Neurodegenerative diseases raise profound questions
BMJ 2002; 324 doi: https://doi.org/10.1136/bmj.324.7352.0/h (Published 22 June 2002) Cite this as: BMJ 2002;324:hAll rapid responses
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We would
like to update readers on expanding failure of the amyloid hypothesis.
This hypothesis claims the primacy of amyloid deposits in the pathogenesis
of Alzheimer's disease (see BMJ
theme issue on neurodegeneration for several editorials on this subject,
also see Ref. 1) and now represents the major dogma
of Alzheimer's disease research [ 1 ].
Our recent dEbate letter in Science and eLetters in BMJ
[ 1 ] commented on the inability of amyloid hypothesis
to advance the disease understanding and to provide its’ pathogenic cure.
The response of the amyloid hypothesis proponents included a review article
in Science (published on July 19, 2002) [ 2
] and a notice of our Science dEbate letter at the Elan Corporate
Satellite Symposia (that held on July 22 evening at Stockholm Grand hotel)
of the 8th International Conference on Alzheimer’s disease and Related
Disorders (held July 20-25, 2002 at Stockholm Congress Center).
Well. The arguments of the amyloid hypothesis proponents are weak. Thus,
one of the congress abstracts states that the “neurotoxic effects of synthetic,
fibrillar amyloid-b (Ab)
protein on cultured neurons suggests a similar role for the protein in
Alzheimer’s disease” [ 3 ]. This is not much evidence
for fifteen years long amyloid saga.
The statement that “more detailed investigations, however, suggest “pre-fibrillar”
Ab species may also mediate the observed neurotoxicity”
[ 3 ] is the major Alzheimer's congress amyloid dogma
"update" also presented in the review article [ 2
]. This statement is based on a recent Nature article (see
Ref.60 in [ 2 ]) and on two duplicated abstracts
of the Stockholm meeting [ 4 ].
We had a chance to comment on the Nature study previously [
5
]. Particularly, we highlighted the lack of important experimental, discussion
and 'competing interest' consideration that could result in the misinterpretation
of the Nature article data and the misleading therapeutic perspective.
We will appreciate readers' study of the subject in greater details
and reading a number of recent articles by others on the failure of the
amyloid approach [ 6 ]. We hope that this will help
one to realize that the amyloid hypothesis time has passed away.
"...as we have unfortunately witnessed with brain inflammation in a number of patients following vaccination, the "therapeutic" (sic) removal of amyloid-, whether by vaccination or other methods such as inhibiting secretase activity, is an extremely dangerous strategy that renders the brain more vulnerable to underlying disease mechanisms". in "Dangers |
Competing interests: none
References
1. Koudinov et al.
Alzheimer's disease and amyloid beta protein. Science. Published
online 25 June, 2002 [ FullText
] [ Readers
responses ] ; Koudinov & Koudinova. Questions are always good.
A dogma is bad. Please help us to eradicate one. BMJ Published online 22
June, 2002 [ FullText
] ; Koudinov & Koudinova. Beware the simplification in defining neurodegenerative
diseases. BMJ Published online 24 June, 2002 [ FullText
] [ Other BMJ eLetters
by Koudinov ].
2. Hardy J & Selkoe DJ.
The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on
the Road to Therapeutics. Science297, 353 (2002) [ PubMed
] ; Get aware of the list of redundant review articles by Selkoe at the
following citation: Koudinov & Koudinova. Alzheimer's anti-amyloid
vaccination and statins: two approaches, one dogma. The time for change"
BMJ.
Published online 20 March, 2002 [ FullText
] ; Also see: Selkoe DJ. Alzheimer's disease results from the cerebral
accumulation and cytotoxicity of amyloid b-protein:
a reanalysis of a therapeutic hypothesis. J Alzheimer's Dis3,
75 (2001) ; Selkoe DJ. The genetics and molecular pathology of Alzheimer's
disease: roles of amyloid and the presenilins. Neurol Clin.18,
903 (2000) [ PubMed
]; Selkoe DJ.Clearing the brain's amyloid cobwebs. Neuron.32,
177 (2001) [ PubMed
].
3. Whalen et al. Protofibrils
of Ab with the arctic mutation induce neuritic
pathology prior to neuronal cell death. Neurobiol Aging.23,
S191 (2002) [ Abstract
No.717 FullText ].
4. Walsh et al. Cell-derived
Ab oligomers potently inhibit hippocampal long-term
potentiation in vivo. Neurobiol Aging.23, S556 (2002) [
Abstract
No.2045 FullText ] ; Klyubin et al. Block of long-term
potentiation in the CA1 area of rat hippocampus in vivo by oligomeric but
not monomeric forms of synthetic and naturally produced b-amyloid
protein Neurobiol Aging.23, S21 (2002) [ Abstract
No.83 FullText ].
5. Koudinov AR, Koudinova
NV. Amyloid hypothesis, synaptic function, and Alzheimer’s disease,
or Beware: the dogma is revitalized. BMJ. Published online 15 May,
2002 [ Full Text
].
6. Smith et al. Dangers
of the amyloid-beta vaccination. Acta Neuropathol (Berl)104,
110
(2002) [ PubMed
]; Bishop et al. Call for Elan to publish Alzheimer's trial details.
Nature416,
677 (2002) [ PubMed
]; Bergmann et al. Alternatives to the suspended Alzheimer's
disease vaccine.
Acta Neuropathol (Berl)104, 111 (2002)
[ PubMed
]; Smith
et al. Predicting the failure of amyloid-beta vaccine.
Lancet359,
1864 (2002) [ PubMed
]; Munch G, Robinson SR. Potential neurotoxic inflammatory responses to
Abeta vaccination in humans. J Neural Transm.109, 1081 (2002)
[ PubMed
]; Imbimbo BP. Toxicity of beta-amyloid vaccination in patients with Alzheimer's
disease. Ann Neurol.51, 794 (2002) [ PubMed
].
a Colleague] [Send us an email] [Authors Internet Office] Search PubMed for: [ AR Koudinov | NV Koudinova ] |
Competing interests: No competing interests
The name
of the dogma is "brain amyloid as a primary cause and defining
feature of Alzheimer's type neurodegeneration".
We would like to invite readers to see our eLetter on the BMJ
neurodegeneration theme issue editorial by Golbe [ 1
] and our other BMJ letters [ 2 ] that provide
extended online bibliography for the subject.
So, click, explore, and justify yourself.
"There is no evidence that the accumulation, oligomerization and aggregation of amyloid beta plays a causal role in the development of Alzheimer's disease". et al. BMJ online, 21 June 2002 |
Competing interests: none
References:
1. Koudinov AR, Smith MA, Perry
G, Koudinova NV.
BMJ. Published online 21 June, 2002 [ Full
Text ].
2. Koudinov et al.BMJ.
[ list of published
eLetters ]
a Colleague] [Send us an email] [Authors Internet Office] Search PubMed for: [ AR Koudinov | NV Koudinova ] |
Competing interests: No competing interests
Don't throw in the towel yet on the Amyloid/Alzheimer's hypothesis
In regard to the 25 June 2002 Science article "Alzheimer's disease
and amyloid beta protein."
It is interesting how " the failure of the first human Alzheimer's
disease (AD) vaccination trial " and " the vaccination failure will
hopefully withdraw the amyloid hypothesis" are within the same article and
within the same year. I have never known of a single failure to be
interpreted as enough counter-evidence of a hypothesis, theory, or dogma
as to entirely withdraw it's legitimacy.
It is true that amyloid beta has not been directly proven to be the
single source of Alzheimer's disease, and indeed if Alzheimer's had a
single cause it may have been elucidated years ago. We do know that
amyloid beta does play a role, quite possibly a significant one, and this
has been known from the very beginning.
The article implies that "failure was the result of an ignorance of
amyloid beta normal physiological function(s)" and that the inflammation
was, in their opinion, due to the reduction of amyloid beta and a
dysregulation of the essential roles that it plays in our CNS.
CNS inflammation was a possibility all along with a vaccine that
enters the brain. I'm sure that was brought up many years before it was
even developed. Along the way the data had looked good enough to proceed.
Sure, we may not know the exact etiology but many of us and millions of
others can't wait. Furthermore, many drugs have been shown to be
effective without having knowlege of their exact mechanism of action. I'm
sure sailors had no concept of the structure and function of ascorbic
acid, but they saw what citrus could do and acted (ate) upon their
observations. We still are ignorant of exactly how lithium ion works in
mood and depression and it's been prescribed for decades.
Futhermore, it is also true that cholesterol, like amyloid beta as
was noted,is an essential component of lipoproteins and is involved in
"lipid metabolism and membrane dynamics."
Drugs to control hypercholesterolemia are widely used and effective. It
may, however, be true that the obliteration of amyloid beta may be less
favorable than reducing it.
The bottom line is that, in my opinion, the unfortunate failure of
the amyloid beta vaccine is not grounds for complete withdrawal of the
amyloid hypothesis. I also don't believe the amyloid hypothesis is
delaying our understanding of the disease.
References:
All quotes from "Alzheimer's disease and amyloid beta protein"
Science, 25 June 2002.
Competing interests: No competing interests