The API project is important and valid, but I'd like to point out one oversight in this story. While the two study populations targeted at present are primarily selected on the basis of genetic risk, the non-genetic risk factors for AD, such as cardiovascular conditions and lifestyle risks, are significant. How intervening in these non-genetic risks will measure up against a drug treatment is unknown. In other words, treating an ApoE4/4 individual who also exercises and eats a Mediterranean diet may have a very different outcome compared to one who does not. Perhaps another benefit of the families in Antioquia is the relative uniformity of their lifestyle risks. Their diets and exercise levels are quite similar throughout the population.

View all comments by Kenneth Kosik

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

This is a very impressive study. It is the kind of pilot biomarker study that every top investigator dreams of doing, and kudos to the team that did it.

I noticed some 15 percent of AD patients were dropped from entering the trial because the scan showed they did not have sufficient amyloid in the brain. Without dropping these people, the study would likely have had no chance of showing a positive result and might have also exposed more people to risks. This shows the power of PET amyloid imaging to select people who have pathology in order to maximize your chance of a drug effect. Prior to this, we were treating AD patients blindly without knowing how much amyloid they had in their brains, a bit like treating people with a statin without knowing their cholesterol level.

With regard to the bapineuzumab therapy, the magnitude of amyloid clearance seems consistent and real, but at around 20 percent is modest. That is far less than was expected from prior autopsy studies of immunized patients or animal studies which suggested the vaccines might have a much bigger...  Read more

This is a very impressive study. It is the kind of pilot biomarker study that every top investigator dreams of doing, and kudos to the team that did it.

I noticed some 15 percent of AD patients were dropped from entering the trial because the scan showed they did not have sufficient amyloid in the brain. Without dropping these people, the study would likely have had no chance of showing a positive result and might have also exposed more people to risks. This shows the power of PET amyloid imaging to select people who have pathology in order to maximize your chance of a drug effect. Prior to this, we were treating AD patients blindly without knowing how much amyloid they had in their brains, a bit like treating people with a statin without knowing their cholesterol level.

With regard to the bapineuzumab therapy, the magnitude of amyloid clearance seems consistent and real, but at around 20 percent is modest. That is far less than was expected from prior autopsy studies of immunized patients or animal studies which suggested the vaccines might have a much bigger effect. This is a new insight and we might need to lower our expectations. The potential promise with this technology is that we might be able to test how different doses of therapy affect amyloid clearance at an early stage, allowing companies to select the most optimal dose for definitive trials.

Going beyond amyloid, at the end of the day, one can clear all the amyloid in the brain and if the patient does not improve, it still is not a useful therapy. So what's missing is for the field to now show that clearing amyloid eventually leads to a meaningful cognitive and functional benefit for the individual.

Some minor methodologic issues: differences at baseline in cognition and amyloid burden (not unexpected in small studies) between treatment groups add a bit of uncertainty as to interpretation. The method for computing standardized uptake values relative to cerebellum (i.e., the amyloid ratios) varies slightly from one study to another, and one sees different ratios being called normal or abnormal. This makes it hard to compare findings across studies and across tracers. So I think we need head-to-head comparisons and also some standardization of the way one determines a positive from a negative scan.

At HAI and AAN in Toronto, and ICAD in Honolulu, we will see lots of new data on these tracers in terms of cognitive correlates in normals and MCI subjects. I also expect AVID's florbetapir (formerly known as AV-45) will be the first to present validation data from a multicenter autopsy study. Once the validation is complete, this will really jumpstart the use of PET amyloid imaging in secondary and primary prevention trials of both drugs and lifestyle interventions. It will also give us more insight into the role of amyloid in aging and dementia, and allow us to test mechanistic hypotheses.

View all comments by P. Murali Doraiswamy

I am delighted that research on prevention of Alzheimer disease is now a high priority for the NIH. This is particularly critical to the population at greatest lifetime risk for development of AD, postmenopausal women. One correction to this report is critical. The comment that "taking conjugated equine estrogen combined with progesterone (not estrogen alone)" is associated with AD or cognitive decline is not entirely accurate. Progesterone was not the progestin used in the WHIMS clinical trial which is likely to be the study from which the panel's conclusion was drawn. The progestin used in WHIMS was medroxyprogesterone acetate (MPA). The distinction is critical as MPA can completely antagonize the benefits of estrogen in brain, whereas progesterone can, in some instances, enhance estrogen action (1-3).

Moreover, recent data indicate that the regimen of progesterone exposure, cyclic vs. continuous, can drastically affect outcomes in brain that are particularly relevant to development of AD pathology. Christian Pike's team, as part of our NIA program project on progesterone,...  Read more

I am delighted that research on prevention of Alzheimer disease is now a high priority for the NIH. This is particularly critical to the population at greatest lifetime risk for development of AD, postmenopausal women. One correction to this report is critical. The comment that "taking conjugated equine estrogen combined with progesterone (not estrogen alone)" is associated with AD or cognitive decline is not entirely accurate. Progesterone was not the progestin used in the WHIMS clinical trial which is likely to be the study from which the panel's conclusion was drawn. The progestin used in WHIMS was medroxyprogesterone acetate (MPA). The distinction is critical as MPA can completely antagonize the benefits of estrogen in brain, whereas progesterone can, in some instances, enhance estrogen action (1-3).

Moreover, recent data indicate that the regimen of progesterone exposure, cyclic vs. continuous, can drastically affect outcomes in brain that are particularly relevant to development of AD pathology. Christian Pike's team, as part of our NIA program project on progesterone, found that continuous progesterone blocked the Aβ-lowering action of estrogen. In contrast, cyclic progesterone significantly reduced β amyloid levels by itself and enhanced rather than inhibited the estrogen effects.

Collectively, these data and those that are emerging from our group indicate that clinically used progestins, such as progesterone and MPA, can have drastically different outcomes on brain responses relevant to AD and that the regimen of delivery of these molecules is also critically important.

References:
1. Brinton RD, Nilsen J. Effects of estrogen plus progestin on risk of dementia. JAMA. 2003 Oct 1;290(13):1706. Abstract

2. Nilsen J, Brinton RD. Divergent impact of progesterone and medroxyprogesterone acetate (Provera) on nuclear mitogen-activated protein kinase signaling. Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10506-11. Abstract

3. Roberta Diaz Brinton, Richard F. Thompson, Michael R. Foy, Michel Baudry, JunMing Wang, Caleb E Finch, Todd E. Morgan, Frank Z. Stanczyk, Christian J. Pike, and Jon Nilsen. Progesterone Receptors: Form and Function in Brain. Front Neuroendocrinol. 2008 May;29(2):313-39. Abstract

4. Carroll JC, Rosario ER, Villamagna A, Pike CJ. Continuous and Cyclic Progesterone Differentially Interact with Estradiol in the Regulation of Alzheimer-Like Pathology in Female 3xTransgenic-Alzheimer's Disease Mice. Endocrinology. 2010 Apr 21. Abstract

View all comments by Roberta Diaz Brinton

In my opinion, the big environmental cause of AD is likely to be refined, antioxidant-depleted seed oils, which have now been linked to both cognitive decline (Psaltopoulou et al., 2008) and incident AD (Barberger-Gateau et al., 2007). These oils are neurotoxic, and their absence in the diet of people using only olive oil accounts for the relative absence of AD in this group.

View all comments by Robert Peers

Absence of proof is not proof of absence.

The committee's conclusions reflect the current standards of evidence-based medicine as regards recommendations for interventions, including preventive interventions. By these standards, the field of AD research has not yet produced substantial findings sufficient to warrant such recommendations. That conclusion was never in doubt.

Certainly, the field has attempted to produce such evidence. With one or two exceptions, however, all RCTs have sought either improvement or stabilization of symptomatic AD, including mild cognitive syndromes thought frequently to represent the early symptomatic expression of the disease. The spectacular failures of these trials have brought puzzlement and demoralization, so that we are now forced to reassess our approach to AD therapeutics. In particular, we must consider ways to intervene in the pre-symptomatic stages of AD pathogenesis. From the perspective of symptoms, at least, this is primary prevention.

Until now, our field has done relatively little work on primary prevention....  Read more

Absence of proof is not proof of absence.

The committee's conclusions reflect the current standards of evidence-based medicine as regards recommendations for interventions, including preventive interventions. By these standards, the field of AD research has not yet produced substantial findings sufficient to warrant such recommendations. That conclusion was never in doubt.

Certainly, the field has attempted to produce such evidence. With one or two exceptions, however, all RCTs have sought either improvement or stabilization of symptomatic AD, including mild cognitive syndromes thought frequently to represent the early symptomatic expression of the disease. The spectacular failures of these trials have brought puzzlement and demoralization, so that we are now forced to reassess our approach to AD therapeutics. In particular, we must consider ways to intervene in the pre-symptomatic stages of AD pathogenesis. From the perspective of symptoms, at least, this is primary prevention.

Until now, our field has done relatively little work on primary prevention. As is well known, primary prevention trials are enormously costly and require many years to complete. Even so, given the looming public health crisis of AD, one may ask why there is reluctance to commit these resources? After all, the U.S. has spent billions on prevention trials for heart disease and cancer. Why not AD?

I suggest that the "elephant in the room" has been our inability—at least until now—to garner preliminary data indicating the probable success of such trials. At present, the best such evidence in AD has come from observational studies, but these have produced inconsistent results, and they are vulnerable to well-known sources of error. Reliance on animal models—an obvious alternative—has proven treacherous, probably because the current models do not resemble human AD sufficiently to provide a realistic test of treatment response.

What we now need, I think, is intensive effort to develop preliminary tests for the "efficacy" of candidate prevention agents in humans. This means finding ways to demonstrate effects of interventions in the pre-symptomatic stages of AD. Fortunately, we are now at the point where we can probe the pre-symptomatic disease process through imaging and biochemical markers. We need to develop the uses of these markers. We need especially to find measures that are sufficiently sensitive and precise to reveal change over time in the pre-symptomatic disease process. Once we have these measures, relatively efficient and short-term experiments can identify which candidate interventions mitigate the progression of pre-symptomatic AD. These same interventions will then become the logical choices for lengthier and more expensive AD prevention trials.

View all comments by John Breitner

With regard to the big picture, I agree with John Breitner that RCTs have largely focused on treatment of established AD. A few have looked at MCI, but it has been defined at a high threshold, such that the likelihood of progression to dementia in a few years is high—and this typically means that AD pathology is probably already present in most of those who do progress. Primary prevention trials would be optimal, but they require a much longer time period before they will yield informative results, and are also much more expensive.

In the meantime, long-term cohort studies such as Framingham, Nurse's, Health Professionals, Honolulu, etc., may be our best bet, as they offer the possibility of measuring exposure long before symptoms develop. (For brief descriptions of these cohorts, see the AlzRisk AD Epidemiology Database.) This, in turn, rules out the possibility that putative risk factors are actually due to the disease process or part of the disease prodrome, which is a significant concern for cognitive activities, for...  Read more

With regard to the big picture, I agree with John Breitner that RCTs have largely focused on treatment of established AD. A few have looked at MCI, but it has been defined at a high threshold, such that the likelihood of progression to dementia in a few years is high—and this typically means that AD pathology is probably already present in most of those who do progress. Primary prevention trials would be optimal, but they require a much longer time period before they will yield informative results, and are also much more expensive.

In the meantime, long-term cohort studies such as Framingham, Nurse's, Health Professionals, Honolulu, etc., may be our best bet, as they offer the possibility of measuring exposure long before symptoms develop. (For brief descriptions of these cohorts, see the AlzRisk AD Epidemiology Database.) This, in turn, rules out the possibility that putative risk factors are actually due to the disease process or part of the disease prodrome, which is a significant concern for cognitive activities, for example.

The call for standardized measures of exposure and outcome is also key. We have made significant gains on the outcome side, though these will need to be enhanced if we move earlier, which we need to do. In contrast, we have a long way yet to go on the exposure side. Convening the principal investigators of major cohort studies to look for common exposure measures might help, although, of course, they will be limited by what they choose to measure years or decades earlier.

In terms of clinical recommendations, one other issue to consider is the "side" consequences of each change. These include other health effects, such as the impact of exercise and dietary changes on cardiovascular health and mortality, and on quality of life. As the old joke goes, "If I do all of this, will I live longer?" "Not necessarily, but it will seem longer."

The consequences of each recommendation may differ from individual to individual, so each person will need to decide based on current evidence and his or her own health history and lifestyle preferences.

View all comments by Deborah Blacker

The NIH State-of-the-Science Conference has set a threshold of evidence required to make recommendations that goes beyond what would best serve the interests of public health. This may seem paradoxical, because as scientists we demand the highest standards of rigor, and critiquing the panel for setting the bar too high may appear to undermine our strong commitment to the scientific method. However, AD prevention simply is not at the point yet of delivering formal proof as per the dictums of evidence-based medicine. Even so, this panel is likely to influence the thinking of policymakers, who routinely operate in a situation of having to make far-reaching decisions in the absence of definitive proof. Hence, policymakers require guidance that has the public health interest at heart.

The expectation that interventions such as treating hypertension, adopting good nutrition, and exercise require the same standard of proof as demonstrating efficacy and safety of a novel drug represents a further setback for the already arduous task of gaining widespread adherence to healthy...  Read more

The NIH State-of-the-Science Conference has set a threshold of evidence required to make recommendations that goes beyond what would best serve the interests of public health. This may seem paradoxical, because as scientists we demand the highest standards of rigor, and critiquing the panel for setting the bar too high may appear to undermine our strong commitment to the scientific method. However, AD prevention simply is not at the point yet of delivering formal proof as per the dictums of evidence-based medicine. Even so, this panel is likely to influence the thinking of policymakers, who routinely operate in a situation of having to make far-reaching decisions in the absence of definitive proof. Hence, policymakers require guidance that has the public health interest at heart.

The expectation that interventions such as treating hypertension, adopting good nutrition, and exercise require the same standard of proof as demonstrating efficacy and safety of a novel drug represents a further setback for the already arduous task of gaining widespread adherence to healthy behaviors. How would we obtain that standard of proof? The NIH panel does not seriously believe that we will conduct trials in which subjects will be randomized to a control group who do not treat their hypertension, follow a poor diet, or refrain from exercise. And even if we found a clever study design, how would the panel stratify for the multiple variables we encounter in all lifestyle studies? Stratification for a myriad of diets, many levels and types of exercise, a large number of anti-hypertensive treatment regimens, and, most challenging, genotype, would require statistical power that exceeds Earth’s population.

Furthermore, the goals of our communities are to prevent dementia rather than to focus on efficacy in a single cause of dementia, Alzheimer disease. The very large contribution of small vessel disease to the dementia phenotype is completely overlooked when the only outcome measure upon which we base recommendations is strictly Alzheimer’s. Ironically, the panel did note health disparities in the occurrence of dementia, but failed to draw the conclusion that the very groups who suffer most also have a higher incidence of hypertension, poor nutrition, and lack opportunities to exercise.

The panel would have served the nation better had it acknowledged that we have achieved a reasonable level of certainty to recommend risk reduction through safe interventions such as eating well, exercise, and the treatment of hypertension. This is sound both scientifically and from a public health standpoint. Risk reduction does not make the same claim as prevention and allows us to pursue more actively the vital public health efforts directed toward nutrition and obesity in our schools, toward health disparities due to the absence of fresh foods in poor inner city communities, and toward the incontrovertible value of exercise for general well-being. As a scientist, I readily concur that the repertoire of laboratory techniques, which ranges from genetically identical mouse strains to precise quantitative assessments of plaques and tangles and their correlations with advanced imaging procedures, is extraordinarily insightful. But as a physician and member of the community, I think it remains crucial that we not conflate these rigorous approaches, essential as they are to scientific progress, with the best interests of the community now. We have to work for the public good even while we have a less-than-complete dataset.

View all comments by Kenneth Kosik

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

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

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

This is fantastic work, but care should be taken not to conflate the common biomarker changes between the Colombian kindred described above and those at risk for late-onset sporadic AD (ApoE4 carriers). In the paper (Valla et al., 2010, cited above), we presented evidence that young adult ApoE4 carriers do not show any amyloid-related changes (increases in soluble amyloid or increased deposition), even though they show functional changes via glucose PET at that age (Reiman et al., 2004, also cited above) and cytochrome oxidase histochemistry. The "common" changes discussed in this article refer to the PET-measured functional changes, not amyloid levels or amyloid deposition. These "common" changes between familial and sporadic AD may be linked by amyloid, but the current evidence suggests they are not.

View all comments by Jon Valla