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Antioxidants Failed an Alzheimer's Test
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Cells in the aging brain undergo the gradual biological “rusting” known to scientists as oxidation.
Because oxidation of brain cells (neurons) is greater in people with Alzheimer’s, it’s likely that oxidation is connected with the disease.
What remains less clear is whether oxidation – whose direct cause is the class of unstable oxygen compounds called free radicals – is a cause or effect of Alzheimer’s disease.
Available evidence suggests the answer is “both”, with oxidative stress both fueling the processes that drive the disease and being increased by their neuro-toxic products.
What about omega-3s?
The human brain is both rich in omega-3 DHA and dependent on it for all key mental functions.
As with the polyphenols in plant foods, there’s a good deal of evidence indicating that the omega-3s in fish oil – especially DHA – exert beneficial effects in our brains.
As a researcher from Chicago’s Rush University put it, “Studies from animal models and cell cultures have shown that omega-3 fatty acids (n-3 FAs) are neuroprotective during development and aging” (Huang TL 2010).
In particular, animal studies and human brain-cell studies show these effects from omega-3 DHA (Huang TL 2010; Hashimoto M, Hossain S 2011; Calon F 2011):
  • Protects against and ameliorates impairment of learning ability.
  • Helps the body eliminate amyloid-beta protein plaque from the brain.
  • Reduces oxidative stress in brain regions key to memory and emotion.
  • Inhibits the damaging “fibrillation” of amyloid-beta protein and cuts amyloid-induced toxicity.
As the Japanese authors of an evidence review wrote last year, “… it [DHA] might be a useful therapeutic agent to prevent and/or delay cognitive impairment ...” (Hashimoto M, Hossain S 2011).
A Canadian researcher made the key point in a paper published last year:
“… clinical trials on neurodegenerative diseases consistently remind us that treating early is critical, and this is likely to be the case with omega-3[s] in Alzheimer's disease as well” (Calon F 2011).
This vicious cycle appears in most degenerative conditions, from diabetes, arthritis, cancer, and cardiovascular disease to Alzheimer’s and other forms of dementia.
Antioxidants vs. Alzheimer’s: Evidence is mixed, with foods beating pills
There’s ample epidemiological evidence linking naturally antioxidant-rich diets to lower risk of Alzheimer’s and other degenerative diseases.
Yet there’s been little to no clinical evidence that supplemental antioxidants can prevent or treat any of these disorders.
The most commonly tested supplemental antioxidants have been vitamins E and C, CoQ10, alpha-lipoic acid, selenium, and carotene compounds.
It’s not really surprising that supplemental antioxidants – when taken over the relatively short term of most clinical trials (one to five years) – wouldn’t make much of a dent in the much longer-term processes that cause Alzheimer’s and other degenerative diseases.
But many animal and cell studies show promising effects at the cellular level.
This suggests that – presuming a fairly healthful diet and lifestyle – taking supplemental antioxidants routinely during the several decades prior to the typical age of diagnosis might help delay or ameliorate degenerative diseases.
However, the negative outcomes of a small, short-term trial seem to dampen hopes that supplemental antioxidants – at least the ones typically tested in trials – play much of a role in preventing or easing Alzheimer’s.
Foods’ synergistic, nutrigenomic effects provide advantage over pills
Whole plant foods abound in “antioxidant” compounds – primarily carotenes (carrots, squash, peppers, and wild salmon) and polyphenols, which occur in most plant foods … but most abundantly in berries, cocoa, tea, onions, beans, and whole grains.
Among other likely beneficial effects, these compounds’ known “nutrigenomic” influences on gene switches and cell signals tend to reduce unhealthful levels of oxidation and inflammation.
The apparent health benefits of plant foods rich in carotenes and polyphenols almost certainly flow from these nutrigenomic effects, rather than from direct antioxidant effects in the body.
Along with ample evidence for the benefits of fiber and other “phyto-nutrients”, evidence linking diets rich in fruits and vegetables to beneficial nutrigenomic effects may well explain why such diets are associated with a lower risk of Alzheimer’s and other degenerative diseases.
In other words, it may take a “village” of food-borne antioxidants and other phyto-nutrients – rather than isolated antioxidants – to make a difference in preventing or ameliorating Alzheimer’s.
And we should add that genetic factors play a major role in the risk for early- and late-onset Alzheimer’s.
This may make it harder to prevent Alzheimer’s in folks who have problematic gene profiles, such as possessing the gene variation (allele) called APOE 4.
Clinical trial finds Alzheimer’s markers unchanged by antioxidant pills
The new trial was led by Dr. Douglas Galasko of the University of California, San Diego (Galasko DR et al. 2012).
His research team set out to measure the effects of antioxidant supplements in 78 patients from the Alzheimer's Disease Cooperative Study (ADCS) Antioxidant Biomarker study.
Each of the antioxidants tested is part of the body’s own “antioxidant network”, and all except alpha-lipoic acid abound in certain foods.
Vitamin E is actually a combination of various compounds with differing effects and roles. The one they tested (alpha-tocopherol) is the form typically used in multivitamins and vitamin E supplements.
The UCSD team looked at changes in cerebrospinal fluid (CSF) biomarkers related to Alzheimer disease and oxidative stress, cognition, and function.
The participants were divided into one of three groups, each of which was assigned to a unique daily regimen for 16 weeks (four months):
  1. Placebo pill
  2. E/C/ALA – vitamin E (alpha-tocopherol) 800 IU + vitamin C 500 mg + ALA (alpha-lipoic acid) 900 mg
  3. Coenzyme Q10 (CoQ10) 1,200 mg (400mg three times daily)
Cerebrospinal fluid (CSF) was drawn from 66 of the 78 patients before and after the trial.
The CSF analyses found no changes to markers for Alzheimer’s disease among the E/C/ALA group.
However, the E/C/ALA group enjoyed a substantial 19 percent drop in levels of a key oxidation marker called F2-isoprostane … a finding that indicates reduced oxidative stress in the brain.
Surprisingly, the E/C/ALA group had lower (worse) scores on a standard test of cognitive decline at the end of the trial, versus their scores at the outset (Mini-Mental State Examination or MMSE).
It’s hard to explain that puzzling finding, which seems both counterintuitive and implausible.
The CoQ10 group showed no changes in CSF markers for Alzheimer’s disease and – unlike the E/C/ALA group – no drop in levels of the F2-isoprostane marker for oxidative stress.
On the other hand, the CoQ10 group showed no decline in their cognitive performance.
While this study showed no change in specific markers for Alzheimer’s disease, it did find potentially beneficial drops in oxidative stress.
But given the odd finding of increased cognitive decline, we’d rely more on whole foods and their synergistic blend of nutrigenomic agents, and less on supplements providing isolated antioxidants.
  • Barberger-Gateau P, Samieri C, Féart C, Plourde M. Dietary omega 3 polyunsaturated fatty acids and Alzheimer's disease: interaction with apolipoprotein E genotype. Curr Alzheimer Res. 2011 Aug;8(5):479-91. Review.
  • Calon F. Omega-3 polyunsaturated fatty acids in Alzheimer's disease: key questions and partial answers. Curr Alzheimer Res. 2011 Aug;8(5):470-8. Review.
  • Galasko DR, Peskind E, Clark CM, Quinn JF, Ringman JM, Jicha GA, Cotman C, Cottrell B, Montine TJ, Thomas RG, Aisen P; for the Alzheimer's Disease Cooperative Study. Antioxidants for Alzheimer Disease: A Randomized Clinical Trial With Cerebrospinal Fluid Biomarker Measures. Arch Neurol. 2012 Mar 19. [Epub ahead of print]
  • Hashimoto M, Hossain S. Neuroprotective and ameliorative actions of polyunsaturated fatty acids against neuronal diseases: beneficial effect of docosahexaenoic acid on cognitive decline in Alzheimer's disease. J Pharmacol Sci. 2011;116(2):150-62. Epub 2011 May 21. Review.
  • Hedskog L, Zhang S, Ankarcrona M. Strategic Role for Mitochondria in Alzheimer's Disease and Cancer. Antioxid Redox Signal. 2011 Oct 26. [Epub ahead of print]
  • Huang TL. Omega-3 fatty acids, cognitive decline, and Alzheimer's disease: a critical review and evaluation of the literature. J Alzheimers Dis. 2010;21(3):673-90. Review.
  • Lukiw WJ, Bazan NG. Inflammatory, apoptotic, and survival gene signaling in Alzheimer's disease. A review on the bioactivity of neuroprotectin D1 and apoptosis. Mol Neurobiol. 2010 Aug;42(1):10-6. Epub 2010 Apr 23. Review.
  • National Institute on Aging. Alzheimer's Disease Genetics Fact Sheet. November 11, 2011. Accessed at
  • Smith MA, Lee HG, Perry G. Oxidative Stress and its Implications for Future Treatments and Management of Alzheimer Disease. Int J Biomed Sci. 2010 Sep;6(3):225-227.
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