E3 appears to double the risk of developing Alzheimer’s and if both ApoE genes are E4 the risk increases another four-fold. However, possessing two E4 genes only represents an increased risk and not inevitability of contracting the disease. Many people in their eighties who possess this gene combination show no signs of the disease. Although genetic testing for the ApoE forms is available now, it will only be of general value once drugs are developed which can slow down or prevent the onset and progression of Alzheimer’s Disease. Of possible relevance here is a report that ex-boxers who have the ‘punch-drunk syndrome’ tend to have one or two copies of the E4 gene. Should boxers be tested for the E4 gene and, if the test is positive, should they be discouraged from continuing to box?

The amount of aluminium in our food has been a controversial risk factor for Alzheimer’s Disease for a number of years and is still the subject of heated debate by scientists. People have thrown away their aluminium cooking pans and concern has been expressed about aluminium levels in drinking water. One of the intrinsic difficulties with this idea is that aluminium is the most abundant metal in the earth’s crust and so everybody is continually exposed to high levels of it. It has been calculated that the combined intake of aluminium from drinking water and the use of aluminium pans is only a very low percentage of the total daily intake from the diet. Furthermore, people taking certain antacids or pain relief remedies often ingest one to two grams of aluminium each day which is up to one hundred times the normal intake. Aluminium levels in the brain do increase with aging but there is no evidence of higher levels in the Alzheimer’s brain. There is evidence that aluminium is present in tangles but not plaques but it is not known whether aluminium causes the formation of tangles or that aluminium sticks to the tangles. Recent evidence suggests that the risk of Alzheimer’s Disease associated with intake of high levels of aluminium in drinking water is small.

Any treatment of Alzheimer’s Disease, be it preventative, palliative or curative, requires a molecular understanding of the disease, its causes and its progression and this has been an area of intense study for many years. One of the main areas of research involves an abundant protein present on the surface of cells in the brain called Amyloid precursor protein (APP). What APP does is not known. Normally, breakdown of this protein by an enzyme produces a smaller soluble protein which is harmless. However, abnormal breakdown by a different enzyme gives another protein, beta-amyloid, which is highly insoluble, forms aggregates and is the major protein present in plaques. Beta-amyloid damages and eventually destroys nerves and is considered by some to be a primary cause of the nerve loss found in the brain in Alzheimer’s Disease. Normally there appears to be a balance between the ‘good’ and ‘bad’ cleavage of APP. In Alzheimer’s Disease the ‘bad’ cleavage is favoured. Any way of tipping the balance towards the good cleavage may stop or reduce beta-amyloid production and thus the progression of the disease. As the ‘good’ and ‘bad’ cleavages are performed by different enzymes, the search is on to identify them and to make a drug which selectively blocks the action of the ‘bad’ enzyme.

Tangles consist of highly insoluble pairs of filaments which are wound round each other like a double-stranded rope. Each filament is made up of many molecules of a protein called tau. Tau is a normal constituent of cells in the nervous system but the tau protein found in tangles has been changed. The formation of tangles within a nerve cell disrupts its normal structure and is thought to lead to nerve death and a consequent disconnection between different parts of the brain, thereby leading to the loss of intellectual function. A drug which selectively prevents the formation of the changed form of tau or interferes with its aggregation could be useful in Alzheimer’s therapy.

Nobody yet knows what events trigger the degenerative mechanisms in Alzheimer’s Disease. However a number of interesting and thought-provoking linkages have emerged between the factors that are thought to be important. Firstly, ApolipoprotienE4 which was mentioned above as one of the genetic risks in Alzheimer’s Disease, appears to bind to both beta-amyloid and to tau in a different way to ApolipoproteinE3. Does ApolipoproteinE4 contribute to Alzheimer’s Disease by enhancing nerve degeneration by either of these routes? Secondly, the APP gene is located on chromosome twenty-one, the same chromosome of which people with Down’s Syndrome have three copies. Does this mean that extra production of APP, and thus beta-amyloid, leads to Alzheimer’s Disease? The linkage between APP and Alzheimer’s Disease is strengthened by the findings that some of the small number of families in which Alzheimer’s Disease is inherited have mutations in their APP genes or in their presenilin genes. Both mutations increase the ‘bad’ processing of APP to beta-amyloid.

In the last few weeks another linkage has emerged. This involves a protein called a transforming growth factor which is produced in the brain in response to the inflammation associated with brain injury, or to diseases like Alzheimer’s Disease and Down’s Syndrome that result in the death of nerves. The growth factor has a central role in governing how the brain responds to injury. It is present in higher levels in Alzheimer’s brains than in normal brains and this may be a trigger that leads to the beginning of plaque formation.

One consequence of the destruction of certain nerves in the brain in Alzheimer’s Disease is that there is a loss of molecules from those nerves that are required for their activity. These molecules, called neurotransmitters, normally act as chemical intermediaries of information transfer between nerves. As all forms of brain function involve information transfer between nerve cells, any loss of such molecules and nerves means a loss of one or more aspects of mental function. These losses are the reason for the symptoms of Alzheimer’s Disease. In the early stages of Alzheimer’s Disease one notable feature is that there is a lowered level of one neurotransmitter called acetylcholine, in those parts of the brain which are important for the formation and recall of memories. At later stages of the disease there is a more generalised loss of other neurotransmitters. Acetylcholine is an interesting molecule in that it also can stimulate the ‘good’ pathway for the cleavage of APP. Abnormally low levels of acetylcholine in the brain may therefore contribute to both increased plaque formation and to the memory problems in the early stages of Alzheimer’s. If the actions of acetylcholine could somehow be brought back to the normal level, then maybe the progression of the disease could be slowed down or even stopped.

One possible treatment is the use of drugs which block the action of the enzyme responsible for the destruction of acetylcholine in the brain and therefore allows the acetylcholine levels to build up to the normal value. One such drug is now available for the treatment of Alzheimer’s Disease in the United Kingdom. These drugs appear to produce a modest slowing of the decline in a particular group of Alzheimer’s patients. It is disappointing that these drugs do not have more dramatic effects, but a treatment that produces any benefit in a previously untreatable disease should be viewed as a significant advance. No magical cure is in sight, certainly nothing which will reverse the nerve damage in the brain. Great efforts are being made to try and understand the causes of Alzheimer’s Disease and how it might be treated, prevented and even cured in its early stages. We still do not know the fundamental cause of the disease. It is a jigsaw puzzle with no picture on the box – we have only a few pieces, some of them are now being joined together although we can not be sure that they have been joined correctly. Many pieces are missing or are turned upside down. We dream of the picture …..

The Vault

Your mind is locked up in the Alzheimer’s vault.
Oh, to have the perfect combination,
To hear the massive door of your brain click open,
Watch you leap out, and, eyes shining, run to us,
Knowing us, knowing all you ever knew.

Janet E. Hildebrand 1995

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