I have posted several blog entries related to Alzheimer’s Disease (AD), including New views of Alzheimer’s disease and new approaches to treating it, The social cost of Alzheimer’s disease and late-life dementia, Diet and cognition, Warding off Alzheimer’s Disease and things in my diet, and a short post Deconstructing Alzheimer’s Disease – role of mitochondria. The purpose of this blog entry is to report on some additional mostly-recent research findings, focusing particularly on dietary substances and supplements and their impacts on AD. Topics covered are research related to 1. Relationship of SIRT1 and taking resveratrol to AD, 2. Dietary substances and supplements and AD, 3. Clinical trials of dietary substances for AD, and 4. Curcumin and AD.
1. SIRT1 and Resveratrol and Alzheimer’s Disease
I have discussed the SIRT1 gene and protein in numerous contexts in this blog. In the blog entry SIRT1, mTOR, NF-kappaB and resveratrol I mentioned links between SIRT1 activation, mTOR signaling suppression, and inhibition of NF-kappaB. And I discussed how some researchers think activation of SIRT1 might confer a strong a therapeutic effect for control of Alzheimer’s disease. Several review articles published in the last couple of years articulate that hypothesis and suggest a potential role for resveratrol in controlling AD. These articles include the March 2010 e-publication Resveratrol as a Therapeutic Agent for Neurodegenerative Diseases, the 2009 publication Resveratrol and neurodegenerative diseases: activation of SIRT1 as the potential pathway towards neuroprotection and the 2008 publication Modulation of sirtuins: new targets for antiageing. “ — increasing SIRT1 has been found to protect cells against amyloid-beta-induced ROS production and DNA damage, thereby reducing apoptotic death in vitro. Moreover, it has been demonstrated that Alzheimer’s and Huntington’s disease neurons are rescued by the over-expression of SIRT1, induced by either caloric restriction or administration of resveratrol, a potential activator of this enzyme. The therapeutic use of resveratrol (a polyphenol present in red wines) and other related compounds, which utilize SIRT1 pathway modulators, in treating aging-related brain disorders will be discussed in this review(ref).”
While these and other review articulate this hypothesis (that resveratrol and SIRT1 activation could be useful in controlling AD), current experimental evidence to this effect seems to be scarce. There were earlier experiments indicating that resveratrol is neuroprotective against beta-amyloid-induced neurotoxicity in rat neurons(ref), but I am unaware of any tests of the effects of taking resveratrol on warding off or treating human Alzheimer’s disease. Personally, I think resveratrol is a great supplement but the hypothesis that resveratrol and SIRT1 activation could be useful in controlling AD remains an untested conjecture as far as I know. Theoretical reasons for taking resveratrol may be strong but clinical data on effectiveness in AD is nonexistent.
2. Alzheimer’s Disease, dietary substances and supplements
A large number publications based on in-vitro and mouse studies suggest that polyphenols occurring in common dietary substances and supplements may be useful for treating or preventing the onset of Alzheimer’s or other neurodegenerative diseases. Examples are:
· The 2009 study Cinnamon extract inhibits tau aggregation associated with Alzheimer’s disease in vitro reports “An aqueous extract of Ceylon cinnamon (C. zeylanicum) is found to inhibit tau aggregation and filament formation, hallmarks of Alzheimer’s disease (AD). The extract can also promote complete disassembly of recombinant tau filaments and cause substantial alteration of the morphology of paired-helical filaments isolated from AD brain.”
· (2009) l-Theanine, an amino acid in green tea, attenuates beta-amyloid-induced cognitive dysfunction and neurotoxicity: reduction in oxidative damage and inactivation of ERK/p38 kinase and NF-kappaB pathways.
Again, the clinical evidence for the effectiveness of most of these substances against Alzheimer’s disease seems to range from being very limited to nonexistent. Pharmaceutical companies are understandably only willing to spend millions or hundreds of millions of dollars on clinical trials of substances that they own the rights to – and that excludes foods and plant-based supplements. However, some public agencies have been stepping in to fill the gaps.
3. Clinical Trials of dietary substances for AD
The clinicaltrials.gov database shows some 781 clinical trials for AD of which approximately 100 are ongoing. I went only through the first 300 trials listed to come up with the following related to dietary substances or supplements.
The Department of Veterans Affairs is currently sponsoring two such trials now in the recruiting phase, A Single Center, Multi-site, Randomized, Double-blind, Placebo-controlled Trial of Resveratrol With Glucose and Malate (RGM) to Slow the Progression of Alzheimer’s Disease. And A Randomized, Clinical Trial of Vitamin E and Memantine in Alzheimer’s Disease (TEAM-AD) Another clinical trial Lipoic Acid and Omega-3 Fatty Acids for Alzheimer’s Disease sponsored by the Oregon Health and Science University is not yet recruiting. The clinical trial Lutein and Alzheimer’s Disease Study (LAD) sponsored by the Oregon Health and Science University is listed as still in the recruiting phase.
A clinical study Prevention of Alzheimer’s Disease by Vitamin E and Selenium (PREADVISE) sponsored by the National Institute on Aging (NIA) is ongoing.
4. Completed clinical trials of dietary substances for AD
A clinical trial VITAL – VITamins to Slow ALzheimer’s Disease (Homocysteine Study) sponsored by the National Institute on Aging has been completed. The substances tested were Folate, Vitamin B6 and Vitamin B12. The 18-month double blind study involved in 409 participants in 38 study locations and was designed to measure differences in decline of cognitive functioning. The study results, reported in the publication High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial, were negative. “A higher quantity of adverse events involving depression was observed in the group treated with vitamin supplements. CONCLUSION: This regimen of high-dose B vitamin supplements does not slow cognitive decline in individuals with mild to moderate AD.”
Another completed clinical trial is OmegAD (Omega-3 and Alzheimer’s Disease), sponsored by Karolinska University Hospital. The randomized double-blind trial involved omega-3 fatty acid treatment of 174 patients with mild to moderate Alzheimer’s Disease . The results were underwhelming as reported in the 2006 paper Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. “CONCLUSIONS: Administration of omega-3 fatty acid in patients with mild to moderate AD did not delay the rate of cognitive decline according to the MMSE or the cognitive portion of the Alzheimer Disease Assessment Scale. However, positive effects were observed in a small group of patients with very mild AD.”
A clinical trial Long-term Use of Galantamine Versus Nootropics (Memory Enhancing Drugs) in Patients With Alzheimer’s Dementia Under Conditions of Daily Routine sponsored by Janssen-Cilag G.m.b.H has been completed but no results of it have yet been published. The nootropics were evaluated secondarily, galantamine being the main focus of the study. The nootropics included ginkgo biloba, nicergoline, and piracetam.
A clinical trial Effect of Panax Ginseng on the Cognitive Performance in Alzheimer’s Disease sponsored by the Seoul National University Hospital has been completed. The results are published in the 2008 publication Panax ginseng enhances cognitive performance in Alzheimer disease. “Consecutive AD patients were randomly assigned to the ginseng (n=58) or the control group (n=39), and the ginseng group was treated with Panax ginseng powder (4.5 g/d) for 12 weeks. Cognitive performances were monitored using the mini-mental state examination (MMSE) and Alzheimer disease assessment scale (ADAS) during 12 weeks of the ginseng treatment and at 12 weeks after the ginseng discontinuation. MMSE and ADAS scales showed no baseline difference between the groups. After ginseng treatment, the cognitive subscale of ADAS and the MMSE score began to show improvements and continued up to 12 weeks (P=0.029 and P=0.009 vs. baseline, respectively). After discontinuing ginseng, the improved ADAS and MMSE scores declined to the levels of the control group. These results suggest that Panax ginseng is clinically effective in the cognitive performance of AD patients.”
A number of clinical trials are shown as completed but no publications report on their results.A competed pilot clinical trial Alzheimer’s Disease: Potential Benefit of Isoflavones shows no publication history up to this point. A clinical trial Fish Oil and Alpha Lipoic Acid in Treating Alzheimer’s Disease Phases I and II sponsored by the Oregon Health and Science University appears to be completed in 2007 but no associated publication is listed. The study Curcumin in Patients With Mild to Moderate Alzheimer’s Disease sponsored by the John Douglas French Foundation is shown as completed but I could find no publication reporting on it.
Please note that the above is only a sample of the available clinical trial information. I reviewed only 300 out of 781 studies listed. Assuming the above-mentioned trials are representative, I am struck by how thin our clinical trial information is with respect to the effectiveness of supplements against Alzheimer’s disease
4. Curcumin and Alzheimer’s Disease
There seems to be a considerable literature with respect to curcumin and AD(ref). While I have not independently verified the statements and citations therein, the October 2, 2007 item Turmeric and Alzheimer ‘s disease by Jacob Schor, ND appears to me to be particularly informative. He makes a compelling case for why curcumin may be helpful in prevention of AD. He points out that the incidence of AD in India where curcumin is commonly found in foods is a quarter that in the US. (Note that some of this might be explainable by differing demographic factors like life expectancy.) As I have been pointing out, we lack the information that could be provided by a large and well-designed clinical trial of curcumin in AD. According to the Pauling Foundation web site: “In Alzheimer’s disease, a peptide called amyloid beta forms aggregates (oligomers), which accumulate in the brain and form deposits known as amyloid plaques (72). Inflammation and oxidative damage are also associated with the progression of Alzheimer’s disease (73). Curcumin has been found to inhibit amyloid beta oligomer formation in vitro (74). When injected peripherally, curcumin was found to cross the blood brain barrier in an animal model of Alzheimer’s disease (74). In animal models of Alzheimer’s disease, dietary curcumin has decreased biomarkers of inflammation and oxidative damage, amyloid plaque burden in the brain, and amyloid beta-induced memory deficits (74-77). It is not known whether curcumin taken orally can cross the blood brain barrier or inhibit the progression of Alzheimer’s disease in humans. As a result of the promising findings in animal models, clinical trials of oral curcumin supplementation in patients with early Alzheimer’s disease are under way , 78). The results of a 6-month trial in 27 patients with Alzheimer’s disease found that oral supplementation with up to 4 g/day of curcumin was safe (4). Larger controlled trials are needed to determine whether or not oral curcumin supplementation is efficacious in Alzheimer’s disease.”
Consistent with the above, last week on April 28, 2010 – The independent panel convened by the NIH to assess the “state of the science” on preventing Alzheimer’s disease and cognitive decline released its draft consensus statement following a 2-day public conference. The
Where does this all leave me?
First of all, there is another whole area of AD research that I left out of this blog writeup but that I want to cover soon. That area is association studies that relate gene polymorphisms to susceptibility to AD.
With regard to supplements there is relatively little clinical data to go on with respect to their usefulness for delaying the onset of AD or for treating early-stage AD. I would not be surprised if clinical trials finally reveal that some combination of supplements or foods might be very useful for these purposes. I specifically see extra-virgin olive oil, green tea polyphenols, resveratrol and curcumin as excellent candidates.
With regard to what I see as the basic cause of AD and how it eventually might need to be addressed on a basic level, I stand by my statements in the blog entry New views of Alzheimer’s disease and new approaches to treating it. My best guess as explained there is that the basic cause of AD is microglial cell senescence. “Based on what we know now, the two most promising general avenues for preventing microglial cell senescence are approaches to preserving or extending telomere lengths in microglia, and approaches to refreshing and reinvigorating the somatic stem cells which differentiate into microglia.” If certain foods and supplements can help stave off AD, and I suspect they can, my strong guess is that they will do so by staving off microglial cell senescence. This is plausible since we know that one of the impacts of certain polyphenol supplements is preserving telomere lengths.
Please see the medical disclaimer for this blog.