Alzheimer's disease: when the mind goes astray

Issue 16, December 2005






Alzheimer’s disease: when the mind goes astray



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Alzheimer’s disease (AD) is the most common mental disorder amongst elderly people, and one that
continues to puzzle the scientific community. And for good reason: its cause is still unknown. Though a
number of symptoms can be alleviated, the disease still cannot be checked in its course. However, new
therapies may be developed in the near future. Various drugs now available appear to focus on one
source only: proteins. The amyloid-β protein is foremost yet it is far from the only one responsible for
the fatal outcome of AD.


18 million people are afflicted with some kind of
Personality breakdown
dementia
worldwide.
The
World
Health
Organization (WHO) defines such pathologies as a
There are two forms of AD. The most common
gradual decline of memory, reasoning power and
form affects people, at random, over the age of
personality. Several types of mental disorder –
70. The second form is hereditary and far more
referred to as senile insanity – develop at an
rare, representing barely 5% of all AD patients. It
advanced age. More than half the cases are caused
is handed down through generations of one family
by AD. In Switzerland alone, 90’000 patients
and is therefore known as the “family” form of the
suffer from a form of dementia. In Europe, 5% of
disease. It can develop as early as the age of 30
the population between the age of 70 and 74 are
but most cases arise around the age of 40. Very
at risk; for those over 85, the risk is 20%. In the
often, and especially in the event of non-
US, about 5% of the population aged between 65
hereditary AD, the illness is difficult not only to
and 74 develop AD, and about 1 person in 2 are
diagnose with precision but also to know when it
afflicted when over 85. Unfortunately, this is only
begins since early symptoms are so similar to the
the beginning. According to experts, by 2025
first signs of the normal ageing process of the
some 34 million people will have succumbed to AD
brain.
or some other mental disturbance. Such an

estimate is directly linked to another observation,
It all starts with small failings of the memory
every bit as breathtaking: in our wealthy part of
such as mild forgetfulness that can be
the world, the population is inexorably growing
bothersome in every day living, or words that will
older. According to the United Nations Population
not come to mind. Recent events have no hold on
Fund, this is a trend which will spread throughout
the memory. Answers to questions such as “What
the world, and by 2050 the proportion of people
did you have for supper last night?” remain vague.
over the age of 65 will have doubled.
On the other hand, memories of old are preserved

far longer.

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Memory, however, is not the only cognitive
generation to generation and the carrier of a
faculty1 to be affected. Concentration and
mutation in any one of these three genes will
attentiveness diminish gradually and it becomes
unfortunately
succumb
to
the
disease.
more and more difficult to follow a conversation
Consequently, it was essential to investigate
with more than one person. Language is slowly
further to understand the role of these proteins
impoverished. Additional disorders are the
in the evolution of AD.
inability to reflect in a coordinate manner, to

make judgments or even to orientate oneself in

space or time. Little by little, patients lose their
capacity to recognize objects or even familiar
faces. Progressively, patients lose their self-
sufficiency to such an extent, that simple actions
such as lighting a candle, eating or dressing
become impossible.

Patients also present a series of symptoms that
can be very difficult to put up with for those
living with them. At the outbreak of the illness,
they frequently become listless, demonstrating a
lack of interest, impassiveness and loss of
initiative. They become unsociable, often irritable,
anxious, depressed or restless; they sometimes
suffer from hallucinations and, in the end, their
behavior and personality are deeply affected. The

illness follows its course for a period of 8 to 12
Fig.1 Aloïs Alzheimer (1864-1915).
years. Currently, there is no curative therapy and
patients usually succumb to complications such as
undernourishment or thrombosis due to lack of
Spotlight on the platelets
exercise.
The amyloid protein and presenilins 1 and 2 play
a central part in the appearance of the senile
One disease, thousands of proteins
plaques. This lesion, typical of all types of AD, is
the result of the excessive accumulation of a key
It was the autopsy of a female patient in 1906,
element between cells: the β-amyloid fragment
known as August D., which brought to light this
(βA). βA is the truncated form of the amyloid
devastating illness. Aloïs Alzheimer, a German
protein. The latter, whose role is not yet well
neuropsychiatrist who treated her from 1901 to
defined, is found in various cells of our organism
1906, was the first to record the clinical
and especially in the membrane of neurons.
descriptions of this mental disorder which was to

take his name. On her death, Aloïs Alzheimer
How then is the βA fragment released into the
examined his patient’s brain. He noted an atrophy
brain? The amyloid protein is systematically split
which later was recognized as being a large
into several fragments, each of which seems to
number of destroyed nerve cells and he identified
offer some kind of protection to the neurons. This
the two lesions that are characteristic of what
splitting-up of the protein is controlled by the
was to be known as AD: senile plaques and
presinilins – amongst others. One of these amyloid
neurofibrillar degeneration (ND). Senile plaques
fragments, however, is toxic and can change its
take on the appearance of flat pastilles of
shape into a folded structure termed a “β sheet”,
proteins aggregated between the brain cells
thus becoming a β-amyloid. This insoluble and
whereas ND resembles strings of proteins within
“indestructible” fragment causes aggregates to
the neurons themselves.
form and which become the core of the senile

plaques.
These lesions are brought about by the action of

many proteins, three of which drew the attention
The deposits of β-amyloid seem in many ways to
of scientists after discovering hereditary cases of
be detrimental to the neurons and there can be no
AD: the amyloid protein and presenilins 1 and 2.
doubt that they gradually threaten their very
Genes containing the “recipe” for these proteins
existence. The brain then retaliates with the help
may present irregularities, also called mutations.
of our immune system, which delegates cells to
These irregularities are then transmitted from
the plaques seemingly to destroy the β-amyloid
fragments. Only these same cells help produce

free radicals that are detrimental to the neurons’
1 The process by which we acquire, organize and use
survival, so they only add to the toxic effect of
information and knowledge constitutes our cognitive
the plaques.
faculties.

2

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Strings of proteins
The loss of neurons in AD is probably mainly due
wrong if the tau protein becomes defective. It
to ND. Unlike the senile plaques which operate on
loses its affinity for the microtubules, which then
the surface of the neurons, ND operates inside
disintegrate. Consequently, the cell is deformed.
them. The tau protein is at the root of these
Moreover, the irregular tau proteins cling
internal disruptions. Tau protein’s customary role
together forming the strings which are so typical
is closely associated with a group of protein
of this kind of lesion. And that is not all. The
cylinders, known as mircrotubules, which it helps
disintegration of the microtubules spells the loss
to assemble. The specific architecture of these
of transport routes towards the cellular
microtubules gives the cell its shape, much in the
prolongations of the neurons, i.e. the axon and the
way that bones shape a body. Microtubules also
dendrites, which are at the heart of neuron
serve as a means of transport for nutrients and
transmission. As a result, the neurons function
other molecules inside the cell. However, for a
badly and finally disappear.
reason which remains unclear, everything goes



NORMAL
ALZHEIMER


Courtesy of Alzheimer's Disease Research, a program of
The American Health Assistance Foundation, http://www.ahaf.org/alzdis/about/adabout.htm
Fig.2 Lesions caused by AD. Neurofibrillar degeneration is characterized by “strings” of tau proteins inside
the neurons, and the senile plaques by β-amyloid deposits which appear as flat “pastilles” situated in between
the cells.


The memory network
The glutamatergic and the cholinergic neurons
In the cortex and the hippocampus, different
are particularly weakened in the lesions caused by
zones related to the processes of learning and
AD. Glutamate and acetylcholine, which give their
memory – both of which are targets of AD –
name to these neurons, are small molecules
harbor cholinergic and glutamatergic neurons. It
essential
to
neuron
communication:
the
seems that the stuff of memory is elaborated at
neurotransmitters. Information is transferred
the center of the neuronal networks. Like clay,
from one neuron to another across structures
these networks are malleable and adapt, so as to
known as synapses. A neuron sends a nerve impulse
be able to keep an imprint of the information we
along its axon. Once the impulse has reached the
receive. How? The synapses are modified and, as a
synapse, neurotransmitters are released, which in
result, the transfer of the message via the
turn will transfer the message to the neighboring
neurotransmitters is more effective. This is what
neuron. The latter traps the neurotransmitters
is called synaptic plasticity. It is thought that the
thanks to a number of receptors on its surface.
βA fragment obstructs this elegant mechanism. A
The nerve impulse is then propagated along this
recent study has indeed revealed that the
second neuron to the next synapse. And so on.
fragment diminishes the number of glutamate type
Furthermore, one neuron is connected not to one
receptors on the neurons’ surface, thus impairing
but to many neurons, and together they form
the quality of transmission.
several networks.

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the brain, the entorhinal cortex and the
hippocampus, where new memories are stored. As
mentioned above, the first symptoms of cognitive
disorder are memory problems. Progressively, the
lesions spread to the whole of the cortex: they
overrun the isocortex – the center where sensory
information is gathered – then reach the reception
areas of our five senses and the motor area where
orders are elaborated. With regard to the senile
plaques, they appear first in the isocortex and are
then associated with the ND.

It has long been thought that the senile plaques
are the first lesions to appear. This theory known
as the “amyloid cascade” holds that the
accumulation of βA fragments results in ND
degeneration and ultimately neuron death. Such a
hypothesis is supported by family cases of AD
where mutations in the amyloid protein or the
presenilins lead to an overproduction of βA.
Moreover, the gene of the amyloid/βA protein is

located on chromosome 21, which would explain
Fig.3 Structure of a synapse. The nerve impulse is
why a person with Down’s syndrome has three
conveyed from one neuron to another thanks to
copies of the gene. It is a fact that on
the release of neurotransmitters in the synaptic
approaching the age of 40, all patients with Down’s
cleft.
syndrome develop AD. This observation reinforces
the “amyloid cascade” theory.
The withering away of the glutamate and
acetylcholine neurons justifies the use of certain

drugs, of which the most current are Exelon,
Aricept and Reminil. Their object is to limit the
degradation of acetylcholine in the synaptic cleft
and so increase its lasting effect. In so doing,
they compensate the cholinergic deficiency and
improve memory performance. Yet another drug,
known as Memantine, acts on a certain type of
glutamatergic receptor. In AD, these receptors
can initiate a cascade of toxic intracellular
reactions, probably due to the βA fragment. By
temporarily blocking these receptors, Memantine
protects the neurons, and so reduces cognitive
disorders. This appears to contradict what has

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just been said, i.e. that fewer receptors affect
neuron transmission. Yet the beneficial effects
Fig.4 The cerebral regions affected by the
are there to be seen and the apparent
lesions. Neurofibrillar degeneration proceeds from
contradiction just goes to show how complex
the hippocampus to the cerebral cortex via the
cellular interactions are. Be that as it may, both
entorhinal cortex; the senile plaques affect the
therapies are symptomatic treatments that are
whole of the cerebral cortex.
far from perfect and whose effects are modest.
Since it is so difficult to give an early diagnosis of
Nonetheless, senile plaques are not confined to
AD, drugs are only prescribed at a relatively
AD alone. Indeed, they are present in the normal
advanced stage. Unfortunately, the illness
ageing process of the brain but in smaller
progresses relentlessly on its degenerative course
quantities – proof that the organism can tolerate
and the drugs offer no hope once the neurons are
amyloid deposits up to a certain degree, though to
destroyed.
which degree exactly is difficult to define.
Currently, there is strong disagreement on the
subject of the “amyloid cascade”, for two reasons
The egg or the chicken
in particular. Many investigations have underlined
the fact that, in most cases, ND occurs before
Neuronal dilapidation progresses from neuron to
any senile plaques appear. Moreover, the
neuron. As far as ND is concerned, lesions have
seriousness of clinical symptoms is measured
been shown to follow a defined course. They are
according to the evolution of ND; the sole
triggered off in the most vulnerable regions of
appearance of senile plaques is not a reliable guide.

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And which is first to strike? Amyloid β protein?
normal ageing process. Second, the cerebral
Or protein tau? There are various conflicting
lesions are microscopic and can only really be
theories. However, all strive to propose a scenario
detected via an autopsy. Third, no biological
that reunites both the formation of senile plaques
molecule can be reliably detected in the
and ND. Which comes first? And what influence
bloodstream or in the cerebrospinal fluid, i.e. the
does the one have on the other? Do they progress
fluid around the brain tissues and the spinal cord.
together? Is there a common denominator? From

what molecular process do these two lesions
What should one do when one’s memory fails
originate? So many questions for one problem
persistently and AD becomes a haunting
alone: the causes of this disease are still well
possibility? It is in fact relations who fear the
hidden.
oncoming of the disease, since those directly
concerned usually underestimate their cognitive
deficiencies. Frequently, they are advised to have
Avoiding the disease
“memory consultations”, where they are subjected
to a whole gamut of neuropsychological tests that
Genes whose mutations lead to early forms of
are supposed to determine the extent of their
AD have been discovered. Could that imply that
cognitive disorders. In an effort to fine-tune the
there are risk factors? Without doubt, age is the
diagnosis, MRI (Magnetic Resonance Imaging)
most important. Moreover, factors of genetic
analyses may be resorted to, where MRI reveals
predisposition have been identified, such as the
atrophied areas of the brain in the hippocampus,
apolipoprotein E (ApoE) gene, for instance. ApoE is
for instance. A brain SPECT (Single Photon
well known for its role as a carrier of cholesterol
Emission Computed Tomography) can also be
in the bloodstream. In humans, there are three
performed on a patient and is a way of measuring
types of ApoE2. Although not a determining
the cerebral blood flow which testifies to the
factor, ApoE4 considerably increases the chances
brain’s activity. Such techniques have raised great
of the illness developing. 30% to 60% of AD
hopes in giving an early diagnosis of AD.
patients are estimated to be carriers. How does

ApoE4 act? It could be one of the causes of the
It is common practice to prescribe Memantine
amyloid deposits, thus contributing to the growth
and drugs that inhibit the deterioration of
of the senile plaques.
acetylcholine, though they only serve to delay

temporarily
the
degeneration
of
neurons.
Environmental factors such as hypertension,
Currently, many believe that vaccination might be
smoking, hypercholesterolemy, a diet low in
the answer. Why? The purpose of vaccines is to
antioxidants or a severe head injury can also bring
stimulate the production of antibodies against
about AD. Several studies also suggest that a poor
specific proteins and, in order to do so, all you
level of education in childhood could be a
need to do is inject the said proteins into the
contributing factor. As for estrogens, they seem
organism. The idea would be to “clear away” the
to have a beneficial effect on the brain;
senile plaques by stimulating the production of
consequently, menopause could be a risk factor
antibodies against the ßA fragments. There have
and women may well be more predisposed to AD
been tentative clinical trials but they have had to
than men.
be discontinued due to some cases of encephalitis.
But in 2006 and on their own initiative, Roche will
carry out a new series of trials, in which they will
Towards a cure?
inject anti-βA antibodies directly to AD patients
Alzheimer’s disease is very difficult to diagnose,
so as to prevent an inflammatory reaction.
for three reasons in particular. First, the initial
Furthermore, other clinical trials were initiated
signs of AD coincide exactly with those of the
with Alzhemed (a drug developed by Neurochem)
in Switzerland last autumn, which should act on

the senile plaques before they actually appear by
2 A gene can exist in a number of different forms. As a
directly blocking the aggregation of ßA fragments.
consequence, so can proteins. And such an event is known

as polymorphism. Proteins are made up of a chain of
There are many therapeutic trails based on
molecules – or amino acids – selected from a choice of 20
various strategies which all aim to check the
amino acids. A protein's sequence determines the structure
evolution of AD lesions…and as much hope for
and function of the protein, in the same way as a sequence
patients struck with Alzheimer’s disease for a
of notes in a music score determines a tune.
cure that will give them complete recovery of
However, even though we all sport the same kind of proteins,
which ensure the same kind of functions, there are details
their identity.
which vary from one person to another. For instance, a

protein can have the same function though it may differ by
∗
one amino acid in two different people. Much in the way that
Séverine Altairac
a varying note in a symphony is not a false note but just the

composer's fantasy. Such a note is called a polymorphism in
∗Translation: Geneviève Baillie
biology. cf. “In vino veritas”

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For further information

On the Internet:
• Alzheimer Society of Canada :
http://www.alzheimer.ca/english/index.php
• On the memory: "PP1: Tracking down the protein of Forgetfulness" :
http://www.expasy.org/prolune/pdf/prolune009_en.pdf
• Unité INSERM "Vieillissement cérébral et dégénérescence neuronale" in Lille :
http://www.alzheimer-adna.com/Alz_/Alzheimer.sommaire.html

A little more advanced (in French):
• Dossier Pour la Science on the memory and Alzheimer’s disease : "La mémoire – Le jardin de la pensée",
number 31, april 2001
• Book : Schenk, Leuba and Büla, "Du vieillissement cérébral à la maladie d’Alzheimer", november 2004,
editions De Boeck Université, ISBN : 2-8041-4595-6


Illustrations:
• Heading illustration (Sleep by Salvador Dali), Source:
http://www.lecerveau.mcgill.ca/flash/i/i_07/i_07_p/i_07_p_oub/i_07_p_oub.htm
• Fig.1, Source: http://en.wikipedia.org/wiki/Image:Alzheimer01.jpg
• Fig.3, Adaptation :
http://www.drogues.gouv.fr/fr/savoir_plus/livrets/action_drogues/action_page2.html
• Fig.4, Adaptation :
http://www.lecerveau.mcgill.ca/flash/a/a_07/a_07_cr/a_07_cr_tra/a_07_cr_tra.htm


At UniProtKB/Swiss-Prot:
• Amyloid beta A4 protein [Precursor], Homo sapiens (human): P05067
• Presenilin-1, Homo sapiens (human): P49768
• Microtubule-associated protein tau, Homo sapiens (human): P10636
• Apolipoprotein E [Precursor], Homo sapiens (human): P02649






















Date of publication: December 22, 2005
Date of translation: March 7, 2006



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