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15 July 2011. Communicating genetic information about Alzheimer’s disease to patients and families can be a daunting challenge. Clinicians and researchers faced with this task can take heart, however, because comprehensive guidelines for AD genetic testing and counseling are now available. Published in the June Genetics in Medicine and jointly issued by the American College of Medical Genetics and the National Society of Genetic Counselors, the guidelines spell out best practices for the field, and update and expand on previous recommendations the groups set forth for apolipoprotein E (ApoE) testing (see 1995 JAMA publication). For testing of asymptomatic people, the guidelines recommend adopting genetic counseling protocols pioneered for Huntington’s disease (HD), which are already in use by most AD researchers (see ARF related news story). The paper cites the Alzheimer Research Forum as one of several Web-based resources; ARF devotes a special section to early-onset familial AD and genetic testing.
Robert Green at Brigham and Women’s Hospital, Boston, said he believes the new guidelines are balanced and conservative. “I think they represent what people are essentially doing now, and reinforce good practices,” Green told ARF.
“The purpose [of the recommendations] was to give a guide to people who are not familiar with AD genetics: primary care doctors, neurologists who do not specialize in dementia, other folks who might be asked to do genetic testing,” explained first author Jill Goldman at Columbia University, New York City.
The paper distinguishes between genetic testing for dominantly inherited AD genes and that for the Alzheimer’s susceptibility gene ApoE (see below). The three early-onset familial AD genes—presenilin-1 (PS1), presenilin-2 (PS2), and amyloid precursor protein (APP)—confer almost 100 percent risk of developing AD, usually before the age of 60. Children of parents with the disease have a 50 percent chance of inheriting the gene, and may request pre-symptomatic testing. The guidelines lay out several strong recommendations for this type of predictive testing, Goldman said. First, the gene mutation must be identified in an affected family member before any pre-symptomatic testing is done. This is because, if researchers do not know which mutation to look for, a negative test result in an asymptomatic person will not be meaningful. Second, testing should never be offered to children, only to adults who can decide for themselves whether they want to have this genetic information. Third, researchers should follow the protocol established for HD, which includes pretest and post-test genetic counseling sessions in the presence of a patient-selected support person, as well as baseline neurological and psychiatric evaluations of the person to be tested. This procedure helps minimize the risk that a person will be overwhelmed by bad news.
After going through this process, Goldman said, most people elect not to find out their results. Those who do choose to learn their genetic makeup are “a very self-selected group of people who probably can cope with the information quite well,” she said. ARF previously interviewed coauthor Jennifer Williamson, a genetic counselor, on this topic (see ARF interview).
These guidelines are good, Lars Lannfelt at Uppsala University, Sweden, told ARF, but he personally believes researchers should be very cautious in revealing genetic information in case it does more harm than good. Lannfelt cites an experience his group had in the 1990s when a young person who tested positive for a dominantly inherited AD gene became despondent and suicidal (see ARF related essay and ARF related essay). “I do not think I would ever recommend testing for AD genes,” Lannfelt said. He advises patients who are worried about AD to get regular checkups rather than genetic testing. “If people really understand and demand [testing], I think it is very difficult to say no,” Lannfelt said, adding that “you have to really take care of the people involved,” by offering counseling and support.
In contrast to dominantly inherited genes, testing for the AD susceptibility gene ApoE is a completely different case, Goldman said. The guidelines do not advocate for such testing. “The general consensus is, we would never deny somebody the ApoE test if he or she really wanted it, but it should not be thought of as diagnostic, and it’s not really pre-symptomatic testing,” Goldman notes. Although carrying a copy of the ApoE4 risk allele increases the odds of getting AD two- to threefold, many people with the risk allele do not get the disease, while others without the allele do develop AD. “We wish the media would stop calling [ApoE] the Alzheimer’s test,” Goldman said (see, e.g., this news story and this health website). “It is not the Alzheimer’s test, and it is not going to tell people what they really want to know.”
Green takes a slightly different view. “I do think people have a right to learn information about themselves. What remains to be seen is whether there are more constructive or less constructive ways for that information to be presented.” Green led the Risk Evaluation and Education for Alzheimer’s Disease (REVEAL) study, which looked at the effects of telling people their ApoE genotype (see ARF related news story). Participants were a select group of highly educated volunteers, who were screened for psychiatric and anxiety disorders and carefully educated about the nature of the information, Green said. Though they may not be representative of the public at large, he noted that these participants handled the genetic information quite well, using the knowledge to make positive changes in their lives, such as exercising or taking vitamins, that might reduce their risk of getting AD. “Increasingly, we are going to be dealing with a world where our goal is to prevent disease rather than just treat it,” Green noted. “In order to know whom to focus on for prevention, both clinicians and patients will have to become comfortable with calculating, communicating, and understanding risk information. We think what we are doing in REVEAL is very important; we think it is pointing toward the future.”
Complicating the picture is the fact that ApoE testing is now available from several commercial companies (see ARF related news story and ARF Live Discussion). This direct-to-consumer testing is disturbing to many in the field, Goldman said, because of the possibility that people may misunderstand test results. For example, most online services do not take into account family history, which is as equally important as ApoE status, Goldman cautioned. She worries about the false reassurance someone with a family history of the disease might feel upon learning he or she is negative for ApoE4. This could lead to poor decision-making, such as a failure to buy long-term care insurance. Lannfelt goes further, characterizing direct-to-consumer testing as “terrible.” Green notes, however, “The genie is out of the bottle. I don’t think there is going to be any way to prevent people who wish to understand genetic risk information from getting it.”
Another factor to consider is that genetic testing recommendations are a moving target, these scientists agreed. Guidelines will change as better AD treatments and diagnostics become available, Goldman said, and will probably be re-evaluated on a yearly basis. Lannfelt concurred. “If we had [AD] drugs that were more effective, that would change the situation completely,” he said.—Madolyn Bowman Rogers.
Reference:
Goldman JS, Hahn SE, Catania JW, Larusse-Eckert S, Butson MB, Rumbaugh M, Strecker MN, Roberts JS, Burke W, Mayeux R, Bird T. Genetic counseling and testing for Alzheimer disease: Joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors. Genet Med. 2011 Jun;13(6):597-605. Abstract
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Comments on Related News |
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Related News: Breakthrough or False Hope? Etanercept Case Report Draws Scrutiny
Comment by: Ben Barres, ARF Advisor
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Submitted 21 January 2008
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Posted 21 January 2008
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Overall, my comment is one of strong doubt because of the possibility that the observed improvement is a placebo effect, and because of the lack of double-blind information. That said, TNFα is a microglial-derived, secreted protein that is likely to be elevated in Alzheimer’s. Given that it is a known inducer of complement proteins such as C1q, it is a provocative idea that TNFα might be playing some role in enhancing neuroinflammation and perhaps even complement-mediated synapse loss in neurodegenerative diseases such as Alzheimer’s.
Until a double-blind trial is run, we simply do not know whether TNFα antibodies will be useful for AD. Given that these antibodies are reasonably safe, I am all for doing a real trial to find out. One big caveat is that most antibodies cannot get across the blood-brain barrier.
One more point: in clinical practice, elderly patients occasionally come to the emergency room with a bladder infection presenting as stupor or coma. The infectious agent or the inflammatory response to them depresses brain function, and these patients quickly...
Read more
Overall, my comment is one of strong doubt because of the possibility that the observed improvement is a placebo effect, and because of the lack of double-blind information. That said, TNFα is a microglial-derived, secreted protein that is likely to be elevated in Alzheimer’s. Given that it is a known inducer of complement proteins such as C1q, it is a provocative idea that TNFα might be playing some role in enhancing neuroinflammation and perhaps even complement-mediated synapse loss in neurodegenerative diseases such as Alzheimer’s.
Until a double-blind trial is run, we simply do not know whether TNFα antibodies will be useful for AD. Given that these antibodies are reasonably safe, I am all for doing a real trial to find out. One big caveat is that most antibodies cannot get across the blood-brain barrier.
One more point: in clinical practice, elderly patients occasionally come to the emergency room with a bladder infection presenting as stupor or coma. The infectious agent or the inflammatory response to them depresses brain function, and these patients quickly become alert on antibiotics. Perhaps there is some inflammatory response in AD that, when suppressed, enables patients to suddenly do better.
 View all comments by Ben Barres |
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Related News: Breakthrough or False Hope? Etanercept Case Report Draws Scrutiny
Comment by: P.L. McGeer
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Submitted 21 January 2008
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Posted 21 January 2008
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Dr. Ed Tobinick has developed a revolutionary approach to deal with the neuroinflammatory damage which occurs in AD. He has administered Enbrel®, a soluble TNF blocker which is too large to cross the blood-brain barrier, perispinally to AD patients. The clinical results he reports are too dramatic to be overlooked by clinicians who plod along prescribing drugs that do not deal with the underlying pathology and which, at best, are only marginally effective in some individuals. Confirmation is urgently required to determine if, for the first time, there is a treatment for AD that really works. Dr. Tobinick reports almost immediate results so, at the start, a long-term trial with hundreds of patients is not needed. Let us hope that clinicians with access to patients will soon test the method and report whether or not they can confirm Tobinick’s results.
Dr. Tobinick himself might want to provide control data by injecting placebo. As for our group, we did PET scans on rats injected by Dr. Tobinick with radiolabeled antibody. In this experiment, etanercept rapidly reached the CSF...
Read more
Dr. Ed Tobinick has developed a revolutionary approach to deal with the neuroinflammatory damage which occurs in AD. He has administered Enbrel®, a soluble TNF blocker which is too large to cross the blood-brain barrier, perispinally to AD patients. The clinical results he reports are too dramatic to be overlooked by clinicians who plod along prescribing drugs that do not deal with the underlying pathology and which, at best, are only marginally effective in some individuals. Confirmation is urgently required to determine if, for the first time, there is a treatment for AD that really works. Dr. Tobinick reports almost immediate results so, at the start, a long-term trial with hundreds of patients is not needed. Let us hope that clinicians with access to patients will soon test the method and report whether or not they can confirm Tobinick’s results.
Dr. Tobinick himself might want to provide control data by injecting placebo. As for our group, we did PET scans on rats injected by Dr. Tobinick with radiolabeled antibody. In this experiment, etanercept rapidly reached the CSF but not the brain parenchyma.
View all comments by P.L. McGeer |
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Related News: Breakthrough or False Hope? Etanercept Case Report Draws Scrutiny
Comment by: Gregory Cole, ARF Advisor
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Submitted 21 January 2008
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Posted 21 January 2008
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I have been told that patients of colleagues received this treatment and it did not help them. I also have been told that the patients pay for it out of pocket, and that it is expensive. Last year the UCLA ADRC invited Dr. Tobinick to present his results to us. Dr. Tobinick’s presentation was for the most part a literature review on TNFα and inflammation. There was very little data and no formal study. Dr. Tobinick showed a videotape of a woman who performed poorly on simple directed tasks such as counting backwards from 10, then she was said to be treated, then she did better within 15 to 30 minutes. Since Amgen owns the drug, we called our contacts there, who said they had taken a look at this work and decided it did not merit follow-up. I asked Dr. Tobinick about Amgen—after all, if it worked, they would make money off it—and he said he presented to them and they didn’t follow up.
There are several other issues:
1. No controls for placebo or test/retest, nothing formal to show a real drug effect.
2. A response so rapid that most TNF mechanisms could not be...
Read more
I have been told that patients of colleagues received this treatment and it did not help them. I also have been told that the patients pay for it out of pocket, and that it is expensive. Last year the UCLA ADRC invited Dr. Tobinick to present his results to us. Dr. Tobinick’s presentation was for the most part a literature review on TNFα and inflammation. There was very little data and no formal study. Dr. Tobinick showed a videotape of a woman who performed poorly on simple directed tasks such as counting backwards from 10, then she was said to be treated, then she did better within 15 to 30 minutes. Since Amgen owns the drug, we called our contacts there, who said they had taken a look at this work and decided it did not merit follow-up. I asked Dr. Tobinick about Amgen—after all, if it worked, they would make money off it—and he said he presented to them and they didn’t follow up.
There are several other issues:
1. No controls for placebo or test/retest, nothing formal to show a real drug effect.
2. A response so rapid that most TNF mechanisms could not be involved. It would have to be an immediate immuno-neutralization and signal transduction effect.
3. Tony Wyss-Coray's panel finds low, not high, plasma TNFα as a diagnostic marker for AD (Ray et al., 2007). So a plasma effect would be in the opposite direction from normal but still might lower central TNFα. I think we can agree that most of the antibody would go to the periphery. This matters because TNFα can cross the BBB, so etanercept would lower peripheral TNF, which may be a significant source for brain TNFα and still have an effect. It is entirely possible that injection via another route would produce the same benefit in patients who have high peripheral TNFα.
4. For the case report with an N = 1 and sudden improvement, it is hard to conclude that there is any real phenomenon to explain. But for the previously published open-label study with 15 patients, there are more interesting results to follow up on. In that study, they found evidence of a more gradual and continuing improvement in cognitive measures with no improvement of MMSE scores at 1 month, but then improvement at 2 months. That would be consistent with a more plausible, slower time course for an anti-TNFα effect.
View all comments by Gregory Cole |
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Related News: Breakthrough or False Hope? Etanercept Case Report Draws Scrutiny
Comment by: Lon Schneider, ARF Advisor (Disclosure)
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Submitted 24 January 2008
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Posted 24 January 2008
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The media have been tripping over themselves about a single case report of what they have pegged as etanercept’s Lazarus-like effect in one patient. To add but one headline to the ones cited as examples in Gabrielle Strobel’s news story, the Methuselah Foundation quotes the author as saying, "the patients improve literally before your eyes" ( http://www.futurepundit.com/archives/004930.html, accessed January 18, 2007).
No matter how strong the underlying science or rationale of why an antagonist to TNFα might help, case reports tell so little and mislead so much. The circumstances of this one are particularly concerning, touting immediate and huge cognitive benefits using a perispinal injection process possibly covered by 17 patents owned by the author. The patient was treated just last October 30 for 7 weeks, with his final assessment on December 19 and journal publication the first week of January.
Now 12 weeks later, would it be presumptuous to ask how the patient is doing? As reported, he was...
Read more
The media have been tripping over themselves about a single case report of what they have pegged as etanercept’s Lazarus-like effect in one patient. To add but one headline to the ones cited as examples in Gabrielle Strobel’s news story, the Methuselah Foundation quotes the author as saying, "the patients improve literally before your eyes" ( http://www.futurepundit.com/archives/004930.html, accessed January 18, 2007).
No matter how strong the underlying science or rationale of why an antagonist to TNFα might help, case reports tell so little and mislead so much. The circumstances of this one are particularly concerning, touting immediate and huge cognitive benefits using a perispinal injection process possibly covered by 17 patents owned by the author. The patient was treated just last October 30 for 7 weeks, with his final assessment on December 19 and journal publication the first week of January.
Now 12 weeks later, would it be presumptuous to ask how the patient is doing? As reported, he was severely demented and confused before treatment, and after extrathecal infusion and being tilted head-below-his-heart for 5 minutes, improved markedly to a level of about moderate dementia in about 1 hour.
I wonder what was the rush to publish this case when 1.5 years ago, the same authors published a 16-patient case series where they exampled one patient with a MMSE of 0 who had even greater effects than this most current case, i.e., a 34-point improvement on the Severe Impairment Battery, and apparently sustained over 6 months. What deadline were they trying to meet?
They state in their case report that they had many similar experiences: “It should also be emphasized that rapid cognitive improvement following perispinal etanercept is not limited to the patient of the present report, but has, in fact, been commonly observed in multiple patients during the authors’ now more than 3-year clinical experience utilizing perispinal etanercept for treatment of probable Alzheimer’s disease.” Why didn’t they report these patients as well and earlier? How many other patients were treated and not reported? Did they have any failures, any non-responders? If you value one case, you have got to value them all.
Uncontrolled case reports at best suggest hypotheses, regardless of how large the effects seem to be. If the efficacy of etanercept is even a fraction as great as that reported in this case or as the average 5-point ADAS-cog or 16-point SIB improvement over 6 months reported previously, then a simple and small double-blind placebo-controlled trial could be done very easily and quickly (preferably by independent investigators). The legal and ethical issues enumerated by Gabrielle Strobel should not be underestimated.
Disclosure: Consultant with Wyeth, co-marketers with Amgen of Enbrel®.
References:
Tobinick E, Gross H, Weinberger A, Cohen H. TNF-alpha modulation for treatment of Alzheimer’s disease: a 6-month pilot study. Medscape General Medicine 2006; 8(2): 25. Abstract
Tobinick EL, Gross H. Rapid cognitive improvement in Alzheimer’s disease following perispinal etanercept administration. Journal of Neuroinflammation 2008; 5:2. Abstract
Tobinick E. Perispinal Etanercept for Treatment of Alzheimer’s Disease. Current Alzheimer Research, 2007, 4, 550-552.
View all comments by Lon Schneider |
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Related News: Breakthrough or False Hope? Etanercept Case Report Draws Scrutiny
Comment by: David Jensen
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Submitted 21 January 2008
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Posted 30 January 2008
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While I am happy that the Alzforum linked to my blog, I don't feel that you sufficiently nailed the point down here . . . that is, extraordinary "wow" headlines have no place in press releases about medical research. This is unfair to those with the disease, or to their caregivers. In this blogger's opinion, these authors lost all credibility when someone labeled their science with a headline like "Alzheimer's Symptoms Reversed In Minutes." -- Dave Jensen, author, Sham vs. Wham, at http://shamvswham.blogspot.com/ View all comments by David Jensen |
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Related News: Breakthrough or False Hope? Etanercept Case Report Draws Scrutiny
Comment by: Gerard Roberts
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Submitted 30 January 2008
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Posted 1 February 2008
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 I recommend the Primary Papers
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Related News: Breakthrough or False Hope? Etanercept Case Report Draws Scrutiny
Comment by: Diane Stephenson
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Submitted 30 October 2011
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Posted 1 November 2011
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Having spent some 25 years in industry focused on advancing therapies to treat patients with neurodegenerative diseases, I am very keenly aware of the critical importance for rigorous clinical trials.
I do think, however, that Etanercept is deserving of further study. There is now a wealth of evidence from preclinical studies in acute and chronic neurodegenerative conditions that elevated TNF exacerbates injury. Dr. Clive Holmes demonstrated that the single best predictor of cognitive decline in AD patients is serum TNF levels (Holmes et al., 2009), a finding that has since been confirmed in larger numbers of subjects. These results suggest that targeting patients with elevated TNF levels might be a strategy for identifying what patients to treat with anti-TNF therapies. Such an approach, if combined with neuroimaging biomarkers for patient enrichment (ARF related news story) and molecular neuroimaging tools to assess neuroinflammation (peripheral benzodiazepine receptor radiotracers) suggests a path forward for...
Read more
Having spent some 25 years in industry focused on advancing therapies to treat patients with neurodegenerative diseases, I am very keenly aware of the critical importance for rigorous clinical trials.
I do think, however, that Etanercept is deserving of further study. There is now a wealth of evidence from preclinical studies in acute and chronic neurodegenerative conditions that elevated TNF exacerbates injury. Dr. Clive Holmes demonstrated that the single best predictor of cognitive decline in AD patients is serum TNF levels (Holmes et al., 2009), a finding that has since been confirmed in larger numbers of subjects. These results suggest that targeting patients with elevated TNF levels might be a strategy for identifying what patients to treat with anti-TNF therapies. Such an approach, if combined with neuroimaging biomarkers for patient enrichment (ARF related news story) and molecular neuroimaging tools to assess neuroinflammation (peripheral benzodiazepine receptor radiotracers) suggests a path forward for designing innovative trials that address key hypotheses.
Numerous comments highlight the concern about lack of BBB permeation of anti-TNF antibodies. This stands in contrast to the growing investment in industry now that is being placed on therapeutic antibody approaches to deliver disease-modifying therapies (reviewed by Paul, 2011).
Note the reference on ClinicalTrials.gov to the study of the safety and tolerability of Etanercept in AD (STEADI-09), which is actively recruiting patients.
References:
Holmes C, Cunningham C, Zotova E, Woolford J, Dean C, Kerr S, Culliford D, Perry VH. Systemic inflammation and disease progression in Alzheimer disease. Neurology. 2009 Sep 8;73(10):768-74. Abstract
Paul SM. Therapeutic antibodies for brain disorders. Sci Transl Med. 2011 May 25;3(84):84ps20. Abstract
View all comments by Diane Stephenson |
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Related News: Breakthrough or False Hope? Etanercept Case Report Draws Scrutiny
Comment by: Gregory Cole, ARF Advisor
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Submitted 10 November 2011
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Posted 10 November 2011
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Reply to comment by Diane Stephenson
In general, the recent GWAS data provide a compelling rationale
for some causal modulatory role for the immune system in the development of
AD. But they don't clarify what this role is. It may be a positive role in
amyloid clearance or a negative role related to neurodegeneration.
The paper by Holmes et al. on which Diane Stephenson comments adds to a rationale to
focus on TNFα, which is known to "orchestrate" inflammation in various
models. That paper argues that TNFα plays a role in the rate
of cognitive decline in AD, but most anti-inflammatory trials in AD patients
have failed.
The reports that some AD patients treated with anti-TNFα
antibodies have had a favorable response are difficult to evaluate without a
larger, more controlled clinical trial without any potential conflict of
interest concerns.
The issue with all anti-inflammatory interventions remains confounded by conflicting information about which population might
benefit. For example, the ADAPT trial results now argue that persons with
cognitive decline...
Read more
Reply to comment by Diane Stephenson
In general, the recent GWAS data provide a compelling rationale
for some causal modulatory role for the immune system in the development of
AD. But they don't clarify what this role is. It may be a positive role in
amyloid clearance or a negative role related to neurodegeneration.
The paper by Holmes et al. on which Diane Stephenson comments adds to a rationale to
focus on TNFα, which is known to "orchestrate" inflammation in various
models. That paper argues that TNFα plays a role in the rate
of cognitive decline in AD, but most anti-inflammatory trials in AD patients
have failed.
The reports that some AD patients treated with anti-TNFα
antibodies have had a favorable response are difficult to evaluate without a
larger, more controlled clinical trial without any potential conflict of
interest concerns.
The issue with all anti-inflammatory interventions remains confounded by conflicting information about which population might
benefit. For example, the ADAPT trial results now argue that persons with
cognitive decline won't benefit from conventional NSAIDs like naproxen, while
the paper by Holmes et al. suggests that anti-TNF therapy with antibody or even
a small molecule like curcumin might actually help a subset of patients with
established AD. This is really an empirical question.
View all comments by Gregory Cole
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