Targeted Nutritional Strategies
Nutritional Interventions Studied in Alzheimer’s
Derived from the plant Huperzia serrata, huperzine A is an NMDA receptor blocker than can help prevent or reduce glutamate-mediated excitotoxicity (Wang 1999). It can also help block acetylcholinesterase, the enzyme that destroys acetylcholine, which is critical for cognition and memory. This mechanism of action is similar to that of several Alzheimer’s drugs, such as donepezil and galantamine (Sun 1999). Some studies show that huperzine A may penetrate the blood-brain barrier, have greater bioavailability, and have longer duration of action than some pharmaceuticals (Wang 2006b; Bai 2000). Although not all studies on Huperzine show positive effects on cognition (Rafii 2011), a review of previous studies revealed that doses of 300-500 mcg of huperzine A daily significantly improved the standardized cognitive test scores of Alzheimer’s patients, and were slightly safer than some drug alternatives (Wang 2009).
This potent antioxidant has been shown to reduce inflammation, chelate metals, and increase acetylcholine levels in animal studies (Milad 2010; Holmquist 2007). Although there have been only a few small human studies on lipoic acid in Alzheimer’s, the results hold promise. In one study, nine patients with Alzheimer’s or similar dementias took 600 mg of lipoic acid daily, for an average of 337 days. At the outset of the study, cognitive scores were declining continuously. By the end of the study, they had stabilized (Hager 2001). A second study extended this regime to 43 patients for 48 months and the disease progressed extremely slowly (compared with the typical disease progression rate seen in untreated patients) (Hager 2007).
Acetyl-L-carnitine (ALC) is an antioxidant that has been shown to correct acetylcholine deficits in animals and protect neurons from amyloid beta by supporting healthy mitochondria (Butterworth 2000; Dhitavat 2005; Virmani 2001). A group of researchers combined ALC with lipoic acid and found they could reverse some mitochondrial decay in aged animals. The same research group conducted a comprehensive review of 21 clinical trials of ALC in cases of mild cognitive impairment and mild Alzheimer’s disease. They found significant benefit in the ALC group compared to placebo (Ames 2004).
ALC has been noted to reduce the effects of high homocysteine levels in mice (e.g., deterioration of blood-brain barrier integrity, increased levels of amyloid beta, neurofibrillary tangle formation, and cognitive dysfunction) (Zhou 2011). Further, a small clinical trial among people with Alzheimer’s disease showed that 3,000 mg of ALC daily resulted in significantly less cognitive deterioration over a 1 year period (Pettegrew 1995). Laboratory studies have found that ALC can reduce amyloid beta neurotoxicity by affecting amyloid precursor protein metabolism (Epis 2008).
Ginsenosides, steroid-like compounds in extracts of the plant Panax ginseng (P. ginseng), are believed to be the active chemicals that produce memory benefits (Christensen 2009). A study that tested 200, 400, and 600 mg of P. ginseng on healthy patients without cognitive problems found that 400 mg produced the greatest benefit and boosted memory for 1-6 hours after dosing (Kennedy 2001). When higher dosages were tested on 58 Alzheimer’s disease patients, 4.5 g of P. ginseng given daily over 12 weeks produced gradually increasing improvements, as compared to the 39 control patients whose cognitive abilities declined over the same period, though the improvements faded 12 weeks after discontinuation (Lee 2008).
Vitamins C and E
Vitamins C and E are well known for their antioxidant properties. Several studies have examined their combined potential in reducing the oxidative damage associated with Alzheimer’s disease (Gehin 2006; Shireen 2008). One observational study showed that supplementation with vitamins C (500 mg/day) and E (400 IU/day) was associated with reduced prevalence of Alzheimer’s disease (Boothby 2005). Another team of researchers found that the combination of vitamin C and E was associated with a reduced risk of Alzheimer’s disease, but neither supplement alone conferred substantial protection (Zandi 2004). However, a placebo-controlled clinical trial found that high doses of vitamin E alone, up to 2,000 IU daily, slowed the mental deterioration of Alzheimer’s patients (Grundman 2000), and in an animal model, vitamin C helped reduced amyloid beta aggregation (Cheng 2011).
Deficiencies of vitamin E in Alzheimer’s patients are associated with increased lipid peroxidation (oxidative deterioration of lipids), which appears to increase platelet aggregation (Ciabattoni 2007). Combination therapy with vitamins C and E has been shown to reduce lipid peroxidation in people with mild-to-moderate Alzheimer’s disease (Galbusera 2004). A high intake of vitamins C and E may be associated with reduced incidence of Alzheimer’s in the healthy elderly (Landmark 2006).
One method by which vitamin E might protect Alzheimer’s disease has to do with its relation to apolipoprotein E4 (apoE4). Researchers suspect that, in people with the apoE4 phenotype, impaired antioxidant defense systems in neurons may increase oxidative damage (Mas 2006). Another theory suggests that vitamin E might be able to reduce the oxidative damage caused by large amounts of inducible nitric oxide synthase, a pro-oxidant that has been linked to progression of Alzheimer’s (McCann 2005). Moreover, a recent study suggested that vitamin E may combat amyloid beta-induced oxidative stress, a characteristic of Alzheimer’s disease (Pocernich 2011). (Note: Inducible nitric oxide synthase should not be confused with endothelial nitric oxide synthase that is needed to maintain healthy arterial function.)
Ginkgo biloba is an antioxidant that may serve as an anti-inflammatory agent, reduce blood clotting, and modulate neurotransmission (Diamond 2000; Perry 1999). In one study, ginkgo was tested on patients with mild-to-moderate Alzheimer’s dementia. The results were inconsistent. However, in a subgroup of those patients with neuropsychiatric symptoms, 120 – 240 mg of ginkgo daily over 26 weeks significantly improved cognitive performance over placebo (Schneider 2005). Another study found that ginkgo inhibited amyloid beta production in the brain (Yao 2004).
Ginkgo, if effectively combined with other brain-supporting nutrients, appears to offer a synergistic cognitive effect, resulting partly from its ability to improve cerebrovascular function (Mashayekh 2011). Research has shown that combining G. biloba with other nutrients such as phosphatidylserine, B vitamins, and vitamin E can deliver cognitive benefits to both animals and humans (Araujo 2008; Kennedy 2007). In addition, a study found that ginkgo extract can rescue neuronal cells from beta amyloid-induced cell death via a mechanism distinct from its antioxidant properties (Aranda-Abreu 2011). Ginkgo also appears to protect against Alzheimer’s disease by inhibiting the formation of amyloid fibrils (Longpré 2006). Finally, a review of six studies found that ginkgo benefits cognition and psychopathological symptoms, with no evidence of negative side effects (Janssen 2010).
Curcumin is derived from the Curcuma longa (turmeric) plant. Many studies have suggested that curcumin may be an effective therapy for Alzheimer’s because it exerts neuroprotective actions through numerous pathways including inhibition of amyloid beta, clearance of existing amyloid beta, anti-inflammatory effects, antioxidant activity, delayed degradation of neurons, and chelation (binding) of copper and iron, among others (Begum 2008; Mishra 2008; Ringman 2005; Walker 2007).
Curcumin has been found to reduce cognitive dysfunction, neural synaptic damage, amyloid plaque deposition, and oxidative damage. It has also been found to modulate the levels of cytokines in brain neurons (Cole 2004; Mishra 2008). The anti-inflammatory effect of curcumin appears to result from a reduction of nuclear factor-kappaB, a nuclear transcription factor that regulates many genes involved in cytokine production (Aggarwal 2004). Curcumin’s ability to chelate toxic metals such as iron and copper and reduce their levels may also help prevent amyloid aggregation (Baum 2004). By inhibiting interaction with heavy metals (e.g., cadmium and lead), curcumin may reduce cerebral deregulation (Mishra 2008). Laboratory studies also suggest that curcumin is more effective at inhibiting accumulation of amyloid beta in animal brains than the over-the-counter NSAIDs ibuprofen and naproxen (Yang 2005). A clinical trial found that doses of regular curcumin ranging from 1 to 4 grams daily were well tolerated and exerted anti-inflammatory effects and possibly reduced amyloid beta aggregation in 27 subjects with probable Alzheimer’s (Baum 2008).
Nutritional Interventions Studied in Cognitive Decline and Dementia
Docosahexaenoic acid (DHA), an omega-3 fatty acid found primarily in fish and fish oil, has been linked to cognitive function (Swanson 2012). DHA constitutes between 30% and 50% of the total fatty acid content of the human brain (Young 2005). It has been shown to reduce amyloid beta secretion (Lukiw 2005) and increase phosphatidylserine levels (Akbar 2005). Studies indicate that omega-3 fatty acids have the ability to inhibit early stages of neurofibrillary tangle formation (Ma 2009) and reduce amyloid plaque development (Amtul 2010). An animal model revealed that fish oil supplementation may combat some of the negative effects of carrying the ApoE4 gene (Kariv-Inbal 2012). In a randomized study involving 485 individuals with age-related cognitive decline, 900 mg of DHA daily for six months resulted in a marked improvement in learning and memory tests (Yurko-Mauro 2010).
Vinpocetine, derived from the periwinkle plant, has neuroprotective properties and increases cerebral circulation (Szilagyi 2005; Dézsi 2002; Pereira 2003). It also protects against excitotoxicity (Sitges 2005; Adám-Vizi 2000). Vinpocetine has been used as a drug in Eastern Europe for the treatment of age-related memory impairment (Altern Med Rev 2002). In a controlled clinical trial, 10 mg of vinpocetine three times a day improved a variety of measures of cognitive function among subjects with vascular senile cerebral dysfunction (Balestreri 1987).
Pyrroloquinoline quinone (PQQ)
Pyrroloquinoline quinone (PQQ) is an important nutrient that stimulates the growth of new mitochondria in aging cells, and promotes mitochondrial protection and repair (Chowanadisai 2010; Tao 2007). Mitochondrial decay contributes to many age-related diseases, including Alzheimer’s (Facecchia 2011; Martin 2010). Laboratory studies indicate PQQ may inhibit the development of Alzheimer’s disease (Kim 2010; Liu 2005; Murase 1993; Yamaguchi 1993; Zhang 2009). PQQ protects neurons from amyloid beta and the protein alpha-synuclein, which contributes to neurodegeneration in Parkinson’s disease (Kim 2010; Zhang 2009).
Supplementation with 20 mg per day of PQQ resulted in improvements on tests of higher cognitive function in a group of middle-aged and elderly people (Nakano 2009). These effects were significantly amplified when the subjects also took 300 mg per day of CoQ10.
Phosphatidylserine (PS) is a naturally occurring component of cell membranes. In a study conducted in Japan on 78 elderly people with mild cognitive impairment, supplementation with PS for six months resulted in significant improvements in memory functions (Kato-Kataoka 2010). In another study, 18 elderly subjects with age-related memory decline took 100 mg of PS 3 times daily for 12 weeks. Tests at 6 and 12 weeks showed cognitive gains compared to baseline measurements (Schreiber 2000). A group of researchers studied the safety and efficacy of phosphatidylserine-containing omega-3 fatty acids (PS-omega-3) in eight elderly patients with memory complaints (Richter 2010). They found that PS-omega-3 had favorable effects on memory functions. Researchers are now finding that phosphatidylserine supplementation works optimally along with docosahexaenoic acid (DHA) (Shyh-Hwa 2012).
Glycerophosphocholine Glycerophosphocholine (GPC) is a structural component of brain cell membranes and a precursor to the neurotransmitter acetylcholine. In Alzheimer’s disease, the concentration of GPC increases in the CSF due to the breakdown of cell membranes during neurodegeneration (Walter 2004). Supplementation with GPC and other nutritive substances like acetyl-L-carnitine, docosahexaenoic acid, α-lipoic acid and phosphatidylserine improves cognitive functions in mice (Suchy 2009). A clinical trial on 261 patients with dementia of the Alzheimer’s type showed improvement in cognitive symptoms with an acetylcholine precursor (Moreno 2003). A larger trial also revealed significant cognitive improvement when patients recovering from stroke were given 1,000 - 1,200 mg of alpha-GPC for 5 months (Barbagallo 1994).
Astaxanthin, a red-orange pigment in the carotenoid family, is highly concentrated in some microalgae and gives color to many crustaceans and fish (Hussein 2006). Like other carotenoids, astaxanthin has strong anti-inflammatory and free radical-scavenging properties (Guedes 2011; Grimmig 2017). Because this carotenoid pigment has been shown to cross the blood-brain barrier, interest in its ability to protect brain tissue from age-related changes has grown. Recent evidence suggests astaxanthin promotes brain plasticity, thereby potentially preventing or ameliorating age-related cognitive impairment (Grimmig 2017; Wu 2015).
A pilot study in 10 healthy subjects with age-related memory problems demonstrated the potential benefits of astaxanthin supplementation. After 12 weeks using an algae extract providing 12 mg astaxanthin per day, improvement was noted on cognitive performance tests (Satoh 2009). These results were confirmed in a randomized controlled trial in 96 middle-aged to older adults reporting age-related memory complaints. This trial also used 12 mg per day of astaxanthin for 12 weeks and found similar improvement in cognitive performance (Katagiri 2012).
A laboratory study found that astaxanthin protected neurons from amyloid beta-induced damage through multiple mechanisms, including an inhibition of inflammatory factors and a sharp reduction of oxidative stress (Chang 2010). In a randomized controlled trial, astaxanthin at doses of 6 and 12 mg daily for 12 weeks inhibited the production of oxidized phospholipids in red blood cell membranes (Nakagawa, Kiko, Miyazawa, Carpentero Burdeos 2011). These oxidized phospholipids can be caused by amyloid beta in the blood, and in a study in mice, astaxanthin reduced red blood cell phospholipid oxidation caused by amyloid beta (Nakagawa, Kiko, Miyazawa, Sookwong 2011).
Preclinical studies have indicated astaxanthin reduces inflammatory signaling in brain cells exposed to neurotoxins and traumatic injury (Kim, Koh 2010; Sifi 2016; Yan 2016; Zhang 2017). In multiple animal models of neurologic damage, including from trauma, stroke, high blood pressure, and diabetes, astaxanthin demonstrated the potential to protect brain tissue and preserve or enhance cognitive function (Wu 2014; Ji 2017; Zhou 2015; Li 2016; Pan 2017).
Life Extension Study: Nutrient Complex May Positively Impact Cognitive Performance
A 2012 study conducted by Life Extension Clinical Research, Inc. assessed the impact of daily dosing of a dietary supplement containing alpha-glyceryl phosphoryl choline (A-GPC), phosphatidylserine, vinpocetine, grape seed extract, wild blueberry extract, ashwagandha extract, and uridine-5’-monophosphate on cognitive performance in forty middle-aged to elderly subjects with subjective memory complaints.
An online cognitive assessment tool (Computerized Neuropsychological Test) was used to assess the change in cognitive performance from baseline to day 30 and day 60; the Global Impression Improvement (CGI-I) scale provided an overall clinically determined summary measure.
Twenty-nine subjects completed the study with no significant adverse events being reported. Preliminary results revealed a statistically significant improvement in three tests: working Memory (N-back), inspection time, and executive function. Based on the CGI-I Scale, improvement was noted after 30 days and 60 days of product dosing.
The study was presented at the Experimental Biology 2012 multidisciplinary scientific conference in San Diego, California April 21-25, 2012.
Additional Nutritional Support for Cognition
Coffee and Caffeine
A review of several studies revealed that coffee consumption is associated with a reduced risk of Alzheimer’s and Parkinson’s diseases (Butt 2011). Long-term caffeine administration to mice can reduce brain amyloid beta deposition through suppression of beta- and gamma-secretase. An animal model showed that caffeine appeared to synergize with another coffee component to increase blood levels of granulocyte colony-stimulating factor (G-CSF). Both higher G-CSF levels and long-term administration of caffeinated coffee have been shown to enhance working memory (Cao 2011).
Chlorogenic acid, an antioxidant polyphenol present in coffee, has been shown to reduce blood pressure, systemic inflammation, risk of type 2 diabetes, and platelet aggregation (Cao 2011; Montagnana 2012). In one study, when mice with impaired short-term or working memory were given chlorogenic acid, their cognitive impairment was significantly reversed (Kwon 2010). Polyphenol availability varies with how long coffee beans are roasted and the roasting method itself. All roasting destroys some polyphenols, the most important being chlorogenic acid. However, there is a patented roasting process that returns polyphenol content back to the coffee beans allowing for a substantially increased polyphenol content compared to conventionally processed coffee (Zapp 2010). Another excellent source of chlorogenic acid is green coffee extract (Jaiswal 2010).
The flavonoids in green tea, known as catechins, have been shown to possess metal-chelating (binding) properties, as well as antioxidant and anti-inflammatory effects (Mandel 2006). Animal studies have demonstrated that the main flavonoid in green tea, epigallocatechin gallate (EGCG), along with other tea catechins, can decrease levels of amyloid beta in the brain (Rezai-Zadeh 2005), and suppress amyloid beta-induced cognitive dysfunction and neurotoxicity (Haque 2008; Kim 2009; Rezai-Zadeh 2008). Studies propose that green tea catechins also act as modulators of neuronal signaling and metabolism, cell survival-and-death genes, and mitochondrial function. Recently, population based studies have determined that intake of catechins in both green and black tea may reduce the incidence of Alzheimer’s disease and dementia (Mandel 2011).
Resveratrol – a polyphenol found in Japanese knotweed, red wine, and grapes – has been shown to reduce amyloid beta levels, neurotoxicity, cell death, and degeneration of the hippocampus, as well as prevent learning impairment (Kim 2007). Several studies indicate that moderate consumption of red wine, in particular, is associated with a lower incidence of dementia and Alzheimer’s disease (Vingtdeux 2008). Red wine also contains many phenolic antioxidant compounds that, research suggests, impede the pathological progress of Alzheimer’s disease (Ho 2009). It has also been observed that stilbenoids – derivatives of resveratrol – lower amyloid beta peptide aggregation in Alzheimer’s models (Richard 2011). Resveratrol has been shown to selectively neutralize detrimental clumps of amyloid peptides while leaving benign peptides intact as well (Ladiwala 2010).
Grape Seed Extract
Grape seed extract contains potent antioxidants called proanthocyanidins (Shi 2003). In laboratory experiments, animal neurons were treated with grape seed extract before being exposed to amyloid beta. Unlike the untreated neurons that readily accumulated free radicals and subsequently died, the cells treated with grape seed extract were significantly protected (Li 2004). In another animal study, administering grape seed polyphenols reduced amyloid beta aggregation in the brain and slowed Alzheimer’s disease-like cognitive impairment (Wang 2008).
Magnesium is involved in the functioning of NMDA-type glutamate receptors, which are integral to memory processing (Bardgett 2005). Studies have found that imbalance of serum magnesium levels causes cognitive impairment (Corsonello 2001; Barbagallo 2011). Recently, scientists have discovered that a specially formulated magnesium compound called magnesium-L-threonate (MgT) boosts brain levels of magnesium more efficiently than other forms of magnesium. These higher brain levels of magnesium improved synaptic signaling, which is essential for proper neuronal and cognitive function, as well as enhanced long-term learning and memory. Testing of MgT on animals showed a substantial improvement in memory, especially long-term memory (Slutsky 2010).
High homocysteine levels, along with low levels of B vitamins (e.g., folate, vitamin B12, and vitamin B6), have been associated with Alzheimer’s disease and mild cognitive impairment (Quadri 2005; Ravaglia 2005; Tucker 2005).
- Vitamin B12. In a study evaluating levels of vitamin B12 in patients with either Alzheimer’s disease or another type of dementia, researchers found that lower B12 levels were linked to greater cognitive deterioration (Engelborghs 2004). A population-based longitudinal study of people 75 or older without dementia found that those with low levels of vitamin B12 or folate had twice the risk of developing Alzheimer’s disease over a three-year period (Wang 2001).
- Vitamin B6. A study found that Alzheimer’s patients after age 60 consumed a significantly lower amount of vitamin B6 compared to control subjects (Mizrahi 2003). In addition, low vitamin B6 levels were associated with elevated numbers of lesions in the brains of patients with Alzheimer’s disease (Mulder 2005).
- Folate. Folate is needed for DNA synthesis (Hinterberger 2012). In a study including 30 subjects with Alzheimer’s disease, levels of folate in cerebrospinal fluid were significantly lower in patients with late-onset Alzheimer’s disease (Serot 2001). Another longitudinal analysis of people aged 70 to 79 years found that those with either high levels of homocysteine or low levels of folate had impaired cognitive function. The link to cognitive impairment was strongest for low folate levels, leading researchers to suggest that folate might reduce the risk of cognitive decline (Kado 2005).
- Niacin. A study of more than 6,000 people, conducted between 1993 and 2002, found that high levels of dietary niacin (vitamin B3) protected against Alzheimer’s disease. The authors researched the dietary habits of initially healthy people aged 65 years or older. As the study progressed, some participants developed Alzheimer’s disease and some remained healthy. Subjects with the highest intake of niacin had a 70% reduction in risk of cognitive decline (Morris 2004).
The wide distribution of vitamin D receptors in the brain may be evidence for vitamin D’s importance in neurological function (Eyles 2005). Studies show that clearance of amyloid beta across the blood-brain barrier is promoted by adequate levels of vitamin D. Animal tests showed 1.3 times greater rate of amyloid beta elimination with vitamin D supplementation, pointing to a potential preventive effect against Alzheimer’s disease (Ito 2011). Among nearly 500 women followed for 7 years, those in the highest quintile (1/5th) for vitamin D intake had a more than 75% reduction in risk of developing Alzheimer’s disease compared to those in the lowest quintile (Annweiler 2012).
Coenzyme Q10 (CoQ10) has been found to improve outcomes in several neurodegenerative disorders involving loss of mitochondrial function (Galpern 2007; Manacuso 2010).
Studies have shown that levels of CoQ10 are altered in Alzheimer’s disease (Dhanasekaran 2005), and supplementation has been suggested as part of an integrated approach to improve mitochondrial function in Alzheimer’s disease (Kidd 2005).
In one animal study, CoQ10 counteracted mitochondrial deficiencies in rats that had been treated with amyloid beta (Moreira 2005), while in another experiment CoQ10 reduced the overproduction of amyloid beta (Yang 2008). Coenzyme Q10 was also shown to destabilize amyloid plaques in laboratory studies (Ono 2005).
Several clinical trials have evaluated the effects of synthetic CoQ10 analogs in Alzheimer’s patients and shown good results. For example, a trial comparing tacrine, a pharmaceutical acetylcholinesterase inhibitor, to a CoQ10 analog among 203 Alzheimer’s patients showed the CoQ10 analog was associated greater improvements on some standardized cognitive assessments (Gutzmann 2002). Another trial revealed dose-dependent improvements on cognitive assessments in Alzheimer’s patients receiving a CoQ10 analog compared to placebo. This trial also showed the CoQ10 analog to be safe and well tolerated (Gutzmann 1998). Similarly, in a trial conducted on 102 Alzheimer’s patients, a CoQ10 analog improved memory, attention, and behavior compared to placebo (Senin 1992).
N-acetylcysteine (NAC) is a precursor to glutathione, a powerful scavenger of free radicals in the body (Forman 2009; Arakawa 2007). Glutathione deficiency has been associated with a number of neurodegenerative diseases (Pocernich 2000). One study showed that NAC significantly increased glutathione levels and reduced oxidative stress in rodents treated with a known free radical–producing agent (Pocernich 2000). Another study showed that glutathione-deficient mice were more vulnerable to neuronal damage from amyloid beta (Crack 2006). An animal model of Alzheimer’s found that NAC alleviated oxidative damage and cognitive decline (Tchantchou 2005).
Ashwagandha or Withania somnifera is a plant used in India to treat a wide range of age-related disorders (Ven Murthy 2010). A 2012 study using an animal model of Alzheimer’s disease found that ashwagandha reversed accumulation of amyloid peptides and improved behavioral deficits (Sehgal 2012). Laboratory studies have shown that ashwagandha can regenerate neurites (i.e., projections from nerve cells) and reconstruct synapses in severely damaged neurons (Kuboyama 2005). In addition to its neuroprotective benefits, ashwagandha has been shown to mimic the action of the Alzheimer’s drug donepezil, an acetylcholinesterase inhibitor (Choudhary 2004).
In 2005, scientists noted that the polyphenols present in blueberries reversed the cognitive and motor deficits caused by aging (Lau 2005). Blueberry extract stimulates neurogenesis and enhances neuronal plasticity (adaptability) in the hippocampus, the region of the brain chiefly affected by Alzheimer’s disease (Casadesus 2004). In one study where researchers analyzed fruits and vegetables for their antioxidant capability, blueberries came out on top, scoring highest for its capacity to neutralize free radicals (Wu 2004b).
Luteolin, a flavonoid found in fruits and vegetables (e.g., green peppers, carrots, and celery), exhibited a protective effect against Alzheimer’s disease in early research. When luteolin was administered to mice with Alzheimer’s disease, there was a significant reduction in levels of amyloid beta. These mice also exhibited a reduction in the activity of glycogen synthase kinase 3, an enzyme that has been implicated in the development of amyloid beta and neurofibrillary tangles (Rezai-Zadeh 2009).
Multi-nutrient deficiencies have been observed in people with Alzheimer’s disease (Kristensen 1993; Jiménez-Jiménez 1997). Recently, scientists found that individuals with higher serum levels of the biomarkers for vitamins B, C, D, and E, as well as for omega-3 oils most commonly found in fish – EPA and DHA – were less likely to exhibit brain shrinkage or reduced cognitive function (Bowman 2011).
A human study of 14 individuals with early-stage Alzheimer’s found that a formulation of multiple nutrients improved all measures of cognition, although the improvement in memory function was not statistically significant. The formulation comprised 400 mcg of folic acid, 6 mcg of vitamin B12, 30 IU of vitamin E, 400 mg of S-adenosylmethionine (SAM-e), 600 mg of N-acetylcysteine, and 500 mg of acetyl-l-carnitine. The cognitive improvement continued throughout the 12-month study (Chan 2008). In a study of 200 healthy middle-aged individuals with no cognitive or memory problems, those who were given a multivitamin for 2 months scored higher on cognitive function tests, showed less fatigue during extended cognitive challenges, achieved greater accuracy, and proved faster in mathematical processing, compared with the placebo-only group (Haskell 2010).
Wild Green Oat Extract
Extracts of oat (Avena sativa L.) contain bioactive components that exert antioxidant and anti-inflammatory properties (Lee 2015). Oat extracts contain flavonoids, saponins, and compounds unique to oat species, avenanthramides (Wong 2012; Dimpfel 2011).
Increased monoamine oxidase B (MAO-B) activity decreases dopamine levels in the brain and increases oxidative stress in neurons (Nagatsu 2006; Mallajosyula 2009). Analyses of brain tissue from deceased individuals with Alzheimer's disease was found to contain up to three times the amount of MAO-B activity than brain tissue of healthy, age-matched controls (Saura 1994; Jossan 1991).
Monoamine oxidase inhibitors are considered promising therapeutic targets for the treatment of Alzheimer's disease because of their ability to reduce accumulation of beta amyloid and improve cognition and memory deficits (Cai 2014; Delumeau 1994; Finali 1991). Wild green oat extract is able to inhibit MAO-B activity (Wong 2012; Moccetti 2006).
Elderly patients with mild cognitive impairment performed substantially better on cognition tests after a single 1600 mg dose of wild green oat extract (Berry 2011). Healthy, middle-aged adults participating in a double-blind placebo-controlled trial improved their performance on multiple cognitive tests after a single 800 mg dose of wild green oat extract (Kennedy 2015).
Nicotinamide riboside is a source of vitamin B3 that the body uses as a precursor for nicotinamide adenine dinucleotide (NAD), a molecule involved in a range of biological processes. NAD+, a biologically active forms of NAD, is necessary for the activation of sirtuins, proteins that modulate cellular metabolism and DNA transcription (Houtkooper 2010; Chi 2013; Imai 2014). NAD+-dependent sirtuins appear to be involved in such fundamental cellular activities as energy metabolism, DNA damage response, stress resistance, proliferation and differentiation, survival, and aging, and in animal research have been shown to modulate brain connectivity and memory formation (Gao 2010; Srivastava 2016). NAD+ levels decrease with age, which may cause dysfunction in cell nuclei and mitochondria, ultimately contributing to a range of age-related disorders, including cognitive decline and Alzheimer’s disease (Srivastava 2016; Imai 2014). In experimental cellular models of neurodegenerative processes, NAD, NAD+, and nicotinamide riboside have prevented the breakdown of neurons and neuronal connections (Deleglise 2013; Sasaki 2006). Restoration of NAD+ with supplemental nicotinamide riboside has been shown to reverse age-related cellular dysfunction, which contributes to many neurodegenerative diseases, while models of Alzheimer’s disease indicate nicotinamide riboside may be neuroprotective (Imai 2014; Canto 2012; Chi 2013).
In a six-month controlled trial in 26 individuals with probable Alzheimer’s disease, those who received the NADH form of nicotinamide adenine dinucleotide had no progression in cognitive decline and significantly better scores on a dementia rating scale compared with the placebo group (Demarin 2004). In rodents, NADH administration in older animals resulted in improved performance on cognitive tests (Rex 2004). In a mouse model of Alzheimer’s disease, three months of nicotinamide riboside supplementation led to increased brain levels of NAD+, prevented cognitive decline, and reduced levels of neuron damaging amyloid-beta proteins (Gong 2013).
Colostrinin (Proline-rich peptide complex)
Colostrum—the first breast milk secreted after childbirth—is known for its high levels of antibodies and other factors with immune-activating effects (Godhia 2013). Findings from preclinical and clinical studies suggest colostrinin, a proline-rich polypeptide complex in colostrum, may help prevent the progression of Alzheimer’s disease (Janusz 2013; Stewart 2008). A number of studies have found a range of possible mechanisms for colostrinin’s beneficial effects, including modulating immune activity; preventing oxidative stress, including oxidative damage to DNA; anti-inflammatory activity; inhibiting overproduction of nitric oxide; and decreasing age-related mitochondrial dysfunction (Boldogh 2008; Janusz 2010; Zablocka 2010; Zablocka 2012; Bacsi 2007; Bacsi 2006).
A double-blind placebo-controlled trial compared colostrinin to placebo in 105 subjects with mild-to-moderate Alzheimer’s disease. The colostrinin group received 100 micrograms colostrinin every other day for three weeks, followed by two weeks with no treatment, for three 5-week cycles. After the first 15-week period, all subjects received colostrinin for a second 15-week treatment cycle. Colostrinin treatment had a stabilizing effect on cognitive function and ability to perform activities of daily living. Participants with mild cognitive impairment responded better to treatment than those with more advanced decline (Bilikiewicz 2004). Another trial used the same dosing schedule for 16 to 28 months in 33 Alzheimer’s patients and found it resulted in stabilization or improvement in health status (Leszek 2002). An earlier double-blind placebo-controlled trial was conducted in 46 patients with Alzheimer’s disease and mild-to-moderate dementia. Subjects received either 100 micrograms colostrinin, 100 micrograms selenium, or placebo every other day in three-week treatment cycles, followed by two weeks of no treatment. Eight of 15 colostrinin patients improved, while seven of them experienced stabilization of their condition; in contrast, none of the patients in the selenium or placebo groups improved (Leszek 1999). Studies reported colostrinin was well tolerated with mild side effects that passed quickly (Leszek 2002; Leszek 1999).
Studies in which cultured nerve cells were treated with colostrinin or a nanopeptide fragment of colostrinin have demonstrated their potential to disrupt amyloid beta fibrils and prevent further accumulation and neurotoxic effects of amyloid beta (Janusz 2009; Douraghi-Zadeh 2009; Bourhim 2007; Schuster 2005).
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