This two-part report aims to critically appraise the current evidence for common dietary supplements that have been linked with slowing the progression of, or preventing, Alzheimer’s disease (AD).
This is part two of a two part article. Part one can be read here.
Dementia affects one in 14 people in the UK over the age of 65,1 and with average UK life expectancy projected to rise to over 88 by 2062,2 it will be an on-going issue in future society. By far the most common cause of dementia is AD, which accounts for approximately 50–70% of cases.3
With any condition where adequate medicinal treatments are not currently available, patients will look for other options, both to treat and prevent. There has been a long-standing interest from the scientific community as to whether dietary supplementation could be the answer, and this has been widely reported in the media. Given 90% of the British population (aged 15 and over) access news, either in print or online format,4 there is the potential for people who don’t have a scientific background to be easily influenced, especially considering the media’s tendency towards sensationalism.
But do supplements work and if so which ones? This is a common consultation question and one that must be met with evidence-based response to save patient’s time, money and potential harm.
For much of medicine an understanding of the pathophysiology of a disease leads to management solutions. This is not the case in AD. Currently, there are two main schools of thought; the Amyloid Cascade Hypothesis and the Tau Hypothesis.3,5
The amyloid cascade hypothesis states that AD is caused by the deposition of beta-amyloid protein, predominantly in areas of the brain associated with cognition and memory.3 These depositions aggregate to form extracellular amyloid plaques, which results in; neuronal death, atrophy, inflammation, neurotransmitter inhibition, tau protein dysfunction and subsequently dementia.5
The dysfunction of tau protein leads to its build-up in the cell bodies of neurones forming neurofibrillary tangles.3,5,6 Neurofibrillary tangles are strongly associated with cell death and their quantities are thought to be proportional to the severity of dementia.3
Although it is not yet clear which, if either hypothesis is correct, the evidence suggests that both amyloid plaques and neurofibrillary tangles have an important role to play in the development of Alzheimer’s.3,6,7,8 Therefore, any methods to reduce either would likely have a positive effect.
Headline: “A megadose of vitamin E ‘slows down’ Alzheimer’s: Patients able to cook, wash and stay independent for six months longer.” The Daily Mail9
Vitamin E is the collective name for a group of naturally occurring, fat soluble chemicals called the tocopherols.10 Alpha-tocopherol is the most biologically active11 of these and is used in vitamin E supplements. Its role in the body is as a potent antioxidant,12 thereby attracting attention as a potential prevention or treatment of AD.
Is it effective?
The headline originated from a randomised controlled trial published in the Journal of the American Medical Association in 2014. Its objective was to analyse whether large doses of alphatocopherol, (2000 International Unit (IU) per day), could slow the progression of mild to moderate AD. In summary, the results showed a delay in the annual rate of clinical progression for the alpha-tocopherol group of 19% as compared to placebo, which equated to an average of 6.2 months over the four-year study period.13
However, there may be factors affecting any conclusions drawn from this study. Participants were not reflective of the broader population, there was a high dropout rate and complex study design. There have also been health concerns raised with long-term use of high doses of alpha-tocopherol.14
A meta-analysis looking at data from over 135,000 participants found that taking over 400 IU of vitamin E supplements per day for at least a year increases all-cause mortality.15 One of the reasons being that in high doses alpha-tocopherol may displace other vital fat soluble antioxidants, causing an imbalance and thus decreasing overall efficiency. Furthermore, because of alpha tocopherols anticoagulant properties, it is feared that in high doses there would be significantly increased risk of bleeding, especially when combined with anticoagulant medication.16,17 This is corroborated by the findings in another large study, which found there was a statistically significant increased risk of haemorrhagic stroke in participates taking high dose alpha tocopherol.18
Moreover, there is early evidence to suggest that in high doses, alpha tocopherol interferes with the absorption of gamma tocopherol, which has antiinflammatory effects.19 This raises the possibility that the beneficial antioxidant effects of vitamin E come from the combination of tocopherols and may not be able to be achieved with just alpha supplements.19
High doses of vitamin E cannot be recommended for the prevention or treatment of AD, particularly as the elderly are already at a higher risk of other comorbidities and polypharmacy.20 In addition, the evidence for its effectiveness is very inconsistent, with the larger prospective observational studies showing no benefit and potential harm.3,21,22
Headline:“Vitamin C curbs dementia. A glass of orange juice a day could be the key to managing Alzheimer’s disease.” The Daily Express23
Otherwise known as ascorbic acid, vitamin C is an important co-factor to many enzymes and is of particular importance in the biosynthesis of collagen.24 It is an essential part of our diet, coming from fruits, vegetables or supplements, as unlike many other animals we cannot synthesise it endogenously.25
Vitamin C’s link to AD, much like vitamin E is through its antioxidant properties.26 However, the antioxidant role of vitamin C goes beyond just directly removing free radicals, it also acts indirectly by regenerating active forms of alphatocopherol.25,26,27 Furthermore, there is evidence from rodent studies suggesting that the increased oxidative stress from even moderate vitamin C deficiencies could accelerate the production of amyloid plaques.28,29,30
Is it effective?
Due to their close physiological links, scientists have hypothesised that a combination of vitamin C and E supplements would form a more potent and therefore effective antioxidant.28 Although, there is moderate amounts of evidence supporting this concept,28,31 there is also a considerable number of studies that found no effect32,33,34,35 and in some cases statistically significant inverse associations.30 Furthermore, the majority of these studies used high dose Vitamin E, which as previously discussed is not advisable due to the potential health implications.
Even though, vitamin C can be tolerated in much higher doses than the Recommended Daily Allowance (RDA) with negligible side effects, there is very limited evidence to suggest any benefit from supplementation on its own.35,36 In addition, the studies that found a benefit tended to focus on those with deficiencies, which is very uncommon in the western world.37,38
In summary, while the role antioxidants play in the development and progression of AD needs studying further, it is unlikely that anything other than maintaining healthy levels of vitamin C would have any effect.
Headline: “Peace of Mind.” The Guardian39
The article from the Guardian in 2005 and other tabloids40 have recommended the herb Ginkgo Biloba, which is extracted from the ‘Memory Tree’ otherwise known as Maidenhair.41 Ginkgo has been of interest to the medical profession and supplement market for many years, and due to its purported clinical efficacy the World Health Organisation (WHO) added it to the Anatomical Therapeutic Chemical (ATC) classification index as an antidementia drug in 2000.42,43
Ginkgo is hypothesised to have antioxidant, anticoagulant and vasodilator properties.44 The normal recommended dose is 120–240mg per day, although over the counter preparations may differ.
Is it effective?
In AD, ginkgo appears to slow the deposition of beta-amyloid, thus reducing the formation of amyloid plaques. Some studies suggest that over time ginkgo is as effective as the cholinesterase inhibitor drugs in restoring memory loss in mild to moderate AD.45 The Guardian reported that a metaanalysis of 33 trials found that the herb is generally safe, and may lead to significant improvements in brain function.49 This was echoed by researchers from Germany, Israel and the Ukraine who found that after 24 weeks the treatment arm of people with mild to moderate dementia had marked improvement in their cognitive performance, functional abilities, neuropsychiatric symptoms and overall well-being compared to placebo.46
Controversy still surrounds the use of Ginkgo in cognitive enhancement and it is currently the most investigated herbal extract for memory problems including AD.47,48 Probably the most statistically significant research was the GEM study (Ginkgo Evaluation of Memory) where 3,069 participants aged 75 or over with normal cognition or mild cognitive impairment were given the standardised 240mg dose (120mgs twice daily) or a placebo.49
It was a multi-centre study with participants followed up for an average of six years. Results showed that Ginkgo had no effect in preventing AD, other dementias or the rate of progression from Mild Cognitive Impairment (MCI) to dementia compared to placebo. The study cost $36.5 million and the researchers noted that the GEM findings are consistent with those of previous smaller studies and with the 2009 Cochrane review of Ginkgo for dementia and cognitive impairment.50,51
However, the Cochrane review has been criticised for the pooled evaluation of dementia and cognitive decline and no subtype analysis. This included other studies that showed limitations through poor design, small sample size, differing doses of Ginkgo, polypharmacy and biases, such as differences in the study population.
Weinmann et al’s meta-analysis in 2010 found that Ginkgo did improve cognition particularly in AD and lesser so in vascular or mixed dementia. Recommendations included a major study to compare the efficacy of Ginkgo to cholinesterase inhibitors.52 Another meta-analysis showed this improvement was more pronounced for people with cognitive impairment or MCI and other neuropsychiatric symptoms.53
Despite reports that Ginkgo has a safe side effect profile, reviews have shown that Ginkgo has a higher rate of haemorrhagic stroke in those taking it daily than among those who were on a placebo.54 There is also evidence of adverse interactions with other prescribed and over the counter medications.
The evidence is contradictory, but caution should still prevail as there remains risk of harm.
This report is not an exhaustive compilation of the current supplements claiming to promote cognitive enhancement as each supplement has its moment in the media spotlight before a new one appears. The supplements examined show that, despite the significant media speculation, there currently is not an evidence-based product on the market that has demonstrated prevention, or slowing the progression of AD. The best advice to patients to reduce the risk of a dementia particularly AD is to reduce vascular disease risk factors by:
- Stopping smoking
- Managing conditions such as hypertension and diabetes
- Keep weight in check and maintain a normal Body Mass Index
- Consume a balanced diet.
Exercise reduces the risk of diseases such as hypertension, diabetes and osteoporosis, and recent studies have shown that exercise can slow mental decline and may improve memory. The recommended amount from NHS Choices is roughly 20 minutes a day or 30 minutes for five days for people over 65 at a moderate intensity. Exercising outdoors also gives the opportunity of exposure to vitamin D from natural sunlight.
In summary, this report should give clinicians more confidence to provide evidence-based responses to patient’s questions about the effectiveness of many products in the market that claim to, ‘ward off’ AD.
Dominic Dewson, 4th Year Medical Student at Plymouth University Peninsula School of Medicine and Dentistry
Allison O'Kelly, Queen’s Nurse. Clinical Lead, East Cornwall Memory Services, Cornwall Foundation Trust
Dr Giles Richards, Consultant Psychiatrist, Cornwall Foundation Trust
Conflict of interest: none declared
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2. The National Archives. [Online]2016; Available at: http://www.ons.gov.uk/ons/rel/lifetables/historic-and-projected-data-from-the-period-and-cohort-life-tables/2012-based/stb-2012-based.html [Accessed 2nd December 2016]
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10.National Institutes of Health. Vitamin E. https://ods.od.nih.gov/factsheets/VitaminE-HealthProfessional/ (Accessed 03/08/15)
12. Grimm MO, Stahlmann CP, Meh J, et al. Vitamin E: Curse or Benefit in Alzheimer’s Disease? A Systematic Investigation of the Impact of α-, γ- and δ-Tocopherol on Aß Generation and Degradation in Neuroblastoma Cells. J Nutr Health Aging 2015; 19(6): 646–56
14. Marchioli R, Levantesi G, Macchia A, et al. Vitamin E increases the risk of developing heart failure after myocardial infarction: Results from the GISSI-Prevenzione trial. J Cardiovasc Med 2006; 7(5): 347–50
18. The Alpha-Tocopherol Beta Carotene Cancer Prevention Study Group. The Effect of Vitamin E and Beta Carotene on the Incidence of Lung Cancer and Other Cancers in Male Smokers. N Engl J Med 1994; 330: 1029–35
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24. National Institutes of Health. Vitamin C. National Institutes of Health Fact Sheet. [Online] (no date) Available at: https://ods.od.nih.gov/factsheets/VitaminCHealthProfessional/ (Accessed 15th August 2015)
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40. Warner F. The healing power of trees. Mail Online [Online] (no date) Available at: http://www.dailymail.co.uk/health/article-74105/The-healing-power-trees.html [Accessed 22nd May 2016].
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48. Tan, M, Yu J, Tan C, et al. Efficacy and Adverse Effects of Gingko Biloba for Cognitive Impairment and Dementia: A systematic Review and Meta-Analysis. Journal of Alzheimer’s Disease 2015; (43): 589–603
53. Hagan P. The truth about ginkgo: Health risks of the brain-boosting herb. Mail Online [Online] 2008; Available at: http://www.dailymail.co.uk/health/article-525160/ The-truth-ginkgo-Health-risks-brain-boosting-herb.html#ixzz40LP2yUPR [Accessed 22nd May 2016].