ALZHEIMERS

What research has taught us about Alzheimer’s and Dementia Diseases

A.F. Jorm, Ph.D. National Health & Medical Research Council Social Psychiatry Research
Unit Australian National University

Five years ago I was in the situation that many of you are in today living with a dementing
relative, but having all too little knowledge of the condition he was suffering from. Since then,
my dementing relative has died and I have become a professional researcher on the topic of
dementia. I wish that 5 years ago I knew as much about dementia as I do now. My aim today
is to provide answers to some of the questions you may have as care-givers. I will pose these
questions one by one and try to give an answer in the light of current research knowledge.

What is Alzheimer's Disease?

Alzheimer's Disease is a disorder affecting the brain which causes severe deterioration in
memory and self-care skills and which can cause distressing changes in personality. In the
early stages of the disorder the changes may be subtle. Often the first changes are in the
area of memory, with particular difficulty in remembering new things. In some cases,
personality changes are the first problem noticed. Sufferers may be suspicious, irritable,
changeable in mood, stubborn, impatient or easily upset. In the early stage, care-givers will
not be aware that brain changes are occurring to produce these effects and the dementing
person may be seen as deliberately willful or difficult. As the disorder progresses, all aspects
of intelligence are affected and the former personality is lost. Eventually, the sufferer may be
bedridden, incontinent, and unable to communicate in any meaningful way. Death usually
occurs sometime after through some other medical condition such as an infection, but the
underlying cause of death is Alzheimer's
Disease.

Alzheimer's Disease has been known about since early this century, but until a few years ago
it was seldom heard about. The reason for this change in awareness is curious. When
Alzheimer's Disease was first described by the German physician Alois Alzheimer in 1907, it
was in a 51 year old woman. Other early cases were also described in people under the age
of 65. It therefore came to be believed that Alzheimer's Disease occurred only in people
under the age of 65 and, because Alzheimer's Disease is rare in middle-aged people, it was
believed to be a quite rare neurological disorder. At this time, Alzheimer's Disease was
distinguished from the common "senile dementia" which affected elderly people. Many
physicians believed (and some still do!) that senile dementia is caused by blocked arteries,
with the brain's blood supply becoming slowly strangled.

This distinction between Alzheimer's Disease (occurring under age 65) and senile dementia
(occurring over age 65) persisted until fairly recent times. It was only in the late 1960s and
early 1970s that researchers studying the brains of people dying from senile dementia found
that most of them had the brain changes of Alzheimer's Disease. It then became common to
say that these people suffered from "senile dementia of the Alzheimer type". More recently,
the term "Alzheimer Disease" has been extended to cover elderly cases as well as the
middle-aged ones. Research on the subject has thus led to a revolution in thinking, where
Alzheimer's Disease has been transformed from a rare neurological disorder affecting the
middle-aged to one of the most common disorders of aging. This broadening of the concept
of Alzheimer's Disease may now be going too far. In the U.S. it has become fashionable to
refer to all elderly dementing people as Alzheimer's sufferers. Although Alzheimer's Disease
is the major cause of dementia in the elderly, it is not the only cause, so where the diagnosis
is uncertain we should refer to them simply as "demented" or "dementing".

What Happens to the Brain in Alzheimer's Disease?

Several different brain changes occur in Alzheimer's disease. Two of the principal changes
were first described by Alois Alzheimer, after whom the disorder is named. These changes
are the "senile plaques" and "neurofibrillary tangles".

Plaques and Tangles

Plaques and tangles can be observed in the brain of an Alzheimer's sufferer under a
microscope at autopsy. Senile plaques occur outside the nerve cells of the brain. In a senile
plaque the nerve cells in a small region of the brain begin to degenerate and a substance
called "amyloid" accumulates in the center of this region of degeneration. Amyloid is a protein
that has no normal role in the body and no one knows for sure why it forms. Senile plaques
also contain quite a lot of aluminum and silicon, which some researchers think is an important
clue to the causes of the disease. I will say more about this later.

Neurofibrillary tangles occur inside the nerve cells of the brain. They are tangles of fibers
which probably disrupt the normal functioning of the nerve cell. Again, nobody is sure why
they form.

Plaques and tangles occur in normal aging as well as in Alzheimer's Disease. Most elderly
people will have some plaques and tangles in their brain. However, in Alzheimer's Disease
these changes become much more frequent. The severity of the mental changes in
Alzheimer's Disease is closely related to the number of plaques and tangles in the sufferer's
brain.

Although one might expect that plaques and tangles occur evenly throughout the brain in
Alzheimer's Disease, this is not the case. Certain areas are greatly affected and others
largely spared. In the early stage of the disorder, the areas of the brain controlling learning
and memory are most affected, explaining the difficulty in acquiring new information, which is
so characteristic of Alzheimer's Disease. Later, areas associated with language, orientation in
space and forward planning become affected. Least affected are the areas of the brain
concerned with sensation and movement.

Chemical Messengers
In the last 15 years, other important brain changes have been discovered. These involve
"neurotransmitters" which are chemicals used by the brain to send messages from one nerve
cell to another. There are many different types of chemical messengers in the brain and each
nerve cell has one of these types for its communication with other nerve cells. One of these
chemical messengers is acetylcholine and it has been found to be severely lacking in the
brains of Alzheimer's Disease sufferers. The nerve cells which are well known, it is
impossible at present to observe these while a person is still alive. It is only after death, at
autopsy, that plaques and tangles can be studied. For this reason, a postmortem diagnosis is
necessary if you want to know for sure whether or not your relative is suffering from
Alzheimer's Disease.
What Causes Alzheimer's Disease?
We do not know what causes Alzheimer's Disease, but there are three plausible theories: the
genetic theory, the toxic exposure theory, and the infectious agent theory.

1. Genetic Theory
Genetic factors seem to be quite important in Alzheimer's Disease, particularly for early-onset
cases. A genetic theory of Alzheimer's Disease accounts for the observations that sufferers
tend to have a family history of Alzheimer's Disease, or a family history of Down's syndrome,
and an excess of the lunar loop fingerprint pattern. However, genetic factors cannot be the
whole story, as can be seen from studies of identical twins. Identical twins are genetically
identical, so if genetic factors were the whole cause of Alzheimer's Disease, both twins
should either be affected or both unaffected by Alzheimer's. However, many cases have been
found where one elderly twin is affected and the other is not. Such cases show that
environmental factors must play some role. We are currently investigating a number of such
twins in Australia to help discover what these environmental factors might be.

The genetic theory has recently received a considerable boost by the discovery that there is a
gene on chromosome 21 which produces the A4 (or beta) protein found in the core of senile
plaques.

This gene probably has some useful function in the body, but in old age it tends to go wrong
and result in senile plaques. This is almost certainly not the gene which causes Alzheimer's
Disease. There are likely to be other genes involved which could, for example, have an effect
on this particular gene and there may also be toxic chemicals which could affect the gene. In
other words, the discovery of this gene is but a link in the chain and not the ultimate cause.
Nevertheless, it is a tremendous breakthrough, and it is noteworthy that Australian
researchers were at the forefront of this work.

The middle-aged occurrence of Alzheimer changes in the brain in Down's syndrome has
been explained in terms of their having an extra copy of this gene. The extra gene leads the
body to produce the abnormal protein in larger quantities. Some researchers have recently
suggested that a similar mechanism might be responsible for Alzheimer's disease in normal
people. Rather than have a complete extra copy of chromosome 21 (as in Down's),
Alzheimer's sufferers may have an extra copy of a small part of this chromosome. This theory
is controversial, however, and we need to wait till the research is confirmed by others.

2. Toxic Exposure Theory

It is quite possible that a toxic chemical could play a role in producing some cases of
Alzheimer's disease. The disorder could be produced by killing off the nerve cells in certain
small regions of the brain which use the chemical messenger acetylcholine. If these nerve
cells were destroyed, the effects would spread to other areas of the brain important to
memory and problem solving.

The possibility that a toxic chemical could produce such an effect has become more plausible
following recent research on Parkinson's disease. In this research some young people were
found to develop Parkinson's disease and it was discovered that they had all used a synthetic
heroin which was contaminated by the chemical MPTP. The chemical was found to
selectively destroy nerve cells in quite a small area of the brain involving the chemical
messenger dopamine. Subsequently, MPTP was found in certain industrial processes where
it can be absorbed through the skin or by inhalation. Workers exposed even briefly to MPTP
have developed Parkinson's symptoms.

A toxic chemical has also turned out to be important to a type of neurological disorder
common on the Pacific island of Guam. This disorder involves elements of Alzheimer's
disease, Parkinson's disease and motor neuron disease. The cause of this disease has been
a mystery for years, but it has just been discovered this year that it is due to a seed used for
food by the natives of this island. The seeds contain a chemical that has toxic effects on
certain regions of the brain. The effects are not immediate, however. It often only shows in
old age. Some Guam natives who stopped eating the seed at age 20 still developed the
disease 30 years later.

It seems that loss of brain cells through the toxin becomes compounded by the steady loss of
cells with aging and eventually produces observable symptoms. Could a similar toxic
chemical be involved in Alzheimer's Disease? So far, none has been definitely found, but it
remains a distinct possibility. The substance that has received the most discussion as a
possible toxic cause of Alzheimer's Disease is aluminum. As mentioned earlier, aluminum is
found in large quantities inside the core of senile plaques. It is also present in nerve cells
containing neurofibrillary tangles. Furthermore, as far as we know, aluminum performs no
necessary function in the human body. To test the aluminum theory, researchers have
injected laboratory animals with aluminum.

These animals did produce a type of tangle in the brain in response to the aluminum, but the
tangles were different from those found in Alzheimer's Disease. Another piece of evidence
against the aluminum theory comes from kidney dialysis patients who can develop a type of
dementia believed to be caused by exposure to aluminum in the large quantities of water
used during dialysis. However, as with the animals, this dementia is different from
Alzheimer's Disease. Other researchers have looked for possible dietary sources of
aluminum. Aluminum cookware is an obvious source, but does not introduce much aluminum
into the diet because it is largely insoluble in water. An exception is where the water is acidic.
For example, if acidic food like lemon juice is boiled in aluminum cookware, much more
aluminum is dissolved in the food. In Europe, there has been some concern over this
phenomenon in the countries which have acid rain. With acid rain, much more aluminum is
dissolved from the ground and enters the water supply. Another potential source of aluminum
is antacids. Many (but not all) of these contain high levels of aluminum. Studies have been
carried out to discover whether Alzheimer's sufferers have taken more aluminum-containing
antacids than other elderly people, but the results have been negative.

I could summarize the aluminum story by saying that large quantities of aluminum are toxic to
the brain, but this does not produce Alzheimer's Disease. It seems more likely that the
accumulation of aluminum in the brains of Alzheimer's Disease sufferers is an effect of the
disorder rather than its cause. It may be that in Alzheimer's Disease damaged nerve cells are
more likely to accumulate aluminum. Because of this possibility, some authorities have
recommended that Alzheimer's Disease patients should avoid aluminum-contain antacids.

Despite the weight of evidence against aluminum as a culprit, there may well be unknown
toxic substances which produce the disorder. Some circumstantial evidence comes from
research showing possible regional differences in the occur