Very interesting. I suggest PET versus SPET studies.

View all comments by alessio dalla libera

Suppose you have a registry or cohort of volunteers on whom you are gathering longitudinal data and can hence characterize their recent past history, and suppose you do so with ratings that are used in prevention trials. Then you have a cohort that you can rapidly recruit from because you know them and they know you. They are following you on Twitter and Facebook. That’s what I mean by recruitment in a nanosecond. Then, because you know their pre-randomization “trajectories” or characteristics, you could better estimate how long a trial might be (taking into consideration how you expect the drug to work), then randomize them into an appropriate strata, and you can customize each individual’s outcome.

View all comments by Lon Schneider

One can only applaud the courage and commitment of the investigators involved in this study. It is surely a wise move to follow people with dominant mutations who are clearly at risk for clinical AD, and the markers to be studied are probably the best available.

But I'd still like to ask two questions: How sure are we that the accumulation of amyloid seen by scanning and the CSF levels of Aβ and tau that are being measured do indeed reflect the earliest pathogenic mechanisms that lead to symptomatic AD?

Secondly, is this the best time to couple this study with a battery of untested experimental therapies? No one is more aware than I of the desperate need for effective treatments, and the pressure on the investigators to add them to the study must surely be suffocating. My concerns are these: Although the evidence linking amyloid Aβ to AD is overwhelming, we still don’t know how or when it becomes toxic, and, equally important, whether other factors, such as inflammation, oxidative damage, and vascular injury are just as critical to the development of clinical disease....  Read more

One can only applaud the courage and commitment of the investigators involved in this study. It is surely a wise move to follow people with dominant mutations who are clearly at risk for clinical AD, and the markers to be studied are probably the best available.

But I'd still like to ask two questions: How sure are we that the accumulation of amyloid seen by scanning and the CSF levels of Aβ and tau that are being measured do indeed reflect the earliest pathogenic mechanisms that lead to symptomatic AD?

Secondly, is this the best time to couple this study with a battery of untested experimental therapies? No one is more aware than I of the desperate need for effective treatments, and the pressure on the investigators to add them to the study must surely be suffocating. My concerns are these: Although the evidence linking amyloid Aβ to AD is overwhelming, we still don’t know how or when it becomes toxic, and, equally important, whether other factors, such as inflammation, oxidative damage, and vascular injury are just as critical to the development of clinical disease. Does this overwhelming focus on amyloid as the primary culprit divert attention and resources away from the study of these other factors? If we continue to ignore them, the best designed therapies for the control of amyloid may be rendered ineffective.

View all comments by Vincent Marchesi

New Guidelines for Diagnosing Alzheimer's—Wishful Thinking, Dangerous Consequences
Previously, I have been quite critical of the DSM-V suggestion to introduce a new diagnosis—Minor Neurocognitive Disorder—on the grounds that it would create a large false-positive problem and would lead to unnecessary worry and cost with no useful intervention. Even more ambitious and dangerous are the recently suggested diagnostic guidelines for Alzheimer's created by a panel jointly sponsored by the National Institute on Aging and the Alzheimer's Association. The proposal is a clear case of narrowly focused experts getting far ahead of the available technology to suggest what will be an enormously costly public health experiment with dire unintended consequences.

The goal of the proposed guidelines is laudable—to identify those at risk for Alzheimer's even before they have developed clinical symptoms and to intervene preventively before the damage is done. The suggested guidelines would divide Alzheimer's into three groups of ascending severity and clarity of presentation: 1)...  Read more

New Guidelines for Diagnosing Alzheimer's—Wishful Thinking, Dangerous Consequences
Previously, I have been quite critical of the DSM-V suggestion to introduce a new diagnosis—Minor Neurocognitive Disorder—on the grounds that it would create a large false-positive problem and would lead to unnecessary worry and cost with no useful intervention. Even more ambitious and dangerous are the recently suggested diagnostic guidelines for Alzheimer's created by a panel jointly sponsored by the National Institute on Aging and the Alzheimer's Association. The proposal is a clear case of narrowly focused experts getting far ahead of the available technology to suggest what will be an enormously costly public health experiment with dire unintended consequences.

The goal of the proposed guidelines is laudable—to identify those at risk for Alzheimer's even before they have developed clinical symptoms and to intervene preventively before the damage is done. The suggested guidelines would divide Alzheimer's into three groups of ascending severity and clarity of presentation: 1) preclinical, i.e., no symptoms, but positive laboratory findings; 2) mild impairment; and 3) classic dementia. The guidelines would recommend laboratory studies to make the diagnosis in the first two groups, neither of which is currently considered an official diagnosis.

If we had well-established diagnostic tools to identify preclinical and mild presentations, the guidelines would make great sense. Unfortunately, however, we do not yet have proven tests, and guidelines that pretend we do are premature and reckless. Laboratory studies for Alzheimer's are of recent vintage, tested only in small, selected samples, will probably have huge false-positive rates in the general population, are expensive, and carry medical risks. None is nearly ready to be used in routine clinical practice, particularly in the general population.

To make matters worse (and the suggested guidelines even more ridiculous), there is no effective treatment for Alzheimer's in any of its stages. So finding out that you are (only possibly) at risk for developing Alzheimer's would provide little or no benefit—but would create needless worry, testing, treatment, expense, risk, and insurance and disability issues. The attempt to provide early identification with fallible tests and no effective treatment serves no useful purpose and can cause great harm, not only to individuals, but also to public health policy. Scarce health dollars should not be wasted on what would amount to a frivolous public health experiment. First, let's do the research necessary to prove the tests are sufficiently specific and to find medications that work.

How could such a bad idea be forwarded by renowned experts sponsored by august organizations? I have in earlier pieces written on the tunnel vision of experts in any given area and their natural enthusiasm for pushing the boundaries of their disorder of interest. No doubt the premature emergence of these guidelines results from the great frustration we all feel at the slow pace of development of diagnostic and treatment tools for Alzheimer's. Most of us expected there to be a well-established laboratory test by now, and drug discovery has also been disappointingly slow. My guess is that the guideline makers hope to jumpstart the field by highlighting the potential of early identification. But this is definitely putting the cart before the horse. Guidelines that will have great influence on how people live their lives and how the country will spend limited healthcare dollars must follow well-established science and an inclusive public policy debate, not lead it.

I am convinced from my experience with experts that they act from naïve good faith that expanding their field of interest will be good for patients. They tend to be blind to false-positive problems and societal costs because they are not trained to think in these terms, not because of conflicts of interest. But such naïve goodwill does not motivate the corporations that market drugs and diagnostic tests. There will be an explosion of testing and treatment if these guidelines are approved, much or all of it unnecessary and expensive, some of it downright harmful. The medical/industrial complex will have a field day.

The suggested guidelines for Alzheimer's are not yet official, so there is still hope. Given the great impact they will have on public health policy, they should not become official until there is a wide public policy debate with input and monitoring that reaches beyond the narrow group of experts in the field. Decisions on Alzheimer's are too important to patients and public policy to be made exclusively by experts on Alzheimer's.

View all comments by Allen Frances

Alzheimer's Tests: A Research Tool Not Ready for Clinical Use
In July, panels sponsored jointly by the National Institute of Aging and the Alzheimer's Association presented controversial proposed guidelines for diagnosing Alzheimer's at three different stages of its progression: 1) preclinical, 2) mild cognitive impairment, and, 3) classic dementia. The preclinical panel stated that laboratory testing (i.e., PET or MRI scans, spinal taps, or blood tests) before the appearance of symptoms was meant to be purely for research. But the other two panels seemed to suggest that laboratory testing was ready, or soon would be ready, to be used in routine clinical practice in diagnosing mild cognitive impairment or dementia. Faced with widespread skepticism, the panels held a conference call to clarify their position. As reported by Gina Kolata in The New York Times, there is reassuring new information. The panels recognize that laboratory testing is still only a research tool and will not be recommending that it be included as part of current clinical diagnosis. This makes...  Read more

Alzheimer's Tests: A Research Tool Not Ready for Clinical Use
In July, panels sponsored jointly by the National Institute of Aging and the Alzheimer's Association presented controversial proposed guidelines for diagnosing Alzheimer's at three different stages of its progression: 1) preclinical, 2) mild cognitive impairment, and, 3) classic dementia. The preclinical panel stated that laboratory testing (i.e., PET or MRI scans, spinal taps, or blood tests) before the appearance of symptoms was meant to be purely for research. But the other two panels seemed to suggest that laboratory testing was ready, or soon would be ready, to be used in routine clinical practice in diagnosing mild cognitive impairment or dementia. Faced with widespread skepticism, the panels held a conference call to clarify their position. As reported by Gina Kolata in The New York Times, there is reassuring new information. The panels recognize that laboratory testing is still only a research tool and will not be recommending that it be included as part of current clinical diagnosis. This makes great sense. All the available tests are at an early stage of development and are not nearly ready for routine use.

Rapid strides are being made in the study of Alzheimer disease, with powerful new methods leading us closer to understanding its causes and mechanisms. But let's not jump the gun and mislead ourselves and the public into the false beliefs that a diagnostic breakthrough has already been made and that a treatment breakthrough is possible in the near future.

It is easy to show that a promising laboratory procedure yields different group mean values when comparing Alzheimer's to a control group. It is difficult to prove that it has sufficient reliability, accuracy, clinical utility, and cost effectiveness to become a useful diagnostic test worthy of use in routine clinical practice. It will require years of testing in very varied populations before we will learn if any of the currently available candidates is indeed the long-awaited diagnostic test for Alzheimer's.

It is understandable that Alzheimer's experts have a strong desire to become preventively proactive. Can amyloid be the early marker of Alzheimer's, in analogy to cholesterol and heart disease? Can early identification and early intervention prevent the ravages of the disease? The problem is that you cannot skip the middle steps. Do the research first—then publish the guidelines.

We should also be cautious in our expectations for a treatment breakthrough. It is possible that learning more about the mechanisms of Alzheimer's may eventually lead to the development of a rational cure or preventive—but it is equally possible that it will not. The general experience in medicine over the past three decades is that an exponential explosion in knowledge about a disease does not often lead to any immediate miracle cure. The lack of success to date in developing medications for Alzheimer's does not inspire confidence. The available drugs—although they have been highly profitable to the drug companies—have little, if any, efficacy for patients. Attempts to develop a new generation of effective drugs have so far failed despite considerable investment. There does not appear to be any low-hanging fruit.

We should have and encourage reasonable hope regarding advances in Alzheimer's. Progress will be steady, but probably much slower than suggested by the recent excitement.

View all comments by Allen Frances

Placebo or Historical Controls: Mathematical Model Offers a Better Choice
I read this informative series about the expert conference organized by EMA with interest. Among the issues discussed, this meeting touched on the question of whether studies with potential therapeutic agents in carriers of autosomal-dominant AD mutations could serve as a model for simplified clinical testing of new medications against pre-symptomatic stages of the more common sporadic forms of AD. My comment pertains to Part 3 of this series, which addresses the topic of placebo-controlled studies as part of clinical trials of new medications. I notice that this discussion, which comprised primarily questions by participants and answers by regulators, failed to distinguish between early and late clinical development phases of new medications. However, this differentiation is essential, because Phases 1, 2, and 3 of clinical development tackle different questions based on quite different knowledge bases about the therapy at hand.

My colleagues and I take the view that long-term use of placebo...  Read more

Placebo or Historical Controls: Mathematical Model Offers a Better Choice
I read this informative series about the expert conference organized by EMA with interest. Among the issues discussed, this meeting touched on the question of whether studies with potential therapeutic agents in carriers of autosomal-dominant AD mutations could serve as a model for simplified clinical testing of new medications against pre-symptomatic stages of the more common sporadic forms of AD. My comment pertains to Part 3 of this series, which addresses the topic of placebo-controlled studies as part of clinical trials of new medications. I notice that this discussion, which comprised primarily questions by participants and answers by regulators, failed to distinguish between early and late clinical development phases of new medications. However, this differentiation is essential, because Phases 1, 2, and 3 of clinical development tackle different questions based on quite different knowledge bases about the therapy at hand.

My colleagues and I take the view that long-term use of placebo in studies of new compounds that are in advanced development, typically Phase 3, is highly ethically problematic. The Declaration of Helsinki (Seoul, 2008, paragraph 32) allows use of placebo instead of the best current proven intervention in situations “where no current proven intervention exists; or where for compelling and scientifically sound methodological reasons the use of placebo is necessary to determine the efficacy or safety of an intervention and the patients who receive placebo or no treatment will not be subject to any risk of serious or irreversible harm. Extreme care must be taken to avoid abuse of this option.“

With regard to long-term treatment of pre-symptomatic stages of all forms of AD, the first condition (i.e., lack of current proven treatments) is met; however, this is not true for the second condition. Without doubt, patients with autosomal-dominant AD face a high risk of serious or irreversible harm if treated with placebo for extended periods of time (18 months or longer, depending on the mechanism of action of the intervention studied). The same applies to patients with amnestic MCI who show specific neuropsychological, neurochemical, or brain imaging markers of pre-symptomatic AD. In the spirit of the Declaration, it is therefore unacceptable to knowingly expose such trial participants for extended periods of time to an ineffective intervention (placebo) when studying a treatment that in prior clinical trials has shown clear potential for clinically relevant efficacy and acceptable tolerability. These latter elements are customarily established in Phase 1 and early Phase 2 trials, which are shorter in duration and do require placebo control. For pre-registration trials, so-called pivotal studies, however, the scientific community and regulatory authorities would be well advised to consider novel study designs. Such designs should combine maximal protection of patients against ineffective treatments with the ability to foster scientifically valid testing of new candidate drugs.

In an attempt to realize an alternative to placebo-based study designs that is both ethically and scientifically sound, our group has developed mathematical models to reliably forecast clinically relevant endpoints and disease trajectories of AD patients in pre-symptomatic stages (MCI subjects). Our models make use of medical history, biological, and neuropsychological measures that are routinely established at baseline of every therapeutic study. Model-based forecasted endpoints and trajectories of decline constitute the background—the “simulated placebo group”—against which potential drug effects can be contrasted. We call this alternative study design the Placebo Group Simulation Approach (PGSA). Our ideas about it were presented at the recent CTAD congress in Toulouse (Poster 25, Abstract in J Nutrition Health & Aging 14: S16, 2010; we will gladly send a PDF file of the poster to colleagues interested in our concept).

First results using data from the ADNI database clearly demonstrate that empirically established and mathematically modelled endpoints and disease trajectories show high concordance in large samples of pre-symptomatic AD patients. We are currently attempting to validate our models using several independent datasets. Based on the first encouraging findings, we hope that the PGSA will replace placebo-controlled long-term studies in advanced stages of development of new anti-AD drugs. Needless to say, trials offering treatment with active drug to all participants are also easier to perform and less costly.

(Previously at Novartis, the author was a project leader in the development of the cholinesterase inhibitor drug rivastigmine; see, e.g., Spiegel, 2002 and Almqvist et al., 2004.)

View all comments by René Spiegel

I am Colombian, and have family near the town of Yarumal. I think even if the treatment fails, many new things will be discovered, so it is worthwhile.

I think Alzheimer’s due to old age is different from the early-onset autosomal-dominant Alzheimer’s disease in Yarumal. There is the possibility that the treatment works, at least partially, but that it won’t necessarily be effective for old age Alzheimer’s, considering that a lot is still unknown about the process of the illness. Still, partial success would be a lot for the people with ADAD.

View all comments by Dina Grutzendler

Comment by Sascha Weggen and Stefanie Hahn
To understand how presenilin mutations affect γ-secretase modulators (GSMs), it's worth elaborating on the differences in the studies by Hahn et al. (Hahn et al., 2011) and Kretner et al. (Kretner et al., 2011). Both studies used similar compounds. Both used E-2012 as an example of a potent non-acidic GSM without a carboxylic acid group. In addition, Kretner et al. used GSM-1 as a potent acidic GSM, whereas we used BB25, which is a close analogue of GSM-1 with similar potency. Kretner et al. concluded from their results that the attenuating effects of most presenilin mutations could be overcome by second-generation GSMs. In contrast, Hahn et al. concluded the opposite: that the efficacy of second-generation GSMs is reduced by presenilin mutations, in a similar fashion to what was previously reported by both of our groups for the less potent NSAID-type GSMs such as sulindac sulfide (Czirr et...  Read more

Comment by Sascha Weggen and Stefanie Hahn
To understand how presenilin mutations affect γ-secretase modulators (GSMs), it's worth elaborating on the differences in the studies by Hahn et al. (Hahn et al., 2011) and Kretner et al. (Kretner et al., 2011). Both studies used similar compounds. Both used E-2012 as an example of a potent non-acidic GSM without a carboxylic acid group. In addition, Kretner et al. used GSM-1 as a potent acidic GSM, whereas we used BB25, which is a close analogue of GSM-1 with similar potency. Kretner et al. concluded from their results that the attenuating effects of most presenilin mutations could be overcome by second-generation GSMs. In contrast, Hahn et al. concluded the opposite: that the efficacy of second-generation GSMs is reduced by presenilin mutations, in a similar fashion to what was previously reported by both of our groups for the less potent NSAID-type GSMs such as sulindac sulfide (Czirr et al., 2007; Page et al., 2008). The different outcomes of the two studies appear to be due to differences in the compound concentrations used and the statistical analysis.

Kretner et al. used higher GSM concentrations. We conducted our experiments in a dose-dependent fashion with a wide range of concentrations from 50-1,000 nM for E-2012 and BB25, whereas Kretner et al. used 1 μM in most experiments. The IC50 of these compounds in cell-based assays is around 50-200 nM. Our experience is that, if you go high enough with the compound concentration, one can break almost every presenilin mutation. However, we do not think that these concentrations are a realistic approximation of the in-vivo situation. A general problem with current GSM structures is that they are highly lipophilic. This means that high doses will be required to reach effective free drug concentrations in vivo. In this respect, concentrations five- to 20-fold above the in-vitro IC50 seem overly optimistic.

We are also not convinced that second-generation GSMs are principally different from the older NSAID-type GSMs. Kretner et al. suggested this because they found that many more mutants did not respond to sulindac sulfide as compared to GSM-1. However, they used sulindac sulfide at 50 μM, which is around its IC50 in cell-based assays, and GSM-1 at 1 μM, which is five times its IC50. Higher sulindac sulfide concentrations are very toxic on cells. Therefore, it is simply not possible to do the experiment, but if one could go high enough with the sulindac sulfide concentrations without inducing toxicity, we would predict sulindac sulfide would behave exactly the same as the new GSMs.

More important are the differences in the statistical analyses between our studies. Kretner et al. tested for significance of drug treatment versus vehicle control in each cell line separately. In many mutant cell lines, they observed a significant drop in Aβ42 levels after drug treatment and concluded that the mutants do respond to the drug. In contrast, we tested (at a given drug concentration) for a significant difference between the Aβ42 reductions in cell lines expressing mutant presenilin versus a control cell line expressing wild-type PS1. In this way, one can observe a significant drug effect with presenilin mutants, but the effect is still less in comparison to wild-type presenilin.

In conclusion, our studies seem to report contradictory results for similar or identical compounds, but these differences can be explained by the experimental design and the statistical analysis. So what is the truth? As an example, imagine treatment of a sporadic AD patient and a PS1 FAD patient with a GSM. Let's say the wild-type patient shows a 35 percent drop in CSF Aβ42 after GSM treatment. Most companies would likely be pleased with such an effect size. Now, in line with the data in both of our studies, the presenilin mutation in the FAD patient might attenuate the drug effect and cause only a 20 percent reduction in Aβ42. If you do a statistical analysis in the FAD patient of treatment versus non-treatment, a 20 percent drop is likely statistically significant. So is the 15 percent difference between treatment efficacy in the wild-type and the mutant patient. In this sense, the statistics in both studies are correct. However, although it may be possible to significantly lower Aβ42 in the FAD patient, the 15 percent difference in Aβ42 reduction could have profound implications for the clinical efficacy of the compound. Obviously, we do not know whether FAD patients with presenilin mutations will ever be treated with a GSM in the future, and this thought experiment might be a purely academic exercise. Nevertheless, these two papers nicely illustrate how differences in statistics can lead to completely different interpretations of the data. By just looking at the experimental raw data, there is very little difference between our studies.

View all comments by Sascha Weggen

We are so grateful for the interest of the New York Times in the efforts of the Alzheimer's Prevention Initiative. Their coverage also means a great deal to Dr. Francisco Lopera, the pioneer who has identified the families afflicted with early-onset Alzheimer’s in Colombia, to Dr. Ken Kosik, who has supported this project throughout, to the families themselves, and to Dr. Adam Fleisher, who is directing the specific imaging project that was covered. At the end of the last trip to Phoenix, William, who was identified in the Times article as having symptomatic Alzheimer’s, stood at our farewell dinner, gestured to the people assembled, and said, “This proves that nothing is impossible.”

We hope to clarify that it is not certain that any of the experimental treatments that we are considering will fail in symptomatic patients. We hope they won't and will look at any available data carefully. The overriding point is that, regardless of which agents are selected, there is a strong and testable scientific rationale to assume that some of them may have a more profound effect when...  Read more

We are so grateful for the interest of the New York Times in the efforts of the Alzheimer's Prevention Initiative. Their coverage also means a great deal to Dr. Francisco Lopera, the pioneer who has identified the families afflicted with early-onset Alzheimer’s in Colombia, to Dr. Ken Kosik, who has supported this project throughout, to the families themselves, and to Dr. Adam Fleisher, who is directing the specific imaging project that was covered. At the end of the last trip to Phoenix, William, who was identified in the Times article as having symptomatic Alzheimer’s, stood at our farewell dinner, gestured to the people assembled, and said, “This proves that nothing is impossible.”

We hope to clarify that it is not certain that any of the experimental treatments that we are considering will fail in symptomatic patients. We hope they won't and will look at any available data carefully. The overriding point is that, regardless of which agents are selected, there is a strong and testable scientific rationale to assume that some of them may have a more profound effect when administered earlier in the course of illness. And, while it would be ideal to start the first treatment trial in late 2012, it could be a bit later, depending on funding, regulatory approval, and so on. Between now and then, we will do whatever it takes to get the design and all requisite conditions right.

View all comments by Jessica Langbaum
View all comments by Eric M. Reiman
View all comments by Pierre Tariot

To the authors: I agree with the visionary 25-scientist gathering in Australia. I look forward with anticipation as they reveal their discourse and suggestions. As we have stated nearly two decades or more ago, the current amyloid- and tau-centric bent is not where most of our resources should be placed. While senile plaques, depositions, and inclusions are not an ideal situation to say the least, chasing these end-stage lesions is like beating a dead horse. We need to extend our efforts to include processes that begin in the vulnerable neurons of the AD and PD patient decades before tell-tale signs of the pathobiology manifest themselves, such as in the hallmark lesions.

References:
Obrenovich ME, Morales LA, Cobb CJ, Shenk JC, Méndez GM, Fischbach K, Smith MA, Qasimov EK, Perry G, Aliev G. Insights into cerebrovascular complications and Alzheimer disease through the selective loss of GRK2 regulation. J Cell Mol Med. 2009 May;13(5):853-65. Abstract

Aliev G, Obrenovich ME, Reddy VP, Shenk JC, Moreira PI, Nunomura A, Zhu X, Smith MA, Perry G. Antioxidant therapy in Alzheimer's disease: theory and practice. Mini Rev Med Chem. 2008 Nov;8(13):1395-406. Abstract

Aliev G, Palacios HH, Lipsitt AE, Fischbach K, Lamb BT, Obrenovich ME, Morales L, Gasimov E, Bragin V. Nitric oxide as an initiator of brain lesions during the development of Alzheimer disease. Neurotox Res. 2009 Oct;16(3):293-305. Abstract

Webber KM, Casadesus G, Zhu X, Obrenovich ME, Atwood CS, Perry G, Bowen RL, Smith MA. The cell cycle and hormonal fluxes in Alzheimer disease: a novel therapeutic target. Curr Pharm Des. 2006;12(6):691-7. Review. Abstract

Obrenovich ME and Monnier VM, Glycation predisposes to amyloid formation Glycation offers new clues into the etiology of “conformational” diseases Science's SAGE KE (2004) pe2.

Atwood CS, Obrenovich ME, Liu T, Chan H, Perry G, Smith MA, Martins RN. Amyloid-beta: a chameleon walking in two worlds: a review of the trophic and toxic properties of amyloid-beta. Brain Res Brain Res Rev. 2003 Sep;43(1):1-16. Review. Abstract

Obrenovich, M. E.; Raina, A. K.; Ogawa, O.; Atwood, C. S.; Smith, M. A. Alzheimer Disease – A New Beginning, Or A Final Exit?, Cell-Cycle Mechanisms in Neuronal Death Nicoletti, Ferdinando, Agata Copani Landis Biosciences. 2003. Vol. 19(6): 71-90.

Reddy VP, Obrenovich ME, Atwood CS, Perry G, Smith MA. Involvement of Maillard reactions in Alzheimer disease. Neurotox Res. 2002 May;4(3):191-209. Abstract

Obrenovich ME, Joseph JA, Atwood CS, Perry G, Smith MA. Amyloid-beta: a (life) preserver for the brain. Neurobiol Aging. 2002 Nov-Dec;23(6):1097-9. Abstract

View all comments by Mark E. Obrenovich

This looks like an excellent trial. How can Latin America participate?

View all comments by Luis Salguero