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Open letter to Public Citizen's Health Research Group on Alzheimer's disease research
- Alexei R. Koudinov (27 February 2003)
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Alexei R. Koudinov, neuroscientist/editor Russian Academy of Medical Sciences; Neurobiol Lipids, P.O.Box 1665, Rehovot 76100 Israel
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Editor, I read with interest about the information on disciplined doctors by the Public Citizen's Health Research Group (BMJ 325: 226, 2002). One of the latest actions of the Public Citizen aimed at stopping an Alzheimer's Anti-Inflammatory Prevention Trial by the National Institute on Aging [1]. The group letter was addressed to Health and Human Services Secretary Tommy Thompson. The letter particularly stated [1]: "In the current amyloid hypothesis, the inflammatory reaction is a secondary response, not the primary event.[19] NSAID effect is now thought to be due to an effect on gamma-secretase, not to an anti-inflammatory reaction. Although some NSAIDs inhibit the gamma-secretase, the two chosen for the ADAPT trial (naproxen and celecoxib) have never been shown to have such activity. They showed no lowering of amyloid levels in model systems[20], no benefit in a population-based cohort study,[21] nor any benefit in a recent clinical trial of AD that used naproxen and rofecoxib, another COX-2 inhibitor.[22]" "The NSAID hypothesis, however, has turned out to be more complicated than this, and it is now felt that the inflammatory response is secondary to amyloid deposition and not the cause of it.[7]" "Even if there was a basis when the ADAPT trial was first proposed for believing that naproxen or celecoxib might have worked in preventing AD, there is no longer a scientific basis to support that hypothesis..." The group claimed that "there is no longer any biological basis for this [ADAPT] trial". Their preference was the amyloid hypothesis. The major support for the amyloid hypothesis in the group letter come from the Science magazine review article by Hardy and Selkoe [2]. What the letter missed is the fact that the key reference for the article by Hardy and Selkoe [2] is red flaged by Science magazine erratum [3]. This is because of the competing financial interest by Dennis J. Selkoe, MD. Dr. Selkoe is not only a Harvard Professor and a recent member of the governmental NIH National Advisory Council on Aging [4]. He also serves as a director for Elan, a company, involved in developing amyloid hypothesis based Alzheimer's therapy. Moreover, Howard L. Weiner, M.D., a co-inventor and co-author of Dr. Selkoe nasal amyloid vaccine [5] serves as a member of the Federal Drug Administration (FDA) Peripheral and Central Nervous System Drugs Advisory Committee [6]. The most eye-catching is the following journalist message [7, also see Ref. 8]: "Elan director and world renowned authority on Alzheimer's disease, Dennis Selkoe MD, sold 2,800 Elan shares for $120,000 indicating a price of $43.65 in "early December 2001" the company has stated to The Sunday Business Post. This was shortly before the pharmaceutical company announced poor results from its major Alzheimer's tests on January 18, 2002. The share price subsequently collapsed to a recent price of around $2. Selkoe also sold 20,000 shares for just over $1 million on February 6, 2001. Elan directors' sales, in all, came to over $43.5 million in February 2001..." [7]. Moreover, shortly after D. Selkoe sale of his Elan shares in February 2001 [7] American Academy of Neurology (AAN) Potamkin Prize Selection committee (chaired since 1999 by Dennis Selkoe) awarded the Prize 2001 to Elan scientist Dr. Dale Schenk [9, 10]. As CNN stated, "The Potamkin -- seen by some as a potential precursor to Nobel consideration -- is a peer award, and the AAN has some 17,500 neurology professionals in its membership" [10]. In my previous letter to BMJ [8] I alarmed the public about Dr. Selkoe conflict and expressed the necessity for the attention to D.Selkoe case and disciplinary actions by the societies' ethics committees and editorial boards of journals where he published or served as board member without acknowledging his competing financial interest. The letter by Public Citizen (signed by Elizabeth Barbehenn, PhD, Peter Lurie, MD, MPH, and Sidney M. Wolfe, MD) states that the authors "have done a search of the medical literature on AD and NSAID use and have discovered that the drugs being used in this study are not only unlikely to be effective but have the potential to inflict harm on these otherwise healthy individuals with little if any possibility of benefit." The letter claims that this is due to "no lowering of amyloid levels" [1]. I have two concerns in this regard. First, I am puzzled why the group did not discover several contributions that question amyloid hypothesis [see Ref. 11 for bibliography details, also see Ref. 12]. Second, although I do not agree with the focus of the letter discussion, I believe that the group statement is not fully supported by the currently available literature. To support the claim Public Citizen cites journal article by Koo, Golde and colleagues [the group letter citation #1], and two meeting reports by the research teams of Paul Aisen and Monique Breteler presented as Alzheimer Forum (AlzForum) news reports, not the primary literature [Public Citizen letter citations #21 and #22, respectively]. AlzForum is an important subject information source [13] that, however, commits no public responsibility to disclose competing financial interests of its' commentators and authors [14]. The reaction of Dr. Aisen on the Public Citizen letter is the following: "I would describe the letter as an inflammatory tirade rather than a scientific argument. While it does review some relevant scientific observations, the discussion is one-sided. I do not agree with the conclusions and recommendations of the letter" [15]. Monique Breteler adds: "I profoundly disagree with the interpretation of the existing evidence and the scientific argument in mentioned letter" [15]. The data of the other citation for a journal article [Public Citizen citation #1] were corrected in Science magazine two weeks after the publication of the letter [16], thus further invalidating the group argument. The later Science correction note stated that "the results of research by Edward Koo, Todd Golde, and colleagues were misrepresented... As the article noted, all experiments showing an effect of nonsteroid anti-inflammatory drugs on beta amyloid production used very high doses" [16]. The above is also present in Dr. Koo testimony to AlzForum [15]. Dr. Koo states that "many of Sidney Wolfe's accusations of ADAPT are unfounded". Dr. Golde further charges Public Citizen of being "irresponsible". He adds: "I am disturbed by the actions of Public Citizen in that they use our data to support their argument, but never once spoke to either Eddie [Koo] or myself for our take on it" [15]. Three weeks after the publication of the group letter [1] the story was communicated to Alzheimer's research community and openly commented on by twelve scientists at the AlzForum web site [17]. Public Citizen's Health Research Group letter also raised significant media interest [18] but did not become the voice of "many researchers in the field of AD research", as no one shared the letter enthusiasm [17]. Oppositely, many scientists now disagree with the group favorite amyloid hypothesis [11, 12], the fact that is erased in their letter to HHS Secretary Tommy Thompson. Below is the citation of a director of a respected institute [19]: "...I agree whole heartily with your letter to Science concerning Alzheimer's disease and the amyloid beta protein. It is amazing how this field has been led down the "amyloid hypothesis" trail to the exclusion of other viable hypotheses. If you don't go along with the amyloid dogma, you have difficulty publishing and extreme difficulty being funded. The anti-intellectual, anti-science mentality displayed by many in this field has slowed progress to a crawl. This is a shame." Another world class neuroscientist added with regard to amyloid-based Alzheimer's immuno-therapeutics [20]: "...the disaster that many of us predicted would result came to pass. I thought common sense would then prevail and this whole idea would be abandoned. But as you have pointed out, the dogma is too strong to be dropped, and now it is the application, and not a faulty theory that is being blamed. More AD cases are in danger..." The above statements call for a task force of safeguarding equal opportunities for different hypotheses of Alzheimer's research [21] and investigating the factual view that amyloid hypothesis is all about business [7, also see Ref. 22]. In light of the above I would like to know who stands behind ill-advised confidence in amyloid hypothesis of Sidney M. Wolfe and the Public Citizen's Health Research Group that he directs. Alzheimer's research field reserves to know this. I and my colleagues look forward hearing from Dr. Wolfe. Competing financial interests: I do not have any
competing financial interest. I aim free information dissemination and
an unbiased development of Alzheimer's neuroscience.
Sincerely, Alexei Koudinov, MD, PhD
References: 1. Barbehenn E, Lurie P, Wolfe SM. Letter to HHS Secretary Tommy Thompson that raises ethical concerns about the “Alzheimer’s Disease Anti-Inflammatory Prevention Trial” (ADAPT) (HRG Publication #1637) Public Citizen publications. Public Citizen web site. (4 Sept 2002) [ FullText ]. 2. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 297, 353-6 (19 July 2002) [ PubMed ] Erratum in: Science. 297, 2209 (27 Sep 2002) [ FullText ]. 3. Corrections and clarifications. Science. 297, 2209 (27 Sept 2002) [ FullText ]. 4. Attachment A: Membership Roster. National Advisory Council on Aging. National Institute on Aging. National Institute of Health web site. Summary Minutes for [ The Eighty-Sixth Meeting May 21-22, 2002 ] [ The Eighty-Fifth Meeting Jan 29-30, 2002 ] [ The Eighty-Fourth Meeting Sept 24-25, 2001 ]. Make a note of Dr. Selkoe citation at the Comments from Retiring Members. 5. Cromie WJ. Alzheimer's vaccine looks promising. Harvard Gazette. (18 Jan 2001) [ FullText ]; Weiner HL, Selkoe DJ. Inflammation and therapeutic vaccination in CNS diseases. Nature. 420, 879-84 (19-26 Dec 2002) [ PubMed ]. 6. Members: Howard L. Weiner, M.D. FDA Roster of the Peripheral and Central Nervous System Drugs Advisory Committee. FDA web site. (last viewed 16 Feb 2003) [ FullText ]. 7. Crowley D. Elan Alzheimer's expert in pre-slump share sale. The Sunday Business Post. (18 Aug 2002) [ FullText ]; Crowley D. Elan directors sold $43.5 million of shares before disastrous downturn. The Sunday Business Post. (11 Aug 2002) [ FullText ]; Elan Corporation PLC. Schedule 11. Notification of interests of directors and related persons. Dennis Selkoe [ 13 Feb 2001 ][ 18 Dec 2001 ]. 8. 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 ]; Waldholz M, King RT, Jr. Did ties to Alzheimer's test maker sway NIH report? The Wall Street Journal (30 Nov 1998) [ FullText ]. Also see: Koudinov AR. Ethical conundrums: an Alzheimer's case. British Medical Journal (12 Sept 2002) [ FullText ]. 9. Rosenberg RN. The Potamkin Prize for Pick's, Alzheimer's Disease and Related Disorders. AAN web site. (last viewed 16 Feb 2003) [ Original .DOC file ] [ HTML cached version ]. 10. Dale Schenk: Alzheimer's researcher. 'The synthesis of a hundred little ideas'. CNN web site. (23 July 2001) [ FullText ]. 11. Koudinov AR. Amyloid was never clearly implicated in Alzheimer's disease, so look at Abeta from a different angle. BMJ online. (1 Dec 2002) [ FullText ]; Koudinov AR, Smith MA, Perry G, Koudinova NV. Alzheimer's disease and amyloid beta protein. Science online. (14 June 2002) [ FullText ]. 12. McGeer and McGeer. Is there a future for vaccination as a treatment for Alzheimer's disease? Neurobiol Aging. In Press article, available online 3 December 2002 [ Abstract ]; Obrenovich ME, et al. Amyloid-beta: a (life) preserver for the brain. Neurobiol Aging. 23, 1097-9 (Nov-Dec 2002) [ PubMed ]; Smith MA, et al. Ill-fated amyloid-beta vaccine. J Neurosci Res. 69, 285 (1 Aug 2002) [ PubMed ]; Atwood CS, et al. Cerebral Hemorrhage and Amyloid-beta. Science. 299, 1014 (14 Feb 2003) [ FullText ]; Koudinov AR, Koudinova NV. Alzheimer’s anti-amyloid vaccination and statins: two approaches, one dogma. The time for change. British Med J. (20 March 2002) [ FullText ][ Related Correspondence ]; Koudinov AR, et al. Alzheimer's disease and amyloid beta protein: dogma is bad for science. 32nd Soc Neurosci Meeting, Program #21.11 (2002) [ Abstract and further reading ]. 13. Site visit: Alzheimer's Roundtable. Science. 286, 1643 (1999) [ FullText ]. 14. E.mail response by June Kinoshita, AlzForum Executive Editor, (23 Sept 2002) on A. Koudinov e.mail letter of 20 Sept 2002. Also see: Guidelines: Responsible Conduct Regarding Scientific Communication. Society for Neuroscience web site. (2002) [ Preface ] [ Acrobat .PDF FullText ]; Smith R. Beyond conflict of interest. British Medical Journal. 317, 291-2 (1998) [ FullText ]. 15. Comments by Scientists. Trials and Tribulations: Does ADAPT Have to Adapt? AlzForum web site. (4 Oct 2002) [ Comment by Paul Aisen ] [ Letter by Monique Breteler ] [ Comment by Eddie Koo ] [ Q&A with Todd Golde ]. 16. Corrections and clarifications. Science. 297, 1996 (20 Sept 2002) [ FullText ]. 17. Trials and Tribulations: Does ADAPT Have to Adapt? AlzForum web site. (Updated 4 Oct 2002) [ FullText ]. 18. Mitchell S. Govt urged to halt Alzheimer's study. The Washington Times. (4 Sept 2002) [ FullText ]. 19. E.mail response to A.Koudinov by a senior scientist (1 Jul 2002) regarding Koudinov et al. Science dEbate letter of 14 June 2002. 20. E.mail response to A.Koudinov by a senior scientist (19 Aug 2002) regarding Sunday Business Post article of 18 Aug 2002. 21. Current hypotheses. AlzForum web site. (last updated 5 Dec 2002) [ FullText ]. 22. Major
Commitment to Develop Immunological Approaches for Alzheimer's Disease.
Senior Journal (3 July 2001) [ FullText
]; Mindset and NYU collaborate on Alzheimer's vaccine. Pharmalicensing
(26 Jul 2002) [ FullText
].
Competing interests: None declared |
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