. National Institutes of Health State-of-the-Science Conference statement: preventing alzheimer disease and cognitive decline. Ann Intern Med. 2010 Aug 3;153(3):176-81. PubMed.


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  1. 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.


    . Effects of estrogen plus progestin on risk of dementia. JAMA. 2003 Oct 1;290(13):1706; author reply 1707-8. PubMed.

    . 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. PubMed.

    . Progesterone receptors: form and function in brain. Front Neuroendocrinol. 2008 May;29(2):313-39. PubMed.

    . Continuous and cyclic progesterone differentially interact with estradiol in the regulation of Alzheimer-like pathology in female 3xTransgenic-Alzheimer's disease mice. Endocrinology. 2010 Jun;151(6):2713-22. PubMed.

    View all comments by Roberta Diaz Brinton
  2. 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.


    . Diet, physical activity and cognitive impairment among elders: the EPIC-Greece cohort (European Prospective Investigation into Cancer and Nutrition). Public Health Nutr. 2008 Oct;11(10):1054-62. PubMed.

    . Dietary patterns and risk of dementia: the Three-City cohort study. Neurology. 2007 Nov 13;69(20):1921-30. PubMed.

    View all comments by Robert Peers
  3. 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
  4. 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
  5. 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

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