Alzheimer's disease - The molecular origins of the disease are
coming to light, suggesting several novel therapies Vernon Ingram
1) The first description of Alzheimer's disease appeared about 100 years ago, published by the
neurologist Alois Alzheimer in Munich. He described the case of a 51-year-old woman with memory
deficits and striking behavioral changes. Her symptoms worsened quite rapidly, and as the condition
progressed she became unable to care for herself. After the woman's death five years later, an
autopsy revealed extensive pathological changes: The cortex was shrunken, and there were many
small, abnormal structures scattered throughout the brain. Using a silver tissue stain to visualize the
structures, Alzheimer noted a profusion of extracellular senile plaques (normally found in the elderly)
and never-before-seen tangles inside neurons. These tangles appeared to be made of long, knotted
filaments, or fibrils, under the microscope. On the basis of these novel fibrillar tangles, plus the
patient's age and the unusual number of senile plaques, Alzheimer distinguished this disease from
"normal" senile dementia, a more benign and gradual age-related loss of mental function. In fact, for a
long time Alzheimer's disease was referred to as pre-senile dementia, indicating that it occurred earlier
2) Alois Alzheimer noted that many of the characteristic changes in brain anatomy were concentrated
in the cortex. For reasons that are still incompletely understood, some brain regions (including frontal
cortex) are especially susceptible to the cellular trauma of Alzheimer's disease. This localized damage
leads to a stereotyped order of decline in specific brain functions. Smell is one of the first to disappear,
followed by memory, orientation and behavioral grooming, self-preservation functions. On the other
hand, locomotion stays intact, distinguishing the disease from Parkinson's disease.
3) What actually goes wrong in the brain of an Alzheimer's patient? There are some half-dozen
different genetic circumstances that can trigger the disease, and probably others that are currently
unknown. They all lead to the same molecular pathology—the formation of aggregates of a
"misfolded" fragment of a normal protein. This normal protein, the amyloid precursor protein or APP, is
embedded in the outer membrane of cells in a variety of tissues. In the course of its normal function,
APP is cut into segments, or peptides, at three specific sites targeted by α-, β-, and γ-secretase
enzymes, respectively. During the development of Alzheimer's disease, the APP protein is cut at the β
and γ sites, resulting in a fragment that folds itself into a sticky, self-aggregating shape. This peptide
can be from 39 to 43 amino acids long, owing to a peculiar variability in the β-secretase cleavage site.
Not all of the versions are produced in equal amounts—the so-called Aβ1-40 is most common—and
some forms are worse than others, with the most toxic peptide being Aβ1-42. This fragment includes
the first 42 amino acids after the β-secretase site and readily forms insoluble clumps in the brain.
These aggregates are toxic and lead aggressively to the dysfunction of nearby brain cells and their
consequent death and removal. Once these brain cells are gone, there is at present no way to replace
4) During much of the 20th century a diagnosis of Alzheimer's disease was difficult to confirm until the
patient's brain could be examined after death—a thoroughly unsatisfactory situation. During the
individual's lifetime the diagnosis was based on exclusion, since some other conditions produce
similar cognitive deficits. For example, certain types of memory loss and certain behavioral changes
can be caused by depression, medication side effects and vascular accident. The lack of rigor in
diagnosis had unfortunate consequences: False positive diagnoses led to needless anxiety, whereas
false negatives prevented suitable care and long-term planning.
5) Current diagnostic criteria rest on a carefully compiled behavioral assessment scale, sometimes
combined with one or more forms of noninvasive functional neuroimaging. The diagnostic scale uses
as many as a dozen different measurable cognitive parameters, all of which must show considerable
changes before a diagnosis is made. This scale is a highly accurate tool in the hands of a skilled
physician—even without imaging data, approximately 90 percent of diagnosed Alzheimer's sufferers
are confirmed at autopsy.
6) Two new methods that directly examine brain activity have become invaluable tools in documenting
the structural and functional changes associated with Alzheimer's disease. Magnetic resonance
imaging (MRI) provides a detailed three-dimensional depiction of brain topography that can reveal the
loss of brain tissue accompanying disease progression. The technique has become remarkably
sensitive, even detecting the loss of brain volume during early stages of the disease when mild
cognitive impairments might not warrant a behavioral diagnosis. Functional MRI (fMRI) and positron-
emission tomography (PET) are both widely used to resolve areas of activity in the living brain. During
the brain scans the subject performs a memory task. Differences between the images of Alzheimer's
subjects and scans of normal brain activity can be dramatic.
7) Early diagnosis using these tools is important now; it will be crucial once effective therapy is
available. Many of the disease symptoms are caused by the death of brain cells, and dead cells
cannot be revived. Emerging treatments promise a not-too-distant future in which therapy will need to
be applied before the patient becomes seriously demented. Eventually, science may perfect the use of
stem cells to replace the dead brain cells, and early diagnostic screening for the disease might include
8) The youngest cases of Alzheimer's disease are found among people with Down syndrome, which is
not usually an inherited condition. Down syndrome patients have an extra copy of chromosome 21, for
a total of three; this genetic cause for Down syndrome is described as trisomy 21. Because the gene
that codes for APP protein is on chromosome 21, Down syndrome individuals have more of the
amyloid protein, and neurotoxic accumulation of the Aβ1-42 fragment becomes noticeable much
earlier. Every person with Down syndrome has already started to develop the characteristic plaques
and tangles of Alzheimer's disease by age 40.
9) The familial form of the disease accounts for fewer than 10 percent of Alzheimer’s cases. This small
percentage represents several different genes, found in different families but sharing a common
inheritance pattern, each one causing Alzheimer's disease in that particular kindred. These individuals
have relatively early onset in the 50s and 60s, and their condition deteriorates rapidly.
10) A much larger number of people have an inherited susceptibility to the disease, but they
experience onset in their late 60s, 70s and 80s with slower progression. That leaves a sizeable
proportion of idiopathic cases—ones without an identified cause, genetic or otherwise. However,
every year more genetic risk factors are discovered, and it is possible that every case will eventually
be traced to some genetic susceptibility. The idea offers mixed hope, as sorting out the genetics will
not necessarily tell us how to intervene in the disease. For the present, only one risk factor is
completely reliable: advancing age.
11) Why is aging such an important risk factor? To date there are only a few speculations about the
mechanism of an old-age trigger for Alzheimer's disease. One of these models suggests that an age-
associated decrease in the all–important, energy–containing molecule adenosine triphosphate, or
ATP, is responsible. Neuronal ATP is reduced in the aging brain, and neurons need lots of it—more
than most other cells, even at rest. Without ATP, the cells may be unable to reestablish their
equilibrium and defend against the neurotoxic effects of the Alzheimer's peptide.
12) Senile plaques from postmortem Alzheimer's brains are largely composed of short amyloid
peptides, as shown in 1984 by George Glenner and his colleagues at the University of California, San
Diego. Identification of the amyloid peptide, originally described as "beta protein" because of its
adoption of a beta-sheet conformation, soon led to the cloning of the APP gene. The relationship of
toxic amyloid fragments to benign full-length APP points to an enduring question in the field: How is
the poisonous peptide produced?
13) In normal or young brains, the full-length membrane-spanning protein is broken down into
functional fragments, including a large cytoplasmic piece used to regulate important cell mechanisms.
But in Alzheimer's brains, degradation of APP takes a wrong turn. – GAP A - , the relative activities
of the three proteases, or protein-cutting enzymes, that cleave APP change dramatically. Dennis
Selkoe at Harvard's Brigham and Women's Hospital, – GAP B -, showed that two of them, the β- and
γ-secretases, become much more active, resulting in overproduction of the 42–amino acid peptide.
Meanwhile, the α-secretase, which acts at a location between them, becomes relatively inactive. This
is unfortunate, because cutting the precursor protein at the α site produces harmless fragments.
14) The newly cleaved Aβ1-42 peptide is immediately exported. This unique feature distinguishes
Alzheimer's disease from most other neurodegenerative diseases, which act inside cells. It also
simplifies potential therapies, since the helpful "drug"—an antibody, peptide or other molecule—does
not have to enter a cell, – GAP C -.
15) Once outside the cell, Aβ1-42 assumes a beta-sheet-containing, aggregate-prone conformation. In
cell culture, the aggregated peptides cause neurons to die, and the same is true when they are
injected into the mammalian brain. This cell death can occur by apoptosis (programmed cell death) or
by necrosis. The former involves cell shrinking, membrane destabilization, and DNA degradation
before garbage-eating macrophage cells clean up the remains. Necrosis, – GAP D - , is less tidy.
Here the cell swells and explodes, releasing a witches' brew of compounds that cause the
inflammation characteristic of Alzheimer's disease. The importance of blocking the products of
necrosis has been emphasized recently with the finding that some anti-inflammatory medications may
delay disease onset and progression.
16) Thirty years ago, studies of degeneration patterns in Alzheimer's disease identified substantial
decreases among groups of neurons in the basal forebrain. These cells all used the transmitter
acetylcholine, and their loss meant that less acetylcholine was being released at their former terminals
in the cortex. The finding was important because cholinergic neurons in the cortex are involved in
regulating attention, the first stage of learning and memory.
17) This knowledge led to the first (and only) Federal Drug Administration–approved drugs for
Alzheimer's disease treatment, marketed under the trade names Aricept, Cognex and Exelon. All three
work by prolonging the effects of individual acetylcholine-release events. They do this by inhibiting the
enzyme acetylcholinesterase, which normally breaks down the neurotransmitter in the space between
cells. This breakdown process goes on unabated even when there is too little acetylcholine being
released, – GAP E -. By preventing acetylcholine metabolism, the levels of free neurotransmitter can
be artificially raised. Unfortunately, clinical trials show that the improvement in memory is small and
transient, whereas the side effects can be troublesome. In Europe the compound memantine, an
inhibitor of a different (nonAMPA) glutamate-sensitive channel, is used for "age-related dementia" with
some reported benefits.
18) Since the overproduction of the noxious Aβ1-42 fragment is now considered the root cause of
Alzheimer's disease, the two enzymes that produce the peptide have become prime targets for
therapy. Another approach to interrupting the disease harnesses the patient's immune system to
identify and remove the toxic Aβ1-42 aggregates. In principle this can be done either by active or by
passive immunization. In the former case, the patient receives an injection or nasal-spray application
of the Aβ peptide, leading to an anti-amyloid immune response. Both injection and spray strategies are
being pursued, and clinical trials have begun. Passive immunization bypasses the beta amyloid
protein, using instead antiserum that has already been produced in response to beta amyloid. This is
also being pursued actively.
19) Part of the excitement about immunotherapy was based on successful animal studies, including
one using transgenic mice engineered to overexpress human APP sequence. As described by Dennis
Selkoe of Harvard and Dale Schenk with Elan Pharmaceuticals, the mice showed a strong immune
response to the Aβ peptide, leading to a substantial reduction in the accumulation of beta protein and
a partial elimination of memory deficits.
20) Such results held great promise for the future of this therapeutic approach. Unfortunately, the
anticipation has sharpened recent disappointment over the termination of a large, international clinical
trial. About five percent of 375 patients enrolled in the trial developed severe brain swelling after being
inoculated with the Aβ peptide. This inflammation could have been due to a mistake in exactly which
part of Aβ to use, or perhaps the peptide needed to be refined more cautiously, or the immunization
procedure itself may need to be altered. However, other trials using other protocols are proceeding,
and the results are eagerly awaited. Clinical trials of passive immunization have also begun, but the
study authors have not yet published results. Passive immunization requires a continuing regimen of
injections of the antiserum preparation, a feature that had been seen as a disadvantage but may yet
prove superior if it bypasses the complications of Aβ inoculation.
Making Aβ Peptides Nontoxic
21) A novel approach to Alzheimer's therapy is needed. One can envisage a drug that would eliminate
the neurotoxicity of the aggregated Aβ1-42 peptide itself. Such a drug would have to be given early in
order to "detoxify" the gradually accumulating aggregated Aβ peptide before any permanent damage
is done to neurons. After all, we do not yet know how to replace dead or dying neurons (although
replacement by stem cells might be possible eventually).
22) The approach taken in my laboratory is to present the aggregating Aβ1-42 peptide with a small
molecule that binds to the peptide and forces it to assume a nontoxic structure. My colleagues and I
have done this with 16 small peptides (5, 6 or 9 amino acids long), which we call "decoy peptides."
They are selected from large libraries of protein fragments by their ability to form a tight association
with tagged Aβ1-42. We have found that when presented to the Alzheimer's peptide during
aggregation, our decoy peptides completely eliminate the neurotoxic effects, and Aβ1-42 no longer
causes massive calcium influx into neuronal cells. We are very excited about these results, and
because the peptide binding is so specific, we anticipate a small chance of harmful side effects. These
peptides are good candidates for further development, and we have constructed them from d-amino
acids (the unnatural form of amino acids) to resist digestion in the body, but a big question remains:
Will they get from the gut to the brain? The answer remains to be seen (or engineered).
I. Decide whether the statements below are True (1) or False (2).
1. Alzheimer’s disease brings about characteristic changes in the brain anatomy.
2. All brain regions are equally susceptible to the cellular trauma of Alzheimer’s disease.
3. Unlike Parkinson’s disease, Alzheimer’s disease does affect the subject’s proper use his or
her lower limbs.
4. The genetics behind Alzheimer’s disease may still be unclear. However, the molecular
process causing progressive brain cell destruction in Alzheimer’s disease subjects is well
5. In recent past Alzheimer’s disease could only be tentatively diagnosed after ruling out all other
possible diseases during the patient’s life.
6. Magnetic Resonance Imaging is used to show the areas of activity of the living brain.
7. Early diagnosis of Alzheimer’s disease will get even more important in the future when
destroyed brain cells can be replaced or revived.
8. A Down Syndrome patient will exhibit the senile plaques and fibrillar filaments typical of
Alzheimer’s disease at the age of 40.
9. The many cases of Alzheimer’s disease that remain unaccounted today probably have a
genetic cause that is most likely to be discovered in the future.
10. It is possible that ATP depletion in ageing brain prevents brain cells from defending against
the Alzheimer’s peptide toxicity.
11. That, unlike most other brain degenerative diseases, Alzheimer’s disease does not act inside
brain cells is good news from a therapeutic point of view.
12. Apoptosis involves brain cell shrinking and DNA degradation.
13. Aricept, the only drug for Alzheimer’s disease approved by the FDA, works by inhibiting the
enzyme acetylcholinesterase, which breaks down the neurotransmitter acetylcholine.
14. It appears from active immunization experiments on transgenic mice that their immune system
can be made to have a strong immune response to the Aβ peptide.
15. Clinical trials of both active and passive immunization procedures are going on and have so
far brought results far beyond all expectations.
II. Decide which of the statements below corresponds to the text.
16. All APP fragments, also called peptides, are …
1) found in equal numbers.
2) equally toxic.
3) made up of 39 to 42 amino acids.
4) None of the above.
17. Aβ1-40 is …
1) the most common misfolded segment of APP involved in Alzheimer’s disease.
2) ,as indicated by its name, a peptide composed of 40 amino acids.
3) one of the abnormal APP fragments that occur in Alzheimer’s disease.
4) All of the above.
18. Now the diagnosis of Alzheimer’s disease is usually made …
1) at autopsy.
2) by observing behavioural changes like memory deficits and depression.
3) using neuroimaging techniques.
4) on the basis of a behavioural assessment scale.
19. The familial form of Alzheimer’s disease …
1) is most common among Down Syndrome subjects.
2) involves a single gene passed on in a common inheritance pattern.
3) progresses much more rapidly than late-onset non-familial forms of the disease.
4) None of the above.
20. The three available drugs for Alzheimer’s disease treatment …
1) lead to permanent improvement in memory.
2) may have troublesome side effects.
3) can result in dementia.
4) None of the above.
21. The novel approach taken in the author’s laboratory consists in …
1) destroying all clumps of Aβ peptide.
2) suppressing the toxic effect of aggregating Aβ1-42 peptide.
3) eliminating all bonds between the toxic Aβ peptide and neighbouring cells.
4) improving the immune system’s ability to fight back.
III. Paragraphs 13-17. Five linking words or subordinate clauses have been removed. Decide
which of the following corresponds to each gap. All capital letters are optional.
1. Where it might cause unwanted effects - 2. However – 3. As is the case in
Alzheimer’s disease – 4. Among others – 5. For reasons that are still not entirely clear
22. GAP A
23. GAP B
24. GAP C
25. GAP D
26. GAP E
IV. Decide what the following sentences (underlined in the text) mean:
27. The technique has become remarkably sensitive, even detecting the loss of brain volume
during early stages of the disease when mild cognitive impairments might not warrant a
behavioral diagnosis. (paragraph 6)
1) The technique is so good that it can show a tiny reduction in brain size before changes in the
patient’s behaviour make it possible to diagnose the disease.
2) The technique is so harmful that is never be used until changes in the patient’s behaviour can
make the diagnosis of Alzheimer’s disease possible.
3) Although the technique is very subtle, and able to show the slightest decrease in brain volume
very early, it is not normally used until behavioural changes make the diagnosis of Alzheimer’s
disease very likely.
4) Though remarkably accurate, the technique is very difficult and unlikely to be used to detect
extremely tiny losses in brain volume if not indicated by cognitive deficits or behavioural
28. A much larger number of people have an inherited susceptibility to the disease, but they
experience onset in their late 60s, 70s and 80s with slower progression. (paragraph 10)
1) A majority of people develop the familial form of Alzheimer’s disease characterized by a
slower course at an older age.
2) That some people only start to suffer from the inherited form of Alzheimer’s disease after the
age of 65 remains unexplained.
3) Most of those genetically prone to Alzheimer’s disease will not develop its more slowly-
evolving form until they are almost 70.
4) The older people get, the more likely they are to develop familial Alzheimer’s disease.
V. Find synonyms for the words below
29. scattered (paragraph 1)
30. clumps (paragraph 3)
31. accurate (paragraph 5)
32. swells (paragraph 15)
4) breaks down
33. released (paragraph 17)
34. noxious (paragraph 18)
35. Provide the correct definition of IDIOPATHIC (paragraph 10)
1) relating to people’s own rather peculiar or unusual behaviour, likes, dislikes, conditions etc.
2) denoting a disease that is almost impossible to diagnose or treat.
3) relating to or denoting any disease or condition for which the cause is unknown.
4) denoting mentally handicapped people.
36. Provide the correct definition of MACROPHAGE (paragraph 15)
1) a type of phagocytic cell, capable of engulfing and absorbing cell particles.
2) visible to the naked eye.
3) highly toxic even to large neighbouring cells.
4) extremely sensitive to all types of tissue degradation.
37. Choose the best subtitle for SUBTITLE A
1) The Diagnosis of Alzheimer’s Disease
2) Lack of Diagnostic Accuracy
3) New Diagnostic Methods Enable Physicians to Cure Alzheimer’s Disease
4) What is Alzheimer’s Disease
38. Choose the best subtitle for SUBTITLE B
1) Alzheimer’s Disease May Start Early
2) The Familial Form of Alzheimer’s Disease
3) Down Syndrome Is Responsible for Alzheimer’s Disease
4) Alzheimer’s Genetics
39. Choose the best subtitle for SUBTITLE C
1) The Molecular Origin of the Disease
2) What Are Aβ peptides ?
3) ATP and APP
4) Cell Apoptosis and Necrosis in Alzheimer’s Disease
40. What is according to the author of the article the root cause of the neurodegenerative
mechanism of Alzheimer’s disease?
2) the toxic action of a protein fragment called amyloid-β1-42
3) the presence of insoluble clumps in the brain
4) Cell apoptosis and necrosis.
1) 1 11) 1 21) 2 31) 3
2) 2 12) 1 22) 5 32) 2
3) 1 13) 2 23) 4 33) 1
4) 1 14) 1 24) 1 34) 1
5) 1 15) 2 25) 2 35) 3
6) 2 16) 3 26) 3 36) 1
7) 2 17) 4 27) 1 37) 1
8) 1 18) 4 28) 3 38) 4
9) 1 19) 3 29) 4 39) 1
10) 1 20) 2 30) 3 40) 2