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SAGE KE Bulletin Board

Hasta la vista, amyloid cascade hypothesis, OR will academic dishonesty yield Alzheimer's cure?

26 May 2003

Alexei R. Koudinov

Kenneth Blum
Neuron, Cell Press
1100 Massachusetts Avenue,
Cambridge, MA 02138

cc: Nobel Foundation, Alzheimer�s neuroscientists worldwide

Editor,

I do not agree with (rather the doubt) your commentary [1] statement (associated with featured Neuron article of May 22, 2003 entitled �Antibodies against b-amyloid slow cognitive decline in Alzheimer's disease�[2]) that i) "the effects of antibody production are impressive� and that ii) �the findings presented are important in providing further evidence for the validity of the prevailing working hypothesis, the Amyloid Cascade Hypothesis�. The doubt is implied in the opinion of a top-level Alzheimer�s researcher David Holtzman [3], and editor-in-chief of the top-level American experimental biology FASEB Journal Vincent Marchesi [4].

Dr. Holtzman found that �the title and some of the conclusions of this study are not yet justified� [3]. He specifies that �the plasma and CSF Ab levels are not interpretable with the technique used here.� Dr. Marchesi is �concerned about the different results that are reported for the ELISA tests and the authors' tissue amyloid plaque assay� (TAPIR) [4]. Dr. Marchesi asks: �Can we rule out some nonspecific immunological reactions that cause improvement independent of the ability of the antibodies to bind to Ab?� No, we can not. Moreover, I did not find experimental evidence that TAPIR assay detects specifically Ab, not some other constituent of the amyloid plaque [2,5]. Many studies showed great number of proteins in amyloid plaques (while amyloid beta deposition was reported in a number of human disorders including cardio-vascular pathology and several other neurodegenerative diseases [6]). Therefore, biological effects of Ab (that Hock et al. [2] as well as the Winblad and Blum [1] are blindly ignoring [7]) may trigger some biochemical changes [8,9] and cause �nonspecific immunological reactions� [4].
 

�The title and some of the conclusions of this [Neuron, Ref.2] study are not yet justified� 

(David Holtzman, Alzheimer's Potamkin Prize 2003 winner, see Ref. 3).

I would call Neuron article [2] and associated commentary [1] a bias in favor of the expired amyloid dogma-based Alzheimer�s therapy approach in case of a confidence of the authors' conflict of interest. Zurich group article acknowledgment claims that there is no conflict: �the authors declare that they have no competing financial interests related to Elan/Wyeth-Ayerst.� Prof. Dr. Roger Nitsch institutional web site [10], however, indicates that his research is funded by �AHP-Wyeth-Elan", a reasonable situation for a researchers performing clinical study �to the pharmaceutical companies ELAN and WEYTH multi-center vaccination trial of Alzheimer's disease� [11]. Dr. Nitsh also chaired the symposium on Alzheimer�s disease on July 15, 1999 during the IBRO Congress 1999 in Jerusalem [12]. This symposium was �kindly supported by Elan Pharmaceuticals, NeoTherapeutics, Parke Davis�, indicating a situation, fitting the conflict of interests definition by BMJ [13], a major general medicine journal.
 

�Science, and biomedical science in particular, is competitive, and for many is a pursuit that generates considerable passion and emotion. No wonder, then, that competing scientists working in the most competitive disciplines occasionally come to blows. Research into HIV and Alzheimer disease seems to suffer more than most in this respect. Judging by recent events, this reputation seems justified, at least for the Alzheimer field. 

Repeating the charges and details of these cases here would only serve to highlight a small number of individuals who are in fact only a subset of a much larger community of biomedical researchers balancing the often conflicting demands of academia and commerce.� 

(Nature Medicine July 1999 5(7):713, see Ref. 17).

The above indicates that there is a conflict by a senior author of the Neuron article by Hock et al. [2]. If so, what is the reason of the dishonesty and breaking the cardinal tenet of academic science to make such conflict public and let readers decide whether the article �speaks for the science or for the company� [14] ?

Neuron readers also must know about the conflict associated with the key reference of the article by Hock et. al. This is �The National Institute on Aging, and Reagan Institute working group on diagnostic criteria for the neuropathological assessment of Alzheimer's disease� [15], a Neurobiol Aging publication that has important follow up competing financial interest disclosure in The Wall Street Journal article �Did ties to Alzheimer's test maker sway NIH report?� [16] and in the Boston Phoenix article �Science for sale: a Harvard researcher stands to profit from a product he "independently" reviewed for the National Institutes of Health� [14]. It was also covered as Nature Medicine report [17].

The above is tightly linked with my earlier correspondence with Neuron requesting editorial investigation and disciplinary action to punish Dennis J. Selkoe, (a Harvard professor, recent member of the NIH National Advisory Council on Aging, Athena founder and Elan director [14,18,19]), apparent non disclosure of competing financial interests in prior Neuron publication, and while serving Neuron editorial board member [20]. You should be in receipt of my letter emailed to you and Emilie Marcus [21] on August 19, 2002. Shortly thereafter I received a reply from Neuron senior scientist Stacie Weninger. Dr. Weninger wrote to me: �I wanted to thank you for bringing this matter to our attention. We take these issues seriously, and we will look into the matter further� [21]. Since then Neuron did not come to any action [that I expected to be] commensurate with the pattern of Dr. Selkoe misconducting academic nondisclosure dishonesty [22]. Moreover, February 2003 Neuron article by Sharon et al. [23] again hided D. Selkoe (a senior author) competing financial interest, disclosure that is required by the academic ethics and the uniform requirements of the manuscripts submitted to the biomedical journals [24].

For a non disclosure of a competing interest in April 18, 2003 Science report on amyloid oligomers (a brand-new Alzheimer's disease culprit substituting amyloid plaque in the pathogenesis scheme by the amyloid cascade proponents [25]) please see Ref. 26.
 
 

�Factors such as the scope of the misconduct, the length of time the misconduct went undetected, the prestige of the individuals or institutions involved, the possible impact on public health or clinical treatment, retaliation against the complainant or other mishandling of the allegation, as well as the extent of media coverage can all play a role in the impact that a particular case may have on individual researchers or their institutions.�

(Office of Research Integrity, Handling Misconduct web page, Ref. 22)

Sincerely,

Alexei Koudinov, MD, PhD
neuroscientist and editor
http://anzwers.org/free/neurology
http://neurobiologyoflipids.org
 

Competing financial interests: I do not have any competing financial interest. I aim free information dissemination and an unbiased development of Alzheimer's neuroscience. I observe the Society for Neuroscience  Guidelines for Responsible Conduct Regarding Scientific Communication.
 

[ Inform a colleague ] [ koudin{at}med.pfu.edu.ru ]

References:

1. Winblad B, Blum KI. Preview: Hints of a Therapeutic Vaccine for Alzheimer's?  Neuron. 38, 517-8 (22 May 2003) [ Abstract ].

2. Hock C, et al. Report: Antibodies against ß-Amyloid Slow Cognitive Decline in Alzheimer's Disease Neuron. 38, 547-554 (22 May 2003) [ Abstract ].

3. Holtzman D, ARF advisor. ARF Commentary on [2]. Alzheimer Research Forum. Published online May 21, 2003 [ FullText ][ Associated ARF news item ].

4. Marchesi V, ARF advisor. ARF Commentary on [2]. Alzheimer Research Forum. Published online May 21, 2003 [ FullText ][ Associated ARF news item ].

5. Hock C, et al. Generation of antibodies specific for beta-amyloid by vaccination of patients with Alzheimer disease. Nat Med. 8, 1270-5 (2002). [ PubMed ].

6. Koudinov AR, Berezov TT, Koudinova NV. Alzheimer's amyloid beta and lipid metabolism: a missing link? FASEB J.  12, 1097-9 (1998) [ PubMed ]; Koudinov AR, Koudinova NV, Beisiegel U. Cholesterol homeostasis failure at neuromuscular junctions and CNS synapses: a unifying cause of synaptic degeneration ? Neurology online.  (Feb 26, 2002) [ FullText ].

7. Koudinov AR. Amyloid was never clearly implicated in Alzheimer's disease, so look at Abeta from a different angle. BMJ online (Nov 30, 2002) [ FullText ].

8. Kamenetz F,  et al. APP processing and synaptic function. Neuron. 37, 925-37 (2003) [ PubMed ] [ Abstract at Neuron ] [ Related correspondence ].

9. Koudinova NV, Kontush A, Berezov TT, Koudinov AR. Amyloid beta, neural lipids, cholesterol and Alzheimer's disease. Neurobiol Lipids. 1, 6 (2003) [ FullText ].

10. Prof. Dr. Roger Nitsch. Neuro Science Center Zurich - Research Groups. University of Zurich web site. Last time viewed: May 26, 2003 [ FullText ].

11. Vaccination study for Alzheimer's disease (14.10.02). Medieninformation. University of Zurich web site. Last viewed: May 26, 2003 [ Acrobat .PDF FullText ] [ HTML Cache ].

12. Symposium on Alzheimer�s disease. Scientific Programme for 15 July 1999. IBRO Congress 1999, Jerusalem, Israel [ HTML Cache FullText ].

13. Smith R. Beyond conflict of interest. BMJ. 317, 291-92 (1998) [ FullText ] [ BMJ declaration of competing interest form ].

14. Ready T. Science for Sale: A Harvard researcher stands to profit from a product he "independently" reviewed for the National Institutes of Health. The Boston Phoenix. (29 April 1999) [ FullText ].

15. The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer's Disease. Consensus recommendations for the post-mortem diagnosis of Alzheimer's disease. Neurobiol. Aging.18, S1-S2 (1997) [ PubMed ].

16. Waldholz M, King RT, Jr. Did ties to Alzheimer's test maker sway NIH report? The Wall Street Journal. (30 Nov 1998) [ FullText ].

17. Editorial. Taking more interest in conflict. Nat Med. 5, 713 (1999)  [ PubMed ] [ FullText ]; Birmingham K, Ready T. Conflict-of-interest problems lead to policy changes. Nat Med. 5, 717-8 (1999) [ PubMed ] [ FullText ].

18. Crowley D. Elan Alzheimer's expert in pre-slump share sale. The Sunday Business Post. (18 Aug 2002) [ FullText ]; Koudinov AR. Ethical conundrums: an Alzheimer's case. BMJ. Published  online Sept 12, 2002 [ FullText ]; Koudinov AR correspondence with American Academy of Neurology, Nov, 2002 - March, 2003 [ FullText ].

19. Koudinov AR. Open letter to Public Citizen's Health Research Group on Alzheimer's disease research. BMJ online. (Feb. 21, 2003) [ FullText ]; SAGE KE (Feb. 21, 2003) [ FullText ].

20. Selkoe DJ. Biography. ISI HighlyCited.com. Last updated August 15, 2001 [ FullText ].

21. Stacie Weninger response on Alexei Koudinov letter of August 19, 2002 (27 August 2002) [ FullText ].

22. Introduction. Handling Misconduct. Office of research integrity web site [ FullText ].

23. Sharon U, et al. The formation of highly soluble oligomers of a-synuclein is regulated by fatty acids and enhanced in Parkinson's disease. Neuron. 37, 583-95 (2003) [ PubMed ].

24. Uniform requirements for manuscripts submitted to biomedical journals. International Committee of Medical Journal Editors. Med Educ.  33,  66-78 (1999) [ FullText ].

25. Robinson SR, Bishop GM, Munch G. Alzheimer vaccine: amyloid-beta on trial. Bioessays. 25, 283-8 (2003) [ PubMed ].

26. Koudinov AR. Alzheimer's amyloid beta oligomers versus lipoprotein Abeta. Science SAGE KE. (May 1, 2003) [ FullText ].
 
 


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