In the current paradigm, a dementia
associated with amyloid
plaques and neurofibrillary tangles in the cerebral cortex is what characterizes
“Alzheimer’s disease”. But the numerous cases where there is
no such association represent a set of abnormal results that undermine this paradigm
of current normal science.
As early as 1911,
Alois Alzheimer himself described the case of Johann F., whose brain contained
amyloid plaques, but no neurofibrillary tangles. (Nowadays, this phenomenon is
referred to as “plaque-only Alzheimer’s”.) Scientists also recognize
that neither the number nor the distribution of the amyloid plaques found in the
cortex post mortem shows any clear correlations with the cognitive deficits
observed while the individual was still alive.
there have been some individuals who met the clinical criteria for Alzheimer’s,
but had only neurofibrillary tangles and no amyloid plaques. And it is also relatively
common to find both amyloid plaques and neurofibrillary tangles in the brains
of older people who had shown no cognitive deficits.
what do cases like these indicate? The presence of conditions other than Alzheimer’s?
Atypical forms of “Alzheimer’s disease"? Or simply a particular
geography of the natural effects of natural aging on certain brains? The
debate and the research continue.
In the course of normal aging, about
half of all people who reach age 50 are going to complain about memory
losses. These losses are attributable to various mechanisms and usually indicate
reduced ability to pay attention,
which negatively affects the storage
and retrieval of information. Less often, however, these isolated memory
deficits may worsen and develop into Alzheimer’s-type dementia.
The concept of “mild cognitive impairment” (MCI) was proposed by Ronald
Peterson to denote a condition in which a person displays greater cognitive deficits
than would normally be expected for a person of his or her age and sociocultural
status but that are not severe enough for that person to be considered to have
MCI is thus based on the idea of a continuum
between normal cognitive aging and dementia. But it does not presuppose any particular
underlying mechanism, so this intermediate form of cognitive deterioration can
have many causes.
It is now known that for people
with MCI, the estimated risk of subsequently developing a dementia is 10 to 15%
per year, whereas in normal persons of the same age, this risk is only 1 to 2%.
And at the end of 6 years of monitoring, 80% of the individuals who initially
had MCI had developed dementia.
But this concept does
not tell us whether people with MCI represent a group at risk for dementia, or
whether MCI simply represents the fist symptoms of an Alzheimer’s-type dementia
that has been identified early. The status of MCI as a distinct entity thus remains
controversial and raises some very real ethical issues, such as whether or not
medication is a good idea at this stage.
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|COGNITIVE LOSSES ASSOCIATED WITH ALZHEIMER’S||
dementia was not accorded the status of a disease until several decades after
it was first described by Dr. Alois Alzheimer in 1906. This attribution occurred
gradually, as the relationship between the deterioration of cognitive abilities
and the types of brain
lesions involved in this form of dementia was discovered.
studies of degenerative
diseases in the late 1960s and the 1970s had shown especially low levels of
certain neurotransmitters in people who had certain disorders: for example, low
levels of dopamine
in people with Parkinson’s disease and low levels of acetylcholine
in people with Alzheimer’s. Pharmacological treatments were then developed
to increase the levels of these neurotransmitters, by delivering either precursors
of these substances (L-Dopa, in the case of Parkinson’s) or inhibitors of
the enzymes that break them down them (cholinesterase inhibitors, in the case
Once medications were available,
people naturally drew the inference that they were being used to treat a disease.
In this way, the general public began to use the expression “Alzheimer’s
disease” to refer to what had long been seen as part of the normal aging
process (follow the intermediate Tool Module link to the left).
the same time, researchers were learning more about how aging affects the functioning
of the brain. Hence we now better understand the mechanisms responsible for the
decline in memory, attention, and language abilities as people age—mechanisms
such as inflammation, free radicals, and hormonal changes. And we also now know
that factors such as cardiovascular disease, head injuries, and unhealthy lifestyles,
as well as genetic and psychological factors, can accelerate these mechanisms
that cause the brain to age.
Thus we are dealing
with a complex situation. We know that in some respects, normal aging of the brain
differs from pathological aging, but that in many respects, the two are similar.
For example, an older person not known to have any disease will nevertheless have
some loss of neurons, albeit minimal and offset by compensatory mechanisms. But
in people with Alzheimer’s or Parkinson’s, the loss of neurons is
massive, irreversible, and specific to certain
areas of the brain.
Many other issues remain
to be clarified, such as the relationship
between the presence of amyloid plaques and normal aging (see sidebar), as
well as the relationships between the lesions that these plaques produce and the
symptoms that are observed.
are still debating whether what people call Alzheimer’s disease might not
simply be an accelerated form of normal aging. In other words, whether the abnormally
high number of lesions in the brains of people with Alzheimer’s represents
a specific pathology with its own specific mechanisms, or whether it is simply
some kind of speed-up in mechanisms that are already at work in normal aging.
way, some neuroscientists think that it is time to stop using the expression “Alzheimer’s
disease”. For example, Dr. Peter Whitehouse is a neurologist
who helped to develop the first medications to treat the symptoms of Alzheimer’s,
working with the pharmaceutical industry for over 30 years. He now says that the
diagnosis of Alzheimer’s disease is exclusionary, in both possible senses
of the term. First, it is a diagnosis arrived at by default, after all other possible
causes of the observed deficits have been excluded. Second, it is a diagnosis
that can result in social exclusion for many people. Knowing that you have an
incurable degenerative disease can make you feel so stigmatized that you don’t
have the heart to maintain your social contacts, even though they might be good
Dr. Whitehouse does not deny the existence
of sometimes very severe cognitive disorders in older people, but, like more and
more of his colleagues, he believes that what people call “Alzheimer’s
disease” is not a specific entity. He says that dementias are too heterogeneous
to be understood using the current “disease” model, which he considers
overly limiting not only for science, but for patients and society as well.
the same reason, he also opposes the concept of “mild cognitive impairment”
(see sidebar), which some regard as a specific disorder with symptoms lying somewhere
between normal cognition and the deficits associated with other dementias.
for Whitehouse, the boundaries between Alzheimer’s and other
dementias are not clearly defined, and hence Alzheimer’s is not so clearly
separated from normal aging as the biomedical model would have us believe. He
therefore argues that there is a continuum among various expressions of aging,
some of which are more problematic than others. He points out that people are
changing constantly throughout their lives and that the ongoing aging of the brain
late in life is part and parcel of this continuum.
the differences in the ways that the brains of elderly people age can be seen
as the result of numerous factors that have influenced them throughout their lives.
Some of these factors may be biological, such as cardiovascular problems, insomnia,
diabetes, alcoholism, and head injuries. Other may be psychological (such as stress,
and still others may be environmental,
social, or cultural (such as isolation, financial insecurity, poor nutrition,
and limited education). This myriad of interwoven factors makes any clear-cut
distinction between “normal” and pathological illusory.
the same interdependency of influences is found in the aging of other parts of
the body besides the brain. The condition of elderly people’s joints, for
instance, will depend on various genetic factors, as well as environmental factors
related to lifestyle. Some people will continue into old age with only minor aches
and pains in their joints, while others may have to resign themselves to moderate
or even severe loss of physical mobility. And in this latter case, it is not always
possible to identify any one pathology that is responsible for the loss.
of the most famous studies that reveals the limitations
of our knowledge when it comes to these multifactorial processes is the Nun
Study of Aging and Alzheimer’s Disease (see box below). This study showed
that one group of nuns whose brains were severely atrophied and contained numerous
“senile plaques” may have lived without the deficits associated with
Alzheimer’s. And the reverse was also true: other nuns whose brains were
almost intact had displayed all the symptoms of Alzheimer’s.
therefore believes it urgent for us to reconsider what we are calling “Alzheimer’s
disease", so that numerous adults who are still functioning when they receive
this diagnosis do not automatically regard themselves as living on a sort of mental
death row. As described in the last box below, experiments have shown that an
Alzheimer’s diagnosis can itself lead to a decline in a person’s cognitive
According to Whitehouse, the aging of the
brain can take a different course if there is sufficient emphasis on lifelong
prevention and psychosocial support. As we now know, with dementia, as with many
other disorders, regular physical activity, a well balanced diet, and good stress
management can delay the onset of symptoms and slow their progress.
credit: Iris Schneider
people begin to show signs of cognitive decline, authors such as Whitehouse argue,
we must give them ways of continuing to exercise their intellectual faculties
and staying involved in their communities. To this end, Whitehouse has established
The Intergenerational School in Cleveland, Ohio, where older people, including
some with cognitive deficits, act as mentors to provide academic support to children
with learning difficulties. |
for Alzheimer’s and other dementias are available and can have benefits
(though they can also have side effects). But more and more physicians feel that
when older people with cognitive losses consult their doctors, medication should
not be the only treatment option offered (see second box below). Physicians should
also consider all of the psychological and social interventions that may enable
these older adults to limit as much as possible the problems caused by the aging
of their brains.
The Nun Study of
Aging and Alzheimer’s Disease began in the mid-1980s and involved
678 Roman Catholic nuns living in Minnesota, in the United States. These sisters
had agreed to undergo annual cognitive, physical, and medical testing, to give
the researchers access to their convent and medical records, and to donate their
brains for neuropathological studies after they died.
great value of this epidemiological study is that it followed, for a long period,
a population that was highly homogeneous in diet, education, income, access to
health care, and so on, thus minimizing the influence of external factors that
often cannot be controlled in such studies.
the most interesting results of this study involved autobiographical essays that
some of the nuns had written when applying for admission to the convent in their
late teens or early 20s. Nearly 80% of those nuns whose essays scored low on “density
of ideas” developed Alzheimer’s later in life, whereas only 10% of
those nuns whose essays scored high on idea density did so. This finding led the
authors to conclude that some personal characteristics in the early, middle, and
final years of a person’s life can be highly correlated with their risk
of developing the cognitive deficits associated with Alzheimer’s.
other major question raised by this study concerns the relationship between the
main recognized biological markers of Alzheimer’s (amyloid
plaques and neurofibrillary tangles) and the symptoms
ascribed to Alzheimer’s. This study showed that this relationship is
less straightforward than had been thought. There were several cases where nuns
had achieved excellent scores on cognitive tests throughout their lives, but when
they died and their brains were dissected, they showed extremely advanced lesions.
And conversely, some of the nuns who had shown severe cognitive decline over their
lifetimes were found to have only slight physical damage to their brains.
As more and more studies demonstrate
that aging of the brain is an extremely complex phenomenon, and as the difficulty
of pigeonholing heterogeneous individual cases into various categories of “dementia”
becomes apparent, a number of neuroscientists have begun calling for a paradigm
These authors are not saying that we should
stop doing neurobiological and pharmacological research on dementia. But they
are saying that scientific research and clinical practice must be integrated into
a multifactorial perspective that places the aging of the brain on a continuum
with the other stages of life. And according to some of these authors, this paradigm
shift could make the various forms of intervention, including medical treatment,
One such author is esteemed neurologist
Vladimir Hachinski, of the University of Western Ontario, in Canada. In the November
2008 issue of the Journal of the American Medical Association, he writes:
“The concept of dementia is obsolete. It combines categorical misclassification
with etiologic imprecision.”
In the same spirit,
in the July 21, 2009 issue of the journal Neurology, neurologists Miia
Kivipelto of the Karolinska Institute in Sweden and Alina Solomon of the University
of Kuopio in Finland argued that some changes are still needed in neurological
thinking about dementia, with a shift in focus from “from the extreme category
of dementia to the continuum of cognitive functioning, from brain damage with
severe functional consequences to the brain at risk”.
few months later, Hachinski and Whitehouse, together with Dr. Majid Fotuhi, published
an article in the December 2009 issue of the journal Nature Neurology
in which they proposed a model of brain and cognitive aging that takes the complexity
of the factors at play into account.
When people are diagnosed with "Alzheimer's
disease", if they already believe the prevailing stereotypes about the most
dramatic aspects of brain aging associated with this condition, that belief in
itself may harm their cognitive abilities.
on physical aging have shown that older people will walk more slowly after they
have read a story about an older person who has trouble in moving—the classic
stereotype that a slower gait is an inevitable part of old age.
findings have also been made in experiments on memory disorders in older people.