Antioxidants No Help for Alzheimer’s, Biomarker Trial Says

The stuff touted to confer anti-aging properties on foods from blueberries to dark chocolate does no good for people with Alzheimer’s disease—and might even make them worse, according to new research. In the March 19 Archives of Neurology online, researchers report that four months of daily antioxidant supplements had no effect on cerebrospinal fluid (CSF) Aβ or tau, and actually appeared to speed cognitive decline in people with mild to moderate AD. In some patients, the therapy reduced CSF levels of an oxidative stress biomarker, suggesting the supplements hit their intended target in the brain—something prior antioxidant trials had not demonstrated. “Based on this study, I think we would not advise people to take large doses of vitamin E, or α-lipoic acid, if they have established AD,” said lead author Douglas Galasko of the University of California, San Diego.

The idea that antioxidants might help people with AD finds support from the scientific literature. Epidemiology studies suggest that diets rich in antioxidants reduce AD risk (Morris, 2009). In AD mouse models, supplementation with vitamin E, a powerful antioxidant, reduces Aβ pathology, preserves neurite health, and improves cognition (see Sung et al., 2004; Garcia-Alloza et al., 2006; Harrison et al., 2009). Before launching the current study, the Alzheimer’s Disease Cooperative Study (ADCS) conducted two antioxidant trials—one in moderate to severe AD patients (Sano et al., 1997), the other in people with mild cognitive impairment (ARF related news story on Petersen et al., 2005). Neither found cognitive benefit with treatment, though some of the AD patients showed functional improvement. Scientists puzzled over how to interpret the data—were the doses high enough, would certain combinations of vitamins work better, etc.? At the same time, a meta-analysis of 19 randomized trials warned that high doses of vitamin E, that is, greater than 400 international units (IU) per day, may be linked to increased mortality (see Miller et al., 2005). But after all these studies, a critical question still remained. “We weighed all these things, took a step back, and decided that we actually didn’t know how well vitamin E (or other antioxidants) reduced oxidative stress in the brain,” Galasko told Alzforum. “So we decided to do a biomarker study to investigate.”

Galasko and colleagues enrolled 78 AD patients at 12 ADCS sites. They looked for change in potential CSF biomarkers of AD (Aβ42, tau, and phospho-tau181) and oxidative stress (F2-isoprostane)—as well as cognition (Mini-Mental State Exam) and daily function (ADCS Activities of Daily Living Scale)—at the end of the 16-week treatment period. One-third of the participants were randomized into a placebo group. The remainder received one of two treatments—a daily supplement of 800 IU vitamin E, 500 mg vitamin C, and 900 mg α-lipoic acid (ALA); or a chewable wafer containing 400 mg coenzyme Q (CoQ), a naturally occurring antioxidant that protects mitochondria from oxidative stress. A similar combination of vitamins E and C and ALA (E/C/ALA) improved skeletal muscle metabolism in healthy seniors (Wray et al., 2009), and the CoQ dose had improved function in some patients in a large Phase 2 trial of Parkinson’s disease (Shults et al., 2002).

None of the AD biomarkers budged with either treatment. CSF levels of F2-isoprostane fell about 19 percent in the E/C/ALA group, suggesting that this antioxidant combination did what it was supposed to, that is, lower oxidative stress in the brain, albeit modestly. “This is a vast improvement over other antioxidant trials where no one knows if the antioxidants are doing anything,” noted Greg Cole of the University of California, Los Angeles. Nevertheless, Galasko said, it is hard to know if the 19 percent reduction in F2-isoprostanes is biologically meaningful. Whereas studies suggest that a 25-30 percent drop in Aβ levels can slow pathology in AD transgenic mice, “we didn’t have a similar framework for evaluating antioxidants,” Galasko noted.

In contrast, CoQ did not even change CSF F2-isoprostane levels. Again, it is difficult to know what to make of that, Galasko said. The study did not measure how well the antioxidants entered the brain. And for CoQ, “it’s not only a question of getting in, but reaching mitochondria where it probably needs to be. It’s not clear how to best measure that,” Galasko said. Furthermore, many biomarkers are global readouts of changes occurring in small compartments, which can further complicate analysis, noted George Perry of the University of Texas at San Antonio.

However, despite the challenges of interpreting biomarker data, “looking at it at face value, we do not suspect that the antioxidants altered the AD process during the four-month period in this study,” Galasko said.

As for the cognitive data, the E/C/ALA group seemed to decline faster. This was suggested by a 2.8 point change on MMSE scores from baseline, compared to 0.9-1.0 point changes in the placebo and CoQ groups. “We did not power the study to detect a valid cognitive signal in four months,” Galasko said. Hence, it is hard to say whether the MMSE decline “was a chance occurrence or if it was some effect of the drug combination,” he told Alzforum. The E/C/ALA formulation has been used in clinical trials for diabetes and other conditions, but those did not include cognitive monitoring, Galasko noted. Nevertheless, the apparent cognitive setback raises a flag, he said. “It’s something that would need to be looked at carefully in further studies.”

Mary Sano of Mount Sinai School of Medicine, New York, found the study convincing. “I completely believe these data,” she said in an interview with Alzforum. “It says that antioxidants do not have a benefit on cognition, and may have a detrimental effect. This is paralleled by a decrease in isoprostanes. It’s a very powerful study.”

The findings challenge the simplistic belief that loading up on vitamins and antioxidants is good for you. “We like to say antioxidants are great and do wonderful things,” Sano said. “But the data are weak and may be contradictory. We have to come to grips with that.” Though the 1997 ADCS study showed that antioxidants improved function in AD patients, the supplements failed to influence cognition in several large prevention trials (Yaffe et al., 2004; Heart Protection Study Collaborative Group, 2002), making it hard to judge whether antioxidants do much good for brain health.

“It is certainly possible for an apparently innocuous cocktail of ingredients to work poorly together,” Cole noted. “The real lesson is that designing antioxidant cocktails is something that shouldn't be left to the supplement makers. They need to be rigorously tested.”

In follow-up, Galasko and colleagues are looking at biological samples from ongoing longitudinal studies to discover plausible correlations between plasma and CSF measures, and reported use of supplements. Galasko said his team does not have plans to test antioxidants in milder AD or at-risk, asymptomatic populations.—Esther Landhuis

Comments

  1. These conclusions are based on a four-month treatment, whereas most trials go on for 18 months, and some even for 36 months. Knowing the complexity of AD pathogenesis, would a four-month treatment be considered sufficiently long to test the efficacy of an approach?

    View all comments by Sanjay Pimplikar
    • User Profile Image Elena Galea
      Universitat Autònoma de Barcelona
    • Posted:

    I believe that the 19 percent decrease in isoprostane, however small, is very relevant because this is the first time that any antioxidant treatment in AD has been proven to engage its target. However, if oxidative stress is a culprit in AD, then antioxidant treatments, like any other disease-modifying drugs, should be tested at presymptomatic stages of the disease.

    View all comments by Elena Galea

  3. Failure of Antioxidants to Treat Alzheimer's Disease: Toward a Homeostatic View of Chronic Disease
    Failure of antioxidants to improve the course of cognitive decline in Alzheimer's disease (AD) underscores a paradox in oxidative stress: that efforts to increase oxidative defenses are without benefit for chronic conditions (Halliwell, 2012). This unfortunate outcome has been demonstrated in essentially every clinical or epidemiological trial of antioxidant supplements. The question that remains is an obvious one: Why this paradox of no antioxidant benefit, when disease states are so often met with increased oxidative damage and stress response (Nunomura et al., 2006; Moreira et al., 2005)? At the outset, it should be pointed out that efficacy of the antioxidant supplements in altering the oxidative balance was not demonstrated in most studies. Moreover, the absorption and subsequent passage through the blood-brain barrier of many antioxidants are poor. Fortunately, new biomarker studies can determine whether functional incorporation of the antioxidants into biochemical pathways in the brain has occurred. Galasko and colleagues elegantly used these methods to demonstrate that their antioxidant therapy was effective in reducing oxidative damage in the brain, while no clinical benefit was found (Galasko et al., 2012).

    In contrast to antioxidants, studies of nutrient-rich food have shown benefit for AD and other chronic conditions (Solfrizzi et al., 2011), leading many to attempt to purify the “magical” component. None has been found, however, probably because food, by its very nature, is a complex amalgam derived from the spectrum of life processes, which require exquisite balance that may influence bioavailability, the polar opposite of purification. Food intake presents as numerous points in the complex network that defines metabolism and oxidative balance. In contrast, antioxidants add at single and narrowly circumscribed points, possibly misbalancing the oxidant defense system. And while antioxidant combinations working along these same lines may show more promise, it is also important to reconsider the definition of oxidative stress—as simply a breach in antioxidant defenses—as too simplistic for chronic disease.

    Humans live with AD for decades. Prior to AD, oxidative damage is generally demonstrable after age 40, meaning oxidative damage is a chronic condition of the middle-aged and aging brain (Nunomura et al., 2012). Is this imbalance or simply a de novo balance of the chronic condition of aging and disease? The de novo balance concept, which has generally not been considered to date, is supported by the ample antioxidant stress responses induced in AD: stress kinases, antioxidant enzymes, pentose phosphate pathway, and metal regulatory proteins (Castellani et al., 2009). The most interesting are the two latter, as the amyloid-β protein precursor/amyloid-β bind and regulate iron and copper redox activity central to oxidation, as these metals are the primary catalysts of oxidative damage.

    The molecular modifications produced by oxidative stress lead to deleterious consequences with damage to neuronal networks and activation of compensatory mechanisms. Antioxidant therapeutics may reduce oxidative stress in specific molecular pathways, but cannot repair the chronic neuronal network damage or restore to previous levels the function of affected brain systems. Thus, dysfunctional and anatomically remodeled neuronal networks cannot be reverted to normality and their anatomy restored by simply reducing oxidative stress levels.

    Adding single-point antioxidants to the delicate balance of the aging brain and AD has the possibility of disturbing a balance that is likely heterogeneous in terms of oxidative state, since we have found a pleiotropic change in the relationship of oxidative damage to amyloid-β and other features with the transition from normal to mild cognitive impairment (Smith et al., 2010). In an environment with abundant free copper and iron, single-point antioxidants (reductants, in most cases) can actually increase oxidative damage of critical compartments not otherwise discerned by examining biomarkers that address bulk state.

    Finally, oxidative damage and response in AD, and to a lesser extent normal aging, involve alterations in every cellular pathway, so how is it that those of us in middle age and older, ostensibly without AD, function normally with so much going wrong in our cerebral parenchyma? Could it be that oxidative alterations are essential to our function with advanced age, in the so-called age of wisdom? Or alternatively, since oxidative stress marks cell activation at the beginning of life and other critical times in development, is it possible that oxidative stress regulates the aging process and drives it forward, providing for normal function into advanced age? The wonder is not that some become demented with age, but rather that many maintain normal function for 100 years or longer.

    References:

    Castellani RJ, Zhu X, Lee HG, Smith MA, Perry G. Molecular pathogenesis of Alzheimer's disease: Reductionist versus expansionist approaches. Int J Mol Sci. 2009 Mar;10(3):1386-406. PubMed.

    Galasko DR, Peskind E, Clark CM, Quinn JF, Ringman JM, Jicha GA, Cotman C, Cottrell B, Montine TJ, Thomas RG, Aisen P, . Antioxidants for Alzheimer Disease: A Randomized Clinical Trial With Cerebrospinal Fluid Biomarker Measures. Arch Neurol. 2012 Mar 19; PubMed.

    Halliwell B. The antioxidant paradox: less paradoxical now?. Br J Clin Pharmacol. 2012 Mar 16; PubMed.

    Moreira PI, Smith MA, Zhu X, Nunomura A, Castellani RJ, Perry G. Oxidative stress and neurodegeneration. Ann N Y Acad Sci. 2005 Jun;1043:545-52. PubMed.

    Nunomura A, Castellani RJ, Zhu X, Moreira PI, Perry G, Smith MA. Involvement of oxidative stress in Alzheimer disease. J Neuropathol Exp Neurol. 2006 Jul;65(7):631-41. PubMed.

    Nunomura A, Tamaoki T, Motohashi N, Nakamura M, McKeel DW, Tabaton M, Lee HG, Smith MA, Perry G, Zhu X. The earliest stage of cognitive impairment in transition from normal aging to Alzheimer disease is marked by prominent RNA oxidation in vulnerable neurons. J Neuropathol Exp Neurol. 2012 Mar;71(3):233-41. PubMed.

    Smith MA, Zhu X, Tabaton M, Liu G, McKeel DW, Cohen ML, Wang X, Siedlak SL, Dwyer BE, Hayashi T, Nakamura M, Nunomura A, Perry G. Increased iron and free radical generation in preclinical Alzheimer disease and mild cognitive impairment. J Alzheimers Dis. 2010;19(1):363-72. PubMed.

    Solfrizzi V, Frisardi V, Seripa D, Logroscino G, Imbimbo BP, D'Onofrio G, Addante F, Sancarlo D, Cascavilla L, Pilotto A, Panza F. Mediterranean diet in predementia and dementia syndromes. Curr Alzheimer Res. 2011 Aug;8(5):520-42. PubMed.

    View all comments by Akihiko Nunomura

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References

News Citations

  1. Early Intervention Trial Bears Little Fruit, but Sows Hope

Paper Citations

  1. Morris MC. The role of nutrition in Alzheimer's disease: epidemiological evidence. Eur J Neurol. 2009 Sep;16 Suppl 1:1-7. PubMed.
  2. Sung S, Yao Y, Uryu K, Yang H, Lee VM, Trojanowski JQ, Praticò D. Early vitamin E supplementation in young but not aged mice reduces Abeta levels and amyloid deposition in a transgenic model of Alzheimer's disease. FASEB J. 2004 Feb;18(2):323-5. PubMed.
  3. Garcia-Alloza M, Dodwell SA, Meyer-Luehmann M, Hyman BT, Bacskai BJ. Plaque-derived oxidative stress mediates distorted neurite trajectories in the Alzheimer mouse model. J Neuropathol Exp Neurol. 2006 Nov;65(11):1082-9. PubMed.
  4. Harrison FE, Allard J, Bixler R, Usoh C, Li L, May JM, McDonald MP. Antioxidants and cognitive training interact to affect oxidative stress and memory in APP/PSEN1 mice. Nutr Neurosci. 2009 Oct;12(5):203-18. PubMed.
  5. Sano M, Ernesto C, Thomas RG, Klauber MR, Schafer K, Grundman M, Woodbury P, Growdon J, Cotman CW, Pfeiffer E, Schneider LS, Thal LJ. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. N Engl J Med. 1997 Apr 24;336(17):1216-22. PubMed.
  6. Petersen RC, Thomas RG, Grundman M, Bennett D, Doody R, Ferris S, Galasko D, Jin S, Kaye J, Levey A, Pfeiffer E, Sano M, van Dyck CH, Thal LJ, Alzheimer's Disease Cooperative Study Group. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med. 2005 Jun 9;352(23):2379-88. Epub 2005 Apr 13 PubMed.
  7. Miller ER, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005 Jan 4;142(1):37-46. PubMed.
  8. Wray DW, Nishiyama SK, Monnet A, Wary C, Duteil SS, Carlier PG, Richardson RS. Antioxidants and aging: NMR-based evidence of improved skeletal muscle perfusion and energetics. Am J Physiol Heart Circ Physiol. 2009 Nov;297(5):H1870-5. PubMed.
  9. Shults CW, Oakes D, Kieburtz K, Beal MF, Haas R, Plumb S, Juncos JL, Nutt J, Shoulson I, Carter J, Kompoliti K, Perlmutter JS, Reich S, Stern M, Watts RL, Kurlan R, Molho E, Harrison M, Lew M, . Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. Arch Neurol. 2002 Oct;59(10):1541-50. PubMed.
  10. Yaffe K, Clemons TE, McBee WL, Lindblad AS, . Impact of antioxidants, zinc, and copper on cognition in the elderly: a randomized, controlled trial. Neurology. 2004 Nov 9;63(9):1705-7. PubMed.
  11. MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002 Jul 6;360(9326):23-33. PubMed.

Further Reading

Papers

  1. Sano M, Ernesto C, Thomas RG, Klauber MR, Schafer K, Grundman M, Woodbury P, Growdon J, Cotman CW, Pfeiffer E, Schneider LS, Thal LJ. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. N Engl J Med. 1997 Apr 24;336(17):1216-22. PubMed.
  2. Petersen RC, Thomas RG, Grundman M, Bennett D, Doody R, Ferris S, Galasko D, Jin S, Kaye J, Levey A, Pfeiffer E, Sano M, van Dyck CH, Thal LJ, Alzheimer's Disease Cooperative Study Group. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med. 2005 Jun 9;352(23):2379-88. Epub 2005 Apr 13 PubMed.
  3. Miller ER, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005 Jan 4;142(1):37-46. PubMed.

Primary Papers

  1. Galasko DR, Peskind E, Clark CM, Quinn JF, Ringman JM, Jicha GA, Cotman C, Cottrell B, Montine TJ, Thomas RG, Aisen P, . Antioxidants for Alzheimer Disease: A Randomized Clinical Trial With Cerebrospinal Fluid Biomarker Measures. Arch Neurol. 2012 Mar 19; PubMed.

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