In 2013, an estimated 5.2 million Americans of all ages were reported to have Alzheimer’s disease (AD) (Alzheimer’s Association, 2013). This includes an estimated 5 million people 65 and older and approximately 200,000 individuals younger than 65 who have younger-onset AD. For individuals with AD and other dementias, the aggregate costs for health care, long-term care, and hospice are projected to increase from $203 billion in 2013 to $1.2 trillion in 2050. Of note, Medicare and Medicaid cover approximately 70% of the costs of care (Alzheimer’s Association, 2013). These statistics are staggering when coupled with the fact that there are no curative medications currently available. Therefore, it may not be surprising that there has been an increasing demand for alternative options, such as nutraceuticals.
Dr. Stephen Defelice created the term nutraceutical and defined it as a “‘food or part of a food that provides medical or health benefits including the prevention and/or treatment of a disease’” (as cited in Chauhan, Kumar, Kalam, & Ansari, 2013, p. 4). Sales of nutraceuticals in the United States have been growing annually over the past 9 years, with 5.5% growth from 2011 to 2012 (Lindstrom, Ooyen, Lynch, & Blumenthal, 2013). Much of this has been attributed to the so-called “Dr. Oz effect” (i.e., the phenomenon of increased popularity of herbal dietary supplements featured on the television show of Mehmet Oz, MD) (Lindstrom et al., 2013). Finding reliable statistics regarding individual use is difficult in part because of reliance on self-reporting. In one U.S. study cohort of patients 80 and older, 59.4% reported multivitamin use, 66.6% used at least one vitamin or mineral supplement, and 27.4% used some type of other dietary supplement (e.g., ginkgo biloba, omega-3 fatty acids) (Nahin et al., 2006).
Many of these supplements may seem innocuous, but the possibility of adverse effects or drug interactions, especially in combination with prescription medications, is of paramount concern. For example, vitamin E and gingko biloba may both increase a patient’s risk of bleeding and should be discontinued if a patient receives anticoagulation therapy (Roland & Nergård, 2012; Szuwart et al., 2000). Due to such risks, it is imperative that health care providers ask their patients about over-the-counter (OTC) supplements and herbal use and consider comorbid conditions and medications when initiating nutraceutical therapy. The intent of this article is to review recent evidence that has been published on commonly used nutraceuticals and their role in dementia care.
Elevated serum homocysteine (Hcy) has been associated with an increased incidence of dementia and AD (Selhub, 2006). Folic acid (B9), cyanacobalamin (B12), and pyrodoxine (B6) aid in the metabolism of Hcy and have been shown to decrease Hcy levels by 25% to 33% (Homocysteine Lowering Trialists’ Collaboration, 1998); therefore, Hcy can be used as a surrogate marker for vitamin B12, B6, and folate levels (Klee, 2000). The combination of these vitamins has also been shown to decrease plasma levels of A-beta protein 1–40, a beta amyloid protein thought to contribute to the pathophysiology of AD (Flicker et al., 2008). Thus, it has been hypothesized that B vitamins can help prevent or treat dementias, namely AD.
A recent systematic review of 19 randomized controlled trials (RCTs) concluded that vitamin B12, B6, and folic acid supplementation alone or in combination does not improve cognitive function in individuals with or without existing cognitive impairment (Ford & Almeida, 2012). A prior systematic review derived the same conclusion (Balk et al., 2007). One RCT not included in the systematic analyses used brain atrophy as measured by magnetic resonance imaging as a surrogate marker for cognitive function. This study found that a 2-year course of B12, B6, and folate slowed the rate of brain atrophy in older adults with mild cognitive impairment (MCI) (Smith et al., 2010).
It is important to note that neither this study nor any of the RCTs included in the systematic reviews listed B12 deficiency as an eligibility criterion. This is relevant because there is evidence that B12 deficiency may be correlated with increased risk of cognitive decline (O’Leary, Allman-Farinelli, & Samman, 2012). B12 therapy should be initiated in deficient patients for this reason and because of other health concerns including anemia, neuropathy, and neurological disorders (Gröber, Kisters, & Schmidt, 2013). However, evidence that vitamin B12 supplementation can improve the cognitive function in B12 deficient patients with coexisting dementia is insufficient (Malouf & Areosa Sastre, 2003). Moreover, fully reversible dementias are exceedingly rare (Clarfield, 2003). However, acute states of confusion secondary to B12 deficiency that are fully reversible with B12 therapy are possible (Kibirige, Wekesa, Kaddu-Mukasa, & Waiswa, 2013). If B12 supplementation is indicated, oral B12 has been shown to be equally efficacious compared to traditional intramuscular dosing and is more cost-effective as well (Castelli et al., 2011; Masucci & Goeree, 2013).
With respect to the other B vitamins, folic acid by itself or in combination with B12 has no beneficial impact on measures of cognition or mood in older patients with normal cognition or mild-to-moderate cognitive decline, including different forms of dementia (Malouf, Grimley, & Areosa, 2003). Furthermore, recent evidence suggests that folic acid supplementation may actually be detrimental to cognition in older adults with low or normal vitamin B12 levels (Moore et al., 2014). Folic acid supplementation in a patient who is B12 deficient can mask this deficiency and lead to irreversible neurological damage (Malouf et al., 2003); however, the mechanism underlying cognitive impairment from excess folic acid in those with normal B12 is unclear (Moore et al., 2014). Vitamin B6 alone has not been shown to positively affect cognition either, although it is less studied than folate and B12 (Malouf & Grimley-Evans, 2003).
Vitamin D deficiency is prevalent, and it is estimated that approximately 70% to 90% of older adults with AD are affected. Low serum concentrations of vitamin D are cross-sectionally associated with global cognitive impairment and an increased risk of AD (Etgen, Sander, Bickel, Sander, & Förstl, 2012). Vitamin D binds to the vitamin D receptor, which triggers neuronal protection against AD through several possible mechanisms, namely: anti-inflammatory action; antioxidant effect; control of calcium homeostasis by regulating the concentration of intracellular calcium in hippocampal neurons; anti-trophic effect by regulating neurotrophic agents; and prevention of acetylcholine defect by increasing the activity of choline acetyltransferase in the brain (Annweiler, Karras, Anagnostis, & Beauchet, 2014).
As noted, vitamin D not only has an effect on bone health but also brain health. A pre-post study of older patients seen in a memory clinic over a 2-year period showed that the vitamin D3 group had higher 25-hydroxy vitamin D (25OHD) concentrations than at baseline. This translated into higher final scores and greater score changes on the Mini-Mental State Examination (MMSE), Clinical Assessment of Behavior, and Functional Assessment of Behavior than the control group (Annweiler, Fantino, et al., 2012). A recent 6-month pilot study looked at the effectiveness of the combination of memantine plus vitamin D on cognition in patients with AD. Overall, patients with AD who took memantine plus vitamin D for 6 months had a 4-point gain in MMSE score, whereas vitamin D alone and memantine alone had no change (Annweiler, Herrmann, Fantino, Brugg, & Beauchet, 2012).
Overall, vitamin D appears to be a viable option for older adults who are vitamin D deficient. The clinical conundrum, however, is determining the optimal formulation to use for supplementation. Emerging evidence supports the use of cholecalciferol (D3) versus ergocalciferol (D2) due to the sustained therapeutic levels (Lehmann et al., 2013). Regardless of the formulation, it is imperative to avoid supratherapeutic levels of vitamin D. Excess vitamin D carries the risk of causing hypercalcemia, which may manifest as anorexia; diarrhea; constipation; nausea; bone, muscle, and joint pain; continuous headaches; irregular heartbeat; and even acute renal failure (Alshahrani & Aljohani, 2013; Granado-Lorencio et al., 2012).
Alpha tocopherol (vitamin E) is another fat soluble vitamin that functions as an antioxidant scavenging toxic free radical. Free radicals may contribute to the pathology of cognitive impairment, including AD. In patients with plasma levels of total tocopherols, total tocotrienols, or total vitamin E in the highest tertile, there was a reduced risk of developing AD versus the lowest tertile (Mangialasche et al., 2010).
A recent Cochrane review evaluating vitamin E for AD and MCI included three RCTs, two in patients with AD and one in patients with MCI. Endpoints in the three studies included death, institutionalization, Clinical Dementia Rating, activities of daily living (ADLs), change in MMSE score, and progression to MCI/AD. The overall conclusion of the authors noted that there is “no convincing evidence that vitamin E is of benefit in the treatment of AD or MCI. Future trials assessing vitamin E treatment in AD should not be restricted to α-tocopherol” (Farina, Isaac, Clark, Rusted, & Tabet, 2012, p. 2).
The most recent study, the Trial of Vitamin E and Memantine in Alzheimer’s Disease (TEAM-AD) Veterans Affairs Cooperative Randomized Trial, evaluated the effect of vitamin E and memantine on functional decline. They enrolled patients with mild-to-moderate AD who were then randomized to receive either 2,000 IU per day of α-tocopherol (n = 152), 20 mg per day of memantine (n = 155), a combination of the two (n = 154), or placebo (n = 152). Despite not reaching adequate study numbers, the authors were able to show the Alzheimer’s Disease Cooperative Study/Activities of Daily Living Inventory scores declined by 3.15 units less in the α-tocopherol group versus the placebo group. Furthermore, there was a reduction in caregiver time in the α-tocopherol group. The results of the TEAM-AD study suggest that high-dose vitamin E use is not associated with a significant increase in adverse effects or increased mortality (Dysken et al., 2014).
Historically, vitamin E at doses >400 IU per day has been associated with an increase in the incidences of heart failure, coagulation disturbances, and all-cause mortality (Lonn et al., 2005; Miller et al., 2005). Caution should be used in patients taking anticoagulant and antiplatelet medications due to the increased risk of bleeding. Therefore, at this time, high-dose vitamin E should be used cautiously due to potential for adverse consequences coupled with limited efficacy.
Omega-3 Fatty Acids
Omega-3 fatty acids have become increasingly popular in the United States in recent years, with fish oil supplement sales alone rising from $425 million in 2007 to more than $1 billion in 2012 (Doyle, 2013). Omega-3 fatty acids refer to an array of molecules among which docosahexaenoic acid (DHA) and eicosapentanoic acid (EPA) are thought to be the most biologically relevant. Interest in their effect on cognition arose when epidemiological studies observed a consistent association of higher fish consumption and a decreased risk for AD (Barberger-Gateau et al., 2007).
In regard to AD, studies of the transgenic mouse model of AD have illustrated that DHA-enriched diets significantly reduced total β-amyloid by 70% compared to regular diets (Lim et al., 2005). It has been postulated that this decrease is due to DHA’s modulation of certain neuronal proteins that regulate β-amyloid production (Ma et al., 2007). AD pathophysiology has been linked to oxidative stress, inflammation, and elevated cholesterol levels as well (Shinto et al., 2014). EPA replaces arachidonic acid and leads to the synthesis of less potent inflammatory mediators (prostanoids). Moreover, several omega-3 fatty acids have been shown to decrease cholesterol (Anderson & Ma, 2009).
However, these mechanisms of neuroprotection by omega-3 fatty acids may be of little clinical significance, as RCTs have failed to consistently show benefits of supplementation on slowing cognitive decline in healthy patients or those with mild-to-moderate AD. One meta-analysis of three RCTs examining omega-3 fatty acid supplementation on memory in cognitively healthy adults older than 60 concluded that omega-3 fatty acids did not improve cognition or slow cognitive decline compared to placebo over 6- to 40-month follow up (Sydenham, Dangour, & Lim, 2012). A recent RCT evaluated the efficacy of omega-3 fatty acid therapy in patients with mild-to-moderate AD. Two experimental groups were included in the study: omega-3 fatty acid (675 mg DHA and 975 mg EPA) alone and omega-3 fatty acid (same dose) plus 600 mg of alpha-lipoic acid per day. Compared to placebo, omega-3 fatty acid and alpha-lipoic acid dual therapy significantly slowed decline in MMSE and instrumental ADLs (IADLs) scores over 12 months. The omega-3 fatty acid–only group showed less decline in IADLs as well. Neither treatment improved Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-cog) scores or ADLs, and the sample was only 39 patients (Shinto et al., 2014).
In conclusion, a paucity of evidence supports the use of omega-3 fatty acids in older patients for the purpose of cognitive enhancement or slowing cognitive decline. More evidence exists supporting supplementation in patients with AD, especially mild AD, but this evidence is variable and inconsistent. Most of the studies with omega-3 fatty acids make a point to mention that the supplements are well tolerated and at most cause occasional gastrointestinal upset, typically in the form of belching. Overall, given the minimal downside to treatment and possible benefits, omega-3 fatty acid therapy may be considered in patients with mild-to-moderate AD.
Ginkgo biloba sales ranked fifth among all herbals in 2012, exceeding $25 million in sales (Lindstrom et al., 2013). The use of ginkgo biloba for purported memory benefits is even higher in Europe, with 15% of patients in one German study reporting use (Franke, Heinrich, Lieb, & Fellgiebel, 2014). The mechanism of action of ginkgo biloba seems to be related to antioxidative properties provided by flavonoids, terpenoids, and organic acids (Maidment, 2001). In animal models, ginkgo biloba extract (EGb 761) has been shown to normalize cognitive deficits in models of AD (Stackman et al., 2003) and improve spatial memory and protect hippocampal neurons in models of vascular dementia (Rocher et al., 2011). Research concerning ginkgo biloba use in preventing and treating cognitive impairment and dementias is vast but often contradictory.
A meta-analysis of RCTs examining ginkgo biloba use in patients with cognitive impairment and dementia found that all doses of ginkgo biloba improved measures of cognition at 12 weeks but not at 24 weeks. Furthermore, benefits in ADL measures were seen in four of five studies at 12- to 24-week follow up, and clinical global improvement was significantly superior to placebo at 24 weeks. Although the results seem promising, the authors had concerns regarding the small sample sizes and questionable methodology of the studies in the meta-analysis (Birks & Grimley Evans, 2007). Another systematic review combined the results of four RCTs including older patients with AD or vascular dementia with neuropsychiatric features (N = 1,294). Patients treated with EGb 761 showed improvements in cognitive performance and behavioral symptoms that were associated with advances in ADLs and reduced caregiver burden (Ihl, 2013). One RCT included in the review used donepezil (Aricept®) as an active control to EGb 761 and revealed no statistical difference between the two in the aforementioned endpoints (Ihl, 2013). But does ginkgo biloba slow cognitive decline in AD as well as cholinesterase inhibitors? Authors of one meta-analysis concluded that “delay in symptom progression, rates of clinically significant treatment response and numbers needed to treat (NNT) found for EGb 761 are in the same range as those reported for acetylcholinesterase inhibitors (AChEIs)” (Kasper & Schubert, 2009, p. 494). A more recent RCT found MMSE and Seven Minute Test scores at 24 weeks to be significantly higher in patients receiving rivastigmine (Exelon®) 4.5 mg per day compared to those receiving ginkgo biloba 120 mg per day (Nasab, Bahrammi, Nikpour, Rahim, & Naghibis, 2012).
The efficacy of ginkgo biloba in treating dementia remains unclear. Studies examining the use of ginkgo biloba to prevent the onset of AD and other dementias seem to unanimously conclude that ginkgo biloba is not superior to placebo (DeKosky et al., 2008; Vellas et al., 2012). Conflicting evidence exists and is further complicated by an array of formulations, dosing, and treatment durations in individual study designs. Supplements in the United States likely have inconsistent levels of active ingredient compared to the EGb 761 used in European studies (“EGb 761,” 2003). Overall, it appears ginkgo biloba supplementation is unlikely to benefit patients with dementia, at least not as much as existing pharmacological therapies (i.e., AChEIs) and is even less likely to benefit healthy patients.
Implications for Geriatric Nurses
This article highlights just the tip of the iceberg when it comes to the vast numbers of OTC medications and nutraceuticals that older adults with dementia may be using to address their cognitive concerns. The Table summarizes recommendations based on the evidence presented within this article. It is important to note that direct-to-consumer advertising coupled with a societal impetus on anti-aging has led to a great demand. All direct care staff and health professionals need to constantly evaluate the use of self-treatments due to the potential for interactions with prescribed medications, increased costs and burdens on patients and families, and potential for adverse effects (e.g., bleeding). Nurses should directly ask patients and caregivers if they are taking these or any other supplements. Patients may not think of them as “medications.”
Summary of Recommendations for Nutraceutical Use in Prevention and Treatment of Dementia
Many nutraceuticals are touted to treat and/or prevent dementia. B vitamins, vitamin D, vitamin E, omega-3 fatty acids, and ginkgo biloba are the most commonly seen in practice. The evidence of efficacy for each is variable, although vitamin D in patients with low 25OHD levels and B12 in those with low B12 levels seem to have the most clinical use. Vitamin E, ginkgo biloba, and omega-3 fatty acids have some promising evidence but not enough to warrant routine clinical use. Each supplement carries a risk of adverse effects and potential for drug interactions of which all practitioners must remain vigilant about monitoring.
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Summary of Recommendations for Nutraceutical Use in Prevention and Treatment of Dementia
Consider use in B12 deficient patients (1,000 mcg per day)
Oral administration less expensive and equally efficacious to intramuscular administration
Folate and B6 have no role in therapy
Supplement in older adults with low levels (25OHD <30 nmol/L)
Cholecalciferol (D3) daily recommended over ergocalciferol (D2) (50,000 IU per month)
Caution with recommending given limited evidence of efficacy and risk of toxicity
|Omega-3 fatty acids|
Cannot recommend for or against given limited evidence of efficacy and limited toxicity
Example dose: 675 mg DHA, 975 mg EPA
No benefit in healthy individuals
EGb 761 has mixed evidence of efficacy in dementia, but risks of bleeding and interactions make use not recommended at this time