See Q&A with author Mathew Hemming at end of story

12 October 2005. A trend is afoot in Alzheimer disease research that is both potentially alarming and hopeful. Researchers from across the field are finding hints that a variety of common dietary and pharmaceutical substances we routinely put into our bodies can subtly influence the balance of amyloid production and clearance over time. The bag is mixed, as some reported effects seem desirable, others not. Each substance differs in its potency and suggested mechanism of action, and certainly the field is far from gaining an overall understanding of their role in the pathogenesis of AD. But even now, the trend raises the broader question of whether many people may be unknowingly modulating their amyloid load with the food they eat and the drugs they take for complaints that, to begin with, have nothing to do with AD. At a time when researchers are developing a renewed appetite for unraveling molecular mechanisms of environmental factors affecting AD, research into the molecular mechanism of action of fairly prosaic items—the components of tea, coffee, common foods, and drugs—may offer new avenues of investigation. Here is a sampling of such studies from the past month.

Drugs of Heart and Mind
First, consider pharmaceutical substances. The widely prescribed antihypertensive medicine captopril has entered the AD scene with a red flag pinned on it. In the September 9 Journal of Biological Chemistry, Matthew Hemming and Dennis Selkoe from Brigham and Women’s Hospital in Boston, Massachusetts, report their discovery of a new Aβ-degrading enzyme. It is angiotensin-converting enzyme (ACE), a zinc metalloprotease that helps dilate blood vessels through its proteolytic cleavage of angiotensin. Inhibitors of this enzyme make up a family of cardiovascular drugs, which are used not only to lower blood pressure but also to prop up a weakening heart muscle in patients who have had a heart attack (for a summary of these drugs, see MedlinePlus.) When tested on cells that produce and release Aβ peptides, captopril caused Aβ to accumulate over time, Hemming and Selkoe report.

The scientists started investigating ACE because genetic evidence linking it to AD risk is growing. The AlzGene database to date has catalogued 45 studies on this gene, including a recent meta-analysis that confirms a particular ACE polymorphism as an AD marker (see Lehmann et al., 2005). One study found that the ACE variant linked to AD risk occurs less frequently than its other alleles in very old people (Katzov et al., 2004), and several postmortem studies of AD brain have pointed to neuronal up-regulation of ACE in relevant regions in cerebral cortex and hippocampus.

Hemming and Selkoe reasoned that ACE might play a role in AD by cleaving the Aβ peptide in the brain. If that is so, then reducing its activity—be it genetically or pharmaceutically—could increase brain Aβ levels, which over time could hasten the onset or progression of AD. They approached this hypothesis with the present, cell-based study. In it, they cloned and characterized human neural ACE and found that it can promote the clearance of both Aβ42 and 40 released from cultured cells. They tinkered with the two active domains of the enzyme and showed that both are similarly able to cleave Aβ. They constructed other variants of the protease to test whether ACE acts on Aβ directly or indirectly through a signal transduction cascade, and conclude it does the former.

When the scientists added micromolar concentrations of the ACE inhibitor captopril to the cultures, they recorded an accumulation of the Aβ peptide. “These results demonstrate that a widely prescribed ACE inhibitor can promote Aβ accumulation of natural, cell-derived Aβ by blocking ACE proteolytic activity,” the authors write. They add that most people who take these drugs for long periods of time have not had their brain or plasma Aβ levels studied. Similarly, clinical data on the rate of cognitive decline in AD patients who take such drugs are sparse and inconclusive. Future in-vivo studies of ACE inhibition and Aβ accumulation must take care to use human Aβ, because the mouse version of the peptide differs from the human one right around the cleavage site of ACE, the authors note. (See Q&A with Mathew Hemming below.)

ACE inhibitors are far from the only drugs that appear to affect the brain and the heart in opposite ways. Another emerging example concerns phosphodiesterase inhibitors. One such inhibitor, the experimental antidepressant rolipram, recently created excitement as a potential future AD treatment (see Gong et al., 2004). Now, a genetic study in last Thursday’s Cell complicates matters by raising the specter of heart failure and arrhythmias with chronic PDE inhibition (see Lehnart et al., 2005 and accompanying comment by Michael Shelanski). The underlying mechanism in this case is not directly related to amyloid economy, however, and this present news update won’t pursue it further.

But even just focusing on amyloid, many common drugs beyond possibly ACE inhibitors affect its production and removal. This space has covered extensively the fate of the most notorious among them, the nonsteroidal anti-inflammatory drugs (NSAIDs). Epidemiologic data that they protect against AD led to an NIH-funded AD prevention trial, but ensuing suspicion about cardiovascular side effects brought the trial to a halt and led to the withdrawal of one such drug from the market (see ARF related news story; see also ARF news story). Researchers believe that compounds in this class tweak the γ-secretase enzyme complex in such a way as to shift the ratio of Aβ peptide generation away from the most problematic form, Aβ42 (see, for example, ARF related news story). Surprisingly, in the course of this research, Todd Golde’s group at the Mayo Clinic in Jacksonville, Florida, hit upon a slew of compounds—some widely consumed drugs, others isoprenoids found in foods—that can affect APP processing in the opposite way, i.e., by cranking up Aβ42 generation (see Kukar et al., 2005). A better understanding of what those substances are, and how large an effect their intake actually has in people, has become an important research area.

Statin drugs, taken widely to reduce cholesterol synthesis and prevent heart disease, also appear to protect against AD in some human studies, though not all (see Wolozin comment). There, too, the mechanism involves amyloid, and, indeed, the latest major contribution to the functional link between cholesterol and APP processing appeared just yesterday in the online version of Nature Cell Biology (Grimm et al., 2005; see separate news story later this week.) A consensus hypothesis for how this works has not yet emerged, but candidates include effects on APP processing in neurons and reduction of amyloid-induced inflammation in glia. Beyond statins, this line of research has made attractive to AD researchers yet another class of drugs that were originally developed to treat elevated cholesterol and atherosclerosis. These are inhibitors of the enzyme ACAT, which are in clinical trials for heart disease (Leon et al., 2005; Hutter-Paier et al., 2004).

A Drug of Abuse
When it comes to common drugs affecting AD pathology, nicotine wafts readily to mind. This compound has a long history of study in the fields of AD, Parkinson’s, and memory, and has been credited repeatedly with being able to reduce amyloid pathology, most recently in another small human study (Court et al., 2005). Given the overwhelming overall health risks of smoking, studies usually call for the development of selective nicotinic agonist drugs. But a recent study from Frank LaFerla’s lab has raised fresh questions about this idea. This group reported that nicotine exacerbates tau pathology in their triple transgenic mouse model by activating p38-mitogen-activated protein kinase, suggesting that any compounds considered as drugs ought to be tested in models reflecting both major arms of AD pathology (Oddo et al., 2005). Net benefits of nicotine, in short, remain nebulous (see ARF related news story).

Now to the food and drink and, with that, to better news. It’s no secret that green tea and a glass of red wine with dinner are healthy habits for most people, but there are new wrinkles on why that may be so. In the September 21 Journal of Neuroscience, a research team led by Jun Tan at the University of South Florida in Tampa report that certain ingredients of green tea modulate APP cleavage sufficiently to reduce Aβ levels and plaques in AD mouse models—but continue reading before you put on the kettle. While some of the flavonoids in green tea potently depress Aβ generation, others actually increase it mildly, implying that drinking green tea packs less of a punch against AD than would a supplement formulated with selected components. This would cut against the conventional wisdom of nutritionists, who generally maintain that whole foods are healthier than isolated vitamins and other components formulated as dietary supplements.

Tan’s team performed a careful study as part of a wide, ongoing effort across the field to analyze the complexities of APP proteolysis and Aβ metabolism in detail. Three different proteases cleave APP in a sequential, regulated process. Every step produces its own cleavage fragments and is subject to modulation by a variety of compounds. One such modulator is green tea extract. The polyphenolic flavonoid structures in that extract were generally thought to be the active ingredients of this beverage, the leading candidate being a putative neuroprotective with a mouthful of a name, (-)-epigallocatechin-3-gallate, or EGCG for short. Moussa Youdim and colleagues have previously suggested that EGCG increases the beneficial α-cleavage of AβPP through an effect on protein kinase C (Levites et al., 2003; Han et al., 2004), but EGCG affects other cellular responses, as well (see, for example, Mandel et al., 2005).

In the present study by Tan, first author Kavon Rezai-Zadeh and colleagues added EGCG to cell lines transfected with human mutant APP to primary neuron cultures from APP 2576 transgenic mice, and injected it into the peritoneum, or brain ventricles, of those mice. The authors found that EGCG reduces both Aβ levels and plaque number, but unlike with ACE, this does not happen through degradation. Rather, the generation of two products of α-secretase cleavage, sAPP-α and α-CTF, proved to be increased, as was the activity of TACE. Also called ADAM-17, TACE is a candidate α-secretase enzyme. These results suggest that EGCG reduces the amyloid burden in vivo by promoting non-amyloidogenic processing of AβPP. At the same time, however, two separate components of green tea, (-)-gallo-catechin (CG) and (-)-catechin (c), promoted Aβ production by opposing the effect of EGCG on α-secretase. “The ability of the purified EGCG alone to inhibit Aβ generation is much greater than that of GT,” the authors write.

The precise mechanism of action of ECGC needs further study. Tan and colleagues suspect the compound promotes expression of TACE but still need to examine in detail possible effects on other TACE substrates, such as tumor necrosis factor-α. Furthermore, it is unclear if TACE is the most important physiological α-secretase in humans (Kojro and Fahrenholz, 2005).

The authors write that they cannot reproduce earlier data suggesting EGCG might act to inhibit β-secretase. Instead, EGCGs demonstrated effect on protein kinase C activity might be important, they note. Whatever the precise molecular mechanism of EGCG, its effect is masked by its fellow green tea ingredients, explaining perhaps why previous work on the effects of green tea extracts has had mixed results. Despite the use of EGCG in one clinical trial (Ullman et al., 2003), it remains unclear whether a safe and effective dose can be found in humans. Pure EGCG, or analogs that are more active or more bioavailable should be tested in clinical trials to assess whether such substances could serve as part of a broader strategy to prevent AD, the authors write.

In the Western world, people have been enjoying wine for much longer than green tea, which is a traditional beverage chiefly in China, Japan, parts of North Africa, and the Middle East. But like green tea, moderate wine drinking has the backing of epidemiologists when it comes to staving off AD (Orgogozo et al., 1997; Luchsinger et al., 2004). The ingredient in wine that has been getting most of the buzz is resveratrol, an antioxidant polyphenol from grapes. (It’s found also in dark chocolate and pomegranates.)

On this compound, two current studies suggest different mechanisms by which it may act. Beyond centering on amyloid metabolism, they have little in common, and further research will need to sort out if one, or both, are truly at play in AD. In the September 14 Journal of Cell Biology, Philippe Marambaud at the North Shore-LIJ Institute for Medical Research in Manhasset, New York, with Haitian Zhao and Peter Davies, report that resveratrol promotes the removal of Aβ. Marambaud has not implicated a particular Aβ endopeptidase, however. His data suggest that resveratrol stimulates the degradation of Aβ in the cells’ protein grinder, the proteasome, by some as-yet unknown, indirect mechanism.

Marambaud treated APP-transgenic cell lines with different polyphenols from wine, including resveratrol, quercetin, and a catechin, and then analyzed Aβ levels. Resveratrol was the most potent at reducing both secreted and intracellular Aβ levels, but it had no effect on APP proteolysis and Aβ production. The known Aβ-degrading enzymes neprilysin, endothelin-converting enzyme, and insulin-degrading enzyme were not responsible for the drop in Aβ levels, either, the scientists report. (The study does not mention ACE.) Instead, Marambaud et al. found that three different proteasome inhibitors blocked the resveratrol-induced drop in Aβ levels, as did siRNA silencing of particular proteasome subunits. Prior data from Fred van Leeuwen’s lab implicates the proteasome in Aβ degradation (de Vrij et al., 2004), and proteasome activity is known to decline with aging. Resveratrol does not stimulate the proteasome directly, Marambaud and colleagues report, and its precise mechanism of action remains up for grabs. The scientists also reported, however, that some analogs of resveratrol proved as potent as the real McCoy in their assay; the hunt for resveratrol look-alikes that make more suitable drugs and can be patented is on in commercial biotech and some academic laboratories.

Regarding the mechanism of action of resveratrol, different options are on the table. Resveratrol’s most prominent molecular targets these days are certain members of the sirtuin (SIRT) family of proteins. These deacetylase enzymes are at the center of a rapidly growing field of molecular aging and metabolic research, and they are also beginning to be implicated in neuroprotection in models of axonal degeneration (Araki et al., 2004) and polyglutamine disease (Parker et al., 2005). Resveratrol activates human SIRT1 in vitro, but whether SIRT1 truly plays a role in Aβ degradation in humans remains an open question.

The other study, in the September 23 early online JBC, takes an entirely different tack on the issue of resveratrol and amyloid. Rather than focus on Aβ degradation inside neurons, its authors approach the problem by studying neurons’ unruly neighbors, the microglial cells. Researchers led by first author Jennifer Chan and senior author Li Gan at the University of California, San Francisco, present a hypothesis whereby resveratrol’s activation of SIRT1 counteracts the stimulation of microglia and thus keeps them from spewing toxic substances back at neurons. By their model, oligomeric Aβ binding to microglia, in the early stages of AD, activates the inflammatory transcription factor NF-κB, which drives up transcription of target genes including iNOS and cathepsin B. Once released, these enzymes help kill off nearby neurons, according to the model. The place where resveratrol interferes with this chain of events revolves around NF-κB regulation by the protein RelA/65. To be fully active, this protein needs to have certain lysine sites acetylated. Driven by resveratrol, SIRT1 can take those acetyl groups off, thereby interrupting the Aβ-mediated toxic signal transduction cascade inside microglia. Conceivably, this action could have broader anti-inflammatory consequences in microglia, as well. Astrocytes, too, show elevated NF-κB and RelA/65 activity in AD brain. By this model, reversible acetylation, not Aβ degradation, would be the means by which this wine ingredient manages to protect neurons.

A diet of wine and tea does not get one through life. Luckily, some heartier fare also contains substances that affect amyloid formation rather directly. Much research remains to be done in the area of dietary constituents and AD pathogenesis. Perhaps the best-studied case concerns curcumin, an ingredient of the yellow curry spice turmeric that is, like resveratrol, an antioxidant polyphenol. Greg Cole and Sally Frautschy at the University of California, Los Angeles, have studied this compound for the past 5 years and have recently begun a human study with AD patients following their earlier work showing that curcumin inhibits formation of Aβ oligomers in vivo (Ringman et al., 2005; Yang et al., 2004). An isoflavone component of soy, called genistein, apparently prevents misfolding and amyloid formation of the protein transthyretin by stabilizing its native tetramer, but this finding, published in the early online version of PNAS, applies to a set of amyloid diseases other than AD (see Green et al., 2005). Potent antioxidant polyphenols also occur in some fruits, for example, blueberries, though they likely do not act primarily via an effect on amyloid (Lau et al., 2005). Other seasonings are thought to be neuroprotective by acting as anti-inflammatory agents, Aggarwal and Shishodia, 2004).

Taken together, compounds such as curcumin, resveratrol, and EGCG likely have therapeutic potential by counteracting amyloid pathology. Other common compounds may promote it. To date, it remains far from clear how any of the mechanistic leads on the beneficial compounds will eventually be realized in the clinic. The AD literature is replete with clinical failures. NSAIDs epidemiology and biology suggested protection against AD, but ensuing trials failed—ditto for estrogen. Resveratrol has pleiotrophic effects, and SIRT1 alone deacetylates numerous proteins besides RelA/65, notably p53 and the transcription factor FOXO. Even so, advancing knowledge about the myriad of chemicals that tip the balance of amyloid production and clearance in our bodies as we go about our lives eating, drinking, and medicating our ills can only be good news in the long run. This news roundup is not comprehensive. Readers are cordially invited to fill the gaps, correct oversights, and comment in general.—Gabrielle Strobel

Q&A with author Mathew Hemming

Q: Have you tested the effect of captopril on APP or PS-transgenic mice?
A: We have not yet tested the effects of ACE inhibitors on APP or PS-transgenic mice. This approach is, however, a very attractive way to determine the effects of semichronic ACE inhibition on Alzheimer-type pathology in the mammalian brain.

Q: Does captopril cross the blood-brain barrier (BBB) in the doses prescribed to people?
A: Captopril is reported to cross the BBB at doses prescribed to people. Other (but not all) ACE inhibitors are also reported to cross the BBB.

Q: You cite a study suggesting the ACE I allele has been found to associate with AD but not with vascular dementia/vascular pathology. What could this mean? Does this reflect somehow the different biological consequences of ACE’s Aβ and angiotensin substrates?
A: Indeed, ACE has been genetically associated with AD, but not with vascular dementia (VD), in several reports. VD is a pathogenically heterogeneous disorder that arises from cognitive decline due to multiple infarctions in the cerebrovasculature. In contrast, hallmark features of AD are neurofibrillary tangles and amyloid plaques. What may complicate this distinction is the fact that cerebral hypoperfusion, akin to VD, might unmask the cognitive defects seen in AD and result in accelerated decline. The involvement of ACE in AD, but not in VD, suggests that ACE plays a critical role in AD independent of these vascular factors. One such role, supported by our work, is the degradation of Aβ. If ACE contributes to the degradation of Aβ in the aged human brain, then polymorphisms within the ACE gene that result in decreased protein production and/or activity and, as a result, reduce the brain’s ability to clear Aβ, may be a predisposing factor to Aβ accumulation and AD. This hypothesis is supported by genetic studies linking ACE to AD. It is unclear how other ACE substrates, including angiotensin I and other neuropeptides, are affected in AD.

Q: What studies should be done on the large number of aging people who currently take ACE?
A: Further evidence demonstrating the accumulation of Aβ as a consequence of ACE inhibition would warrant studies on the aged human population currently taking ACE inhibitors. The most direct approach would measure Aβ levels in the CSF and plasma of aged individuals with prolonged antihypertensive therapy using ACE inhibitors. Analysis of epidemiological data containing information on patients chronically taking ACE inhibitors, and their relative risk of developing AD, would be another informative approach.

Q: Some of my (and probably most everyone else’s) relatives take ACE inhibitors. Should they talk to their doctor about your study?
A: ACE inhibitors have been immensely valuable for the treatment of hypertension, heart failure, kidney disease, and other disorders. Further, there are no definitive reports connecting ACE inhibitors to an elevated risk for AD. Our results will hopefully increase scrutiny over whether these drugs are having a biologically important impact on AD susceptibility or progression.

Q: The list of Aβ-degrading enzymes is growing. Which are the most important ones in aging human brains? Do you have any data about the relative contribution ACE makes to lowering Aβ, compared to neprilysin, IDE, and ECE?
A: It is unclear which of the Aβ-degrading enzymes is most important in the aging human brain. In-vitro and animal model studies using genetic manipulation or pharmacological inhibitors are suggestive, but it is difficult to translate these results into a rank of which proteases are most important for Aβ degradation. Our work directly compared ACE and IDE, but the relative contributions of other proteases were not examined. It seems that the rank of the most important proteases may be cell-type and brain region-specific.

Q: Beyond ACE inhibitors, could there be a whole range of pharmaceutical and dietary substances that large fractions of the population ingest, which all affect Aβ levels in some way? Isoprenoids, ACE inhibitors, NSAIDs, resveratrol, green tea components, blueberries, and more, unknown ones?
A: It’s fascinating to think that we’re modulating our susceptibility to Alzheimer disease by the choices we make regarding foods, supplements, medications, exercise, and mental activities. There is strong and growing evidence that these choices factor into the risk towards many other diseases, in addition to dementia. It’s as good an excuse as any to eat your blueberries and enjoy the outdoors.


  1. The identification of ACE as a possible AD gene and ACE inhibitors as potential risk factors for AD are both potentially very important observations. Similarly, the many reports on relatively nontoxic dietary factors modulating amyloidosis in animal models is reason to believe that we will be able to find ways to prevent AD. The fact that there are so many possible approaches should not jade people, or convince them that we can’t all be right.

    It seems highly likely that Alzheimer’s, like most other late-onset diseases of aging, has multiple and usually weak genetic and environmental influences that modulate susceptibility. In contrast, diseases with strong single genetic or environmental risk factors will typically be more clearly causal, with earlier onset due to the potent genetic risk factors (e.g., autosomal dominant) or gross deficiencies of essential nutrients (scurvy, rickets, etc.). In this situation, common sense suggests a multifactorial approach to address these multiple risk factors for the prevention of late-onset AD. And common sense suggests that this is what current research is setting the stage for.

    This is not a new lesson. With intense cancer research over the last 50 years, we have fairly good epidemiology and preclinical data to support a spectrum of risk and protective factors. We have a well-developed list of oncogenes, and multiple carcinogens and anticarcinogens present in the environment and diet. We also have some idea about initiation and promotion phases and very good animal models. We can make sensible recommendations about diet, smoking, and pollutants to minimize mutagen and carcinogen exposure.

    Unfortunately, though, apart from a few successes like sunscreens, cancer chemoprevention lags behind. We can only hope that with AD, researchers will fare better, as indeed they have with atherosclerosis. There, some 50 years of concerted research has also led to a well-established list of risk and protective factors that allows the formulation of “heart healthy” recommendations with some strong clinical trial support for efficacy. With the great overlap between risk factors for AD and heart disease, we can only hope that controlling the common risk factors will limit our risk for both diseases. With this in mind, the knowledge that ACE inhibitors may increase AD risk is certainly significant, but somewhat disconcerting news.

    With Alzheimer’s and other neurodegenerative diseases of aging, 20 years of intense effort have brought us less far along, but, unsurprisingly, put us on a similar track. AD researchers at the bench have only recently developed suitable (albeit still imperfect) animal models. AD clinicians were at a comparative disadvantage in establishing biomarkers. They lacked large populations of clearly high-risk patients in “remission” or at high risk of second cardiovascular events to conduct prospective clinical trials. Now that AD researchers have the animal models and the MCI patient pools, we will begin to see what translates.

    We will likely end up with a set of “alzogens” to limit our exposure and “anti-alzogens” whose intake we want to optimize, albeit being mindful of potential side effect profiles. The polyphenolic antioxidants including green tea catechins, resveratrol, and curcumin (and doubtlessly others as yet unexplored) have real potential as protective factors for several diseases of aging, including AD. While these polyphenols have several overlapping antioxidant and anti-inflammatory properties, each of them also has its own unique targets, issues, and merits that add up to a reasonable case for further investigation. The catechins seem to reduce Aβ production, while curcumin limits Aβ aggregation and resveratrol may be particularly useful in protecting DNA via sirtuin.

    I am personally convinced that cocktails of protective agents, notably including the polyphenols, would be a logical way to go, but optimizing and clinically testing more than one drug is a formidable task. Our choice to pursue curcumin for AD came after an initial in-vivo Aβ infusion model drug screen made some 10 years ago, together with a broad consideration of multiple factors, including the advanced stage of preclinical and clinical drug development for other diseases, costs of production, remarkably benign toxicity profile, and long history of use. Another factor was curcumin’s “cocktail” of active products tetrahydrocurcumin, vanillin, and ferulic acid. Today we can point to multiple mechanisms of action and an ever-increasing list of diseases where curcumin and its natural products look useful in animal models. There is even data on lifespan extension.

  2. So much for ACE inhibitors being the "perfect pill" and protective as one ages. I find this upsetting, but clinically important information. I am hopeful that more data will be accumulated on this issue quickly.

  3. I was very interested to see the Hemming and Selkoe study regarding the possibility that ACE inhibition may not be advisable in AD.

    I refer to the recent ARF news article (1), which reports that Wolozin and colleagues find that the relative risk for AD in the CABG group was 1.7-fold that of the PTCA group.

    It's interesting that Pell et al. (2) report that 22 percent of CABG patients were on angiotensin-converting enzyme inhibitors, compared with 15 percent of PTCA patients.

    See also:

    ARF related news story.


    . Outcomes following coronary artery bypass grafting and percutaneous transluminal coronary angioplasty in the stent era: a prospective study of all 9890 consecutive patients operated on in Scotland over a two year period. Heart. 2001 Jun;85(6):662-6. PubMed.

  4. It is difficult to know whether the anti-amyloid effect of the mentioned natural compounds (i.e., resveratrol or EGCG) observed in cell culture systems or even in mouse models may explain or support the beneficial effect of specific diets. This effect may represent only the tip of the iceberg. Indeed, wine contains more than 600 different components, including well-characterized antioxidant molecules. It is, therefore, difficult to narrow down the beneficial effect of wine or green tea intake to one specific compound. Furthermore, we cannot exclude the possibility that several compounds work in synergy to slow down the progression of the neurodegenerative process in human.

    The oral bioavailability of resveratrol is almost null due to efficient metabolism by the kidney system (see Wenzel and Somoza, 2005). Therefore we do not believe that resveratrol could be used per se as an anti-amyloidogenic drug in vivo. Its potential biological activity in the brain after peripheral administration is, therefore, very questionable. However, this observation is a powerful starting point for screening analogues of resveratrol for more active and more stable compounds, a task in which our laboratory is actively involved.


    . Metabolism and bioavailability of trans-resveratrol. Mol Nutr Food Res. 2005 May;49(5):472-81. PubMed.

  5. Regarding the impact of certain foods, beverages, and drugs on the development of AD, I think it is likely a situation similar to that in cancer epidemiology: A healthy lifestyle lowers risk; a bad life style enhances risk. Of course, genetic factors provide a background which may determine how effective these changes in risk prove to be. It doesn't much matter what you eat or drink if you have an aggressive PS1 mutation; you'll get AD. And it may not matter too much, either, if you have an ApoE2 allele, since you are well protected (this is less certain, but makes the point). For the rest of the population, there is probably a sliding scale of risk. Nothing is absolutely protective or absolutely causal.

    We need to try to think in terms of risk/benefit ratios. I take vitamin C and vitamin E every day, and have done so for years, as it seems reasonably clear that the risk/benefit ratio is in favor of these compounds. They may lower my risk of AD more than they raise my risk of cardiovascular disease. It's hard to come up with real numbers, or any degree of certainty, with the compounds Gabrielle Strobel discusses.

    I've been thinking about our approach in this area. We test everything in short-term studies to see if it makes a difference to the cognitive performance of AD patients, but this is a high hurdle to climb, and most of the compounds discussed in this article are unlikely to succeed in these studies. Does this mean that they are useless? Probably not. A diet rich in fruit and veggies, moderate or no alcohol consumption, no smoking, lots of exercise, physical and mental—all this probably lowers your risk of AD.

    Would switching patients who already have the disease to a healthy lifestyle improve cognitive function? Unlikely, and so we dismiss these factors in favor of the next "wonder drug." But I suspect that if we all adopted this kind of lifestyle, the incidence of AD would decline significantly. If you believe the epidemiology, adding vitamins C and E would cut the incidence of AD by about 50 percent. Add the other goodies, and perhaps we could do even better.

    But we don't think this way because we don't care about populations; we care about individuals, especially ourselves. I want a drug that will stop me from getting AD, or treat AD if I do get it. I don't want my relative risk decreased—I want it eliminated! It isn't likely that any of the lifestyle factors will do this, and they will probably end up being largely ignored. We want cures that can be taken "just in time," not major, lasting changes to our lifestyles that may or may not work for us.

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News Citations

  1. Safety Concerns Halt ADAPT Trial
  2. Merck Withdraws Vioxx®
  3. FRETting Pays off—NSAIDs Target Presenilins, Reduce Aβ42
  4. Atorvastatin, Vaccine Trial Data Published
  5. Smoking Debate Still Smolders

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  18. . Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration. Science. 2004 Aug 13;305(5686):1010-3. PubMed.
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  20. . A potential role of the curry spice curcumin in Alzheimer's disease. Curr Alzheimer Res. 2005 Apr;2(2):131-6. PubMed.
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  24. . Suppression of the nuclear factor-kappaB activation pathway by spice-derived phytochemicals: reasoning for seasoning. Ann N Y Acad Sci. 2004 Dec;1030:434-41. PubMed.

Other Citations

  1. See Q&A with author Mathew Hemming at end of story

External Citations

  1. MedlinePlus
  2. AlzGene

Further Reading


  1. . Prevention of Alzheimer's disease: Omega-3 fatty acid and phenolic anti-oxidant interventions. Neurobiol Aging. 2005 Dec;26 Suppl 1:133-6. PubMed.

Primary Papers

  1. . Amyloid beta-protein is degraded by cellular angiotensin-converting enzyme (ACE) and elevated by an ACE inhibitor. J Biol Chem. 2005 Nov 11;280(45):37644-50. PubMed.
  2. . Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice. J Neurosci. 2005 Sep 21;25(38):8807-14. PubMed.
  3. . Resveratrol promotes clearance of Alzheimer's disease amyloid-beta peptides. J Biol Chem. 2005 Nov 11;280(45):37377-82. PubMed.
  4. . SIRT1 protects against microglia-dependent amyloid-beta toxicity through inhibiting NF-kappaB signaling. J Biol Chem. 2005 Dec 2;280(48):40364-74. PubMed.
  5. . Chronic nicotine administration exacerbates tau pathology in a transgenic model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):3046-51. PubMed.
  6. . A potential role of the curry spice curcumin in Alzheimer's disease. Curr Alzheimer Res. 2005 Apr;2(2):131-6. PubMed.