The public fear of cognitive decline is at epidemic proportions. This fear is mostly associated with the worry of developing Alzheimer’s disease. But despite misconceptions, we know that the current treatment of mild-to-moderate AD can slow decline for a number of years, delay the need to enter a dementia center, and help many of the impaired behaviors that develop. A neurologist’s goal in evaluating cognitively impaired patients is to make the correct diagnosis and offer the best treatments available. Giving all facts will help reduce the caregiver and public fear of the disease. This includes addressing nutritional aspects of cognitive impairment.

Numerous papers have been published on the role of nutrition in the prevention and treatment of cognitive decline, most of which focus on AD. Unfortunately much of this information has not been scientifically well-documented, especially in the treatment of cognitive decline. My goal in this piece is not to do an exhaustive literature review, but to mention a number of pertinent studies that shed some light on the topic and especially suggest the glass is half full, not half empty.

One of the most “upbeat” articles I reviewed on this topic was authored by D.E. Bredesen1 from UCLA in September 2014. He presented 10 patients with varied diagnosis of subjective mild cognitive impairment (SMCI), amnestic mild cognitive impairment (AMCI) and AD who displayed subjective or objective improvement in three to six months that lasted up to 2.5 years. One case failed due to late stage AD. Six cases who stopped working or had major difficulty cognitively at work prior to treatment returned or improved their work performance. The therapeutic program is shown in Table 1, and as you can see, the list of treatments is very extensive and mostly nutritional related. The article is limited due to lack of controls, detailed information on the cognitive testing, and only showing some pertinent history in three of the 10 cases. Additionally, the authors stated that three of their cases modified the therapeutic program and provide no details about the changes. However, the value in mentioning this article is found in the extensive list of potential nutritional treatment options suggested, and used mostly together concurrently for the possibility of multiple mechanisms to play a role in cognitive impairment.

Currently, as clinicians we know the limitation of the acetylcholinesterase and glutamine inhibitors in the degenerative and vascular dementias. We welcome anything else, especially nutritional information that is helpful in these disorders. There is increasing strong evidence that partaking in aerobic exercise (120 minutes/week) and cognitive and memory therapy can stabilize/slow decline in cognitive function.2

THE EVIDENCE

Lopes Da Silva et al.3 did a meta-analysis of published articles on the nutrient status of patients with AD covering 1990-2012. This is the first study of its kind reported. They compared plasma levels of micronutrients and fatty acids in cognitively intact elderly controls and AD patients. The other important feature of their study was to ensure AD patients and controls did not differ in protein/energy nutrients so that malnutrition was not present. All subjects with vitamin supplements were excluded. To be sure there was no malnutrition, they evaluated body mass index, mini nutritional assessment score and albumin levels corrected for different ages. Only 80 articles out of 3397 met their criteria for inclusion.

The researchers required a minimum of eight articles in each nutrient topic for statistical purposes. The B vitamins, antioxidants (vitamin A, C, E and selenium), choline and omega-3 fatty acids (DHE, EPA) have been found to likely play a role in the pathophysiological process of cognitive function and decline.4,5,6 For example, antioxidants reduce reactive 02 species induced damage and stabilize neuronal membranes. The fatty acid DHA affects abnormal protein processing (amyloid Beta and Tau). DHA, choline and Uridine modulate neuronal membrane formation. Plasma levels of all these nutrients including iron, zinc, copper and magnesium were reviewed in all the studies.

The study showed statistically significantly lower plasma levels of folate, vitamin B12, C and E in the AD patients (15 to 30 percent) vs. controls. Vitamin A showed a trend toward lower levels but was not statistically different. DHA and EPA plasma levels and part of the cholesterol moiety showed significant lower levels in AD vs. controls. Vitamins B1 and B6 levels (only two papers found) were significantly lower in AD vs. controls. Plasma levels of calcium, selenium, magnesium (three papers) did not show lower levels than controls. Putting together all published studies provides unequivocally that folate, vitamins C, E, and B12 (and possibly vitamin A), DHA, EPA and Choline,are significantly low in healthy, not malnourished AD patients. Studies have shown that three percent of mild to moderate AD patients have evidence of malnutrition, increasing to 50 percent in severe AD.7,8 The exact cause of these lower plasma nutrients is unclear but clearly not due to low protein and energy metabolism. Altered feeding behavior, nutrient absorption and metabolism are possible causes, according to the authors.

The latter two processes have been implicated in the pathophysiology of AD.9 Vitamin A, C, E, and selenium are antioxidants that help to protect these lipid precursors from peroxidation and resultant neuronal membrane damage. Bourdel- Marchasson, et al.10 measured lipid oxidation in AD vs. controls. They found that low plasma levels of antioxidants were due to enhanced brain consumption due to excessive production of free radicals. This may be another reason why vitamins and fatty acids were found to be low in the meta-analysis study. Reduced DHA and EPA may also be due to impaired liver synthesis, which converts dietary alpha linolenic acid to DHA and EPA. The B vitamins (B6, B12 and folate) are also important in methylation capacity of the cell and are responsible for converting toxic homocysteine to methionine or cysteine.

There are two randomized control studies of a liquid nutrient (Souvenaid) containing DHA, EPA, UMP, choline, folate, vitamins B6, 12, C, E, and selenium. The studies showed improved memory formation in mild AD and preserved functional connectivity, important for synaptic function.11,12

To further support the use of multiple nutrients in cognitive function, Fotuhi, et al.13 studied 3,376 elderly residents in Utah with MMSE testing. They carefully monitored by checking their medicine bottles and history, their intake of vitamins C, E and NSAIDs. The residents had to be on these nutrients and NSAIDs at least four times a week for at least a month. Vitamin C (500mg) and E (400 IU) could also be taken in multivitamins tablets. Controlling for age, sex, education, history of stroke/diabetes and the presence of APOE4, users showed a slower rate of cognitive decline than nonusers over eight years. NSAIDs are not micronutrients and could cloud the study.

Another study14 that many may remember was a randomized, double blind placebo controlled trial in Alzheimer’s from 23 sites. Vitamin E at 2000 IU/day increased median survival, needed less supervision and had reduction in bad behaviors. Dysken et al.15 used a randomized clinical trial of older veterans with AD and MMSE scores of 12-26 (mild to moderate) and receiving acetylcholinesterase inhibitors. They were assigned to four groups; vitamin E plus memantine placebo; memantine and vitamin E placebo; vitamin E plus memantine; vitamin E and memantine placebo. Vitamin E was given 1000 IU bid. Some of the problems with this study included moderate medication adherence and greater than optimal loss-to-follow-up. The primary outcome was activities of daily living scales and secondary outcomes were MMSE scores and ADAS-cog.

The best results in these scales were in the vitamin E only group, who had a 19 percent lower reduction in the ADL scales. The other groups were the same as placebo. The MMSE and ADAS-cog scores were no different in all groups. There was no surprise the memantine group didn’t change because memantine has not been shown to be effective in mild-to-moderate AD. Why vitamin E and memantine together showed no changes from placebo is not clear. No adverse effects in this trial were noted. Other vitamin E trials in MCI and people with normal cognition were not effective.16 In Miller et al’s17 meta-analysis of 19 randomized studies, vitamin E in doses greater than 400 IU was associated with higher all cause mortality. This vitamin E dose is astronomical; the institute of medicine recommends doses no higher than 22.4 IU/day. Studies using lower doses are underway.

Blasko et al.18 studied effect of folate and B12 in 81 cases of MCI. Serum levels of homocysteine, B12 and folate were measured and detailed history of supplement use was taken. The group was followed for five years. Individuals who reported use of folate and B12 corroborated by blood levels and caregiver information were less likely to develop dementia. Higher levels of folate correlated with lower conversion rate of MCI to dementia compared to nonusers.

PHOSPHATIDYLSERINE PLUS OMEGA-3FATTY ACIDS (VAYACOG)

Phosphatidylserine (PS) is a naturally occurring phospholipid present in the inner leaflet of mammalian plasma membranes. In humans it is most concentrated in the brain where it makes up 15 percent of the total phospholipid pool. It has shown to play a role in neuron membranes such as signal transduction, secretory vesicle release and cell to cell communication.19 Crook et al. in 199120 used PS extracted from bovine cortex, which contains high levels of omega-3 long chain polyunsaturated fatty acids, attached to its backbone. This combination was shown to improve learning and memory in subjective MCI and to improve cognitive performance in AD patients. Because of safety concerns in using this product regularly and risk of developing bovine spongiform encephalopathy prions, an alternative product such as soy-derived PS has been developed. Vakhapova et al.21 studied this alternative product in non-demented elderly (ages 50-90) with memory complaints. They evaluated 157 subjecys randomized to receive PS-DHA/EPA (3x 100mg tabs/d) or placebo for 15 weeks followed by an additional open label extension of 15 weeks with a smaller dose (100mg/day). All conditions that could produce cognitive impairment including use of medications were not allowed in the study. At the end of the study they verified that the product was safe, well-tolerated and did not produce any major side effects except some minor GI discomfort, which can be reduced by taking the medication with food.

The clinical benefit of PS-DHA/EPA was reported by Vakhapova et al.,22 for 15 weeks but not open label afterwards. Cognitive measures were evaluated, which included Clinical Global Impression of change and various cognitive tests including the Rey auditory verbal learning test, etc. One hundred thirty-one out of 157 completed the study and dropouts were equal in the active and placebo groups. They also studied a subgroup that might be differently responsive to treatment. This subgroup had a MMSE score >26, delayed recall trial above the mean score, academic education >12 years. This group had 78 participants (38 placebo, 40 PS-DHA/EPA). The key outcome of this study showed that this treatment improved verbal immediate memory, subjectively and objectively. The subset population with higher cognitive status prior to treatment in addition showed improvement in long-term memory and learning ability. The authors’ explanation for this is that the subset group likely had a better cognitive performance in their earlier years and actually suffer from a deep age-related cognitive decline and are therefore more likely to respond to the treatment.

There were a number of limitations to the above study. No primary endpoint of the participants was predetermined. The study population was not homogeneous, and the inclusion criteria did not correspond to a single clinical entity. They believed, however, that the participants qualified to be included under subjective MCI or amnestic MCI. The exact mechanism of PS has not been established.

More research with this product in a larger but well-defined cognitive impaired population including mild dementia should be done, since it is safe and suggests a benefit. Its only current limitation in its use is it is considered a medical food (prescription only) and is not covered by health insurance.

VITAMIN D

In a recent edition of Practical Neurology,23 I reviewed the cognitive consequences of vitamin D deficiency. I stated that there was evidence that vitamin D was important in the health of the cerebral and systemic vasculature, and low levels increased cerebral infarcts and secondary cognitive decline. Since my review, there has been a number of further published articles24,25 that show a strong correlation between cognitive decline and low vitamin D levels. The big question that has not been definitively answered is whether treating low vitamin D reverses or slows cognitive decline. This has been suggested. More studies are certainly needed. I suggested that measuring vitamin D levels in the cognitive impaired elderly and treating low levels <30ng/ml with vitamin D3 2000 IU/day (one capsule) was cost effective and could possibly reduce strokes and delay/improve cognitive decline. Definitive studies could take a long time, and there is no risk and nothing to lose with vitamin D supplements.

CAROTENOIDS

Carotenoids are fat-soluble organic plant pigments and antioxidants found in fruits and vegetable in western diets. They include: alpha carotene, beta carotene, lycopene, leutin, zeaxanthin, and beta cryptoxanthin. Most studies have been done in animal models of Alzheimer’s, showing that in combination with vitamins they may reduce levels of oxidative stress.26 Retinoic acid, a metabolite of vitamin A that reduces a-beta proteins and tau hyperphosphorylation in the mouse hippocampus,27 improved spatial learning vs. controls. Large controlled studies in humans with cognitive decline are needed.

POLYPHENOLS

Polyphenols, abundant in our diet, have been shown to provide anti-inflammatory, anti-tumerogenic, antimicrobial and antioxidant effects. Curcumin is a powerful polyphenol commonly found in Indian food, shown to neutralize free radicles and protect cortical neurons against cell death induced by a-beta peptides.28 Polyphenols in red wine (0.4ml) significantly reduced cortical degeneration and accumulation of a-beta neuropathology in a transgenic AD mouse model.29 This equates to 5oz. of red wine in humans. They found that the type of grape works differently in the mouse model of AD. Cabernet Sauvignon promotes non-amyloidogenic alpha secretase activity, while muscadine wine interferes with accumulation of a-beta peptide into high molecular weight oligometric a-beta species in the brain. Both of these effects are positive in reducing neurodegeneration in the AD mouse model.

The authors of this paper discussed the problems with the use of polyphenols in possible treatment for cognitive concerns: 1) Brain levels of polyphenols in animal brain models are very low, 2) most foods are not eaten in isolation,making it difficult to isolate the effects specifically related to polyphenols, 3) future research needs to determine how diets rich in polyphenols work in combination with lifestyle factors to provide neuro-protective properties.

CALORIC RESTRICTION

Studies have suggested that excessive caloric intake and sedentary lifestyle are associated with a higher risk of cognitive impairment in later life and developing AD.30 High calorie diets have shown to reduce Brain Derived Neurotrophic Factor (BDNF), which impairs hippocampal activity.31 Diets that include caloric restriction result in less oxidative stress.32 Witte et al.,33 studied 49 people, divided into three groups: 1) Caloric restriction (min. 1,200 calorie diet or 30 percent calories reduction) over three months, 2) high polyunsaturated fatty acid group, 3) controls (normal diet and increase polyunsaturated fatty acids 20 percent). Criteria for study entrance were: age 50-80, BMI>21, no drug or alcohol dependence, no severe medical disorders, no psychiatric medications, and MMSE <26.

The calorie-restricted group had improved memory performance that correlated with decreased fasting insulin compared to the other two groups. Levels of BDNF and insulin growth factor were no different in any of the groups. Reduced fasting insulin is due to lower insulin resistance and increased insulin sensitivity, which may lead to better synaptogenesis.33 Caloric restriction led to weight loss and reduced BMI. The authors recommend similar studies with more participants, less restrictive caloric diet, and subjects with and without cognitive decline.

DISCUSSION

What can we take away currently as clinical neurologists treating our normal patients who ask how they can best keep their brain from cognitive impairment and our obviously cognitively impaired patients with SMCI, MCI or dementia?

1. AD patients clearly have shown to have impaired systemic availability of several nutrients even in the absence of malnutrition (vitamins C, E, B12, folate, A, DHE, EPA, choline and uridine). This has not been shown in a similar meta-analysis in SMCI or MCI.

2. Replacing these nutrients in the above cognitive disorders along with some caloric restriction (30 percent) and physical exercise (120 minutes/week) suggests this may be helpful in reducing cognitive decline. More aggressive diets suggesting more complex carbs, polyunsaturated fats, low salt and perhaps less gluten seem reasonable but will require major discipline and support from family members who may not decide to make their own dietary changes. These dietary changes will help control and help reduce systemic and cognitive complications that occur in diabetes, high cholesterol, and hypertension. This program with or without general vitamins and supplements has not shown at this time to prevent AD.

3. Existing reviews of the literature have suggested that there is insufficient evidence for many vitamins and supplements that mitigate normal cognitive decline in humans.

4. Definite exceptions are folic acid, vitamin B12 and in the correct clinical situation vitamin B1 (Wernicke/Korsakoff, chronic GI disorders, Hyperemesis of pregnancy) and B6 (Pellagra suspicion).

5. Vitamin D deficiency has some support to be diagnosed and treated to reduce stroke risk and may reduce or delay cognitive decline.

6. Elevated homocysteine has been shown to increase risk of stroke and cognitive impairment by promoting vascular disease and beta-amyloid 42 production (both increasing cognitive decline). Lowering high homocysteine levels has not been proven to delay or improve cognitive decline at this time. It is still not unreasonable to lower levels by B12/folate supplements or Cerefolin with NAC until definitive studies are conclusive.

7. Current research in cognitive disorders is focusing on pre-symptomatic diagnostic markers so that earlier treatment interventions can be instituted before nervous system damage occurs or is still reversible. This would be a perfect time to institute the above suggested nutritional changes which are low cost and have low side effects. More research is needed to further support this treatment program.

8. More research is needed to investigate the changes in AD specific eating behavior, nutrient metabolism, causes of low nutrient levels in AD, and when they start to lower.

9. The therapeutic system described in Table 1 by Bredesen in 2014 is derived from basic studies of the role of APP signaling and proteolysis in plasticity and the imbalance in this receptor proteolysis that reproducibly occurs in cognitive decline especially in AD. There are numerous parameters that feed into this balance such as hormones, trophic factors, glucose metabolism, inflammatory mediators, ApoE gene status, sleep related factors, and exercise related factors. The major side effect of this treatment system is the difficulty of patients to follow the program as evidenced in the small study. However, the positive result is a lower BMI and improved health in general.

Let us assume that Dr. Bredesen’s multiple therapeutic program as outlined in Table 1 has proven to stabilize cognitive impairment for 2.5 years or more in SMCI, MCI, and AD. How exactly can this program be instituted in our patients/general public? How easily can this be done? My answers are hypothetical but based on a long history of treating cognitively impaired patients and their caregivers. (Note: I included only those nutrient and supplements and changes that three of his patients incorporated [the only ones reported in his paper] which does not cover all his treatment suggestions in Table 1.)

PARTS OF THERAPEUTIC PROGRAM ARE RELATIVELY EASY TO INCORPORATE

A, b, c and I depend on treating physician lab testing, unless refused, but also requires help and support from spouse and/ or caregivers to stay on medications/vitamins and C-pap machine, if required. Caregiver may have to observe the patient take their medications/supplements to verify intake.

a. We must still insist that if an individual or his/her family member(s) notice cognitive changes, a full neurological evaluation be done to determine the level of cognitive impairment and possible cause. This may include neuropsychological testing, MRI/CT scan and standard lab work, which usually includes CBC and complete metabolic profile often done by referring physician, plus TSH, B12 and folate. I would also include vitamin D (>50ng/ml), homocysteine blood levels (<9) and a methylmalonic acid level if B12 is low or low normal. Based on Table I, consider getting additional lab tests for: CRP (normal<1.0), heavy metals if clinically suspected (Hg, Pb, Cd), hormone levels of testosterone, progesterone and cortisol.

b. Be sure to exclude sleep disorders (sleep apnea, periodic leg movements, REM sleep behavior disorder) and treat as needed.

c. If vitamin D is low, treat with vitamin D3 2000 IU capsules/ day. If homocysteine is high, treat with vitamin B12 and folate supplements over the counter (though they may not be well absorbed in the elderly) or Cerefolin with NAC (an active form of vitamin b12 and folate and more effective in lowering homocysteine) that is only available by prescription and not covered by insurance.

d. Optimize sleep. Assuming a sleep disorder is diagnosed and treated, encourage 8 hours sleep/night. There must be good sleep hygiene, and be sure there are no urinary/prostate disorders. Add melatonin 0.5-2mg/night if needed.

e. Help reduce a-beta and lower CRP (if elevated). Start curcumin 400mg/day.

f. Optimize mitochondrial function. Start CoQ 10 (200mg/day), alpha lipoic acid (100mg/day).

g. Optimize antioxidants: Mixed tocopherols (vitamin E 400mg/day), blueberries.

h. Provide synaptic structural components; citicoline (500mg bid), DHA 320-700mg and EPA 180-500mg bid.

i. Optimize hormonal balance. Low testosterone, estrogen and progesterone should be treated to the normal range.

j. Increase middle chain triglycerides—a non-carbohydrate source of brain energy and metabolism by forming a ketone (beta hydroxyl-butyric acid): Coconut oil one teaspoon bid.

k. Cognitive enhancement. Use herbs Bacopa monniera 250mg and ashwagandha 500mg each day.

PARTS OF THERAPEUTIC PROGRAM MORE DIFFICULT TO INCORPORATE

The suggestions below require discipline, help and caring support from spouse and/or caregivers, especially in memory and cognitive impaired individuals. If medication/supplements are required, caregiver must observe individual taking them.

l. Optimize dietary suggestions that increase complex carbohydrates, reduce or eliminate simple carbohydrates and increase polyunsaturated fatty acids to lower glycemic index; avoid processed food; increase healthy protein to include 2 servings of fish, lean meat, chicken and soybean per week and reduce gluten containing products. Increase vegetables and fruits. This will also help reduce weight, lower calories and help treat high blood pressure, diabetes and high cholesterol, all of which are important risk factors for cognitive decline.

m. Enhance autophagy and ketogenesis. Fast 12 hours every night including 3 hours prior to bedtime.

n. Exercise 120 minutes or more per week (30 minutes, 4 times a week). The safest activities for the elderly—not necessarily requiring good balance and normal strength—would include pedaling an indoor bicycle or pedaling a machine that sits in front of a chair.

o. Reduce stress; Incorporate meditation, yoga, music, etc.

p. Encourage increasing brain stimulation, some preferably with family members, such as: games, puzzles, crosswords, Scrabble, cards, computer games, reading regular books or books on tape (easier for memory impaired), arts and crafts, bingo, family photographs, socializing, etc.

CONCLUSION

As you can see, the current scientific nutrient and supplemental information on cognitive decline as it relates to normal aging, SMCI, MCI and dementia (AD) is not quite ready for prime time. However two important provisos must be included in the practical and clinical use of this information: 1) we are dealing with cognitive disorders of the brain, many which invariably progress to severe impairment in quality of life and loss of independence; 2) the majority of recommended nutrient and supplemental information is without significant side effects and harm to the individual.

The most difficult part of this information is implementation. It requires discipline and a good memory, which in most individuals, will require loving assistance from spouses, family or other caregivers. In this proper setting I believe a good part of this program can be implemented. As I stated in my introduction, the fear of cognitive decline especially memory loss and dementia is epidemic across the world. We all grab at anything we hear that may be beneficial and safe (and sometimes not safe) even if not scientifically proven. There is some reasonable evidence in the nutritional and supplemental research literature that interventions can help improve, slow and may delay—but not prevent—cognitive decline.

Other recommended changes regarding various supplements and herbs are still not clear. Waiting for more definitive studies in cognitively impaired and pre-symptomatic individuals will take a lot more time. We as clinicians, who are aging or have cognitive problems, as well as our patients, will want to consider part or the whole therapeutic program. This is a real challenge and we should give our patients and caregivers the information and let them decide for themselves. Remember: “the glass is half full, not half empty.”

Dr. Ronald Devere is director of the Taste and Smell Disorder Clinic. He is a board certified neurologist, fellow of the American Academy of Neurology and the American Academy of Disability Evaluating Physicians.

  1. Bredesen, Dale E. Reversal of Cognitive decline: A novel therapeutic program. AGING. September 2014, Vol. 6, #9, pp 707-717.
  2. Barnes, DE et al, The projected effect of risk factor reduction on Alzheimer’s disease prevalence. Lancet Neurology 2011; 10: 819-28.
  3. Lopez da Silva et al, Plasma nutrient status of patients with Alzheimer’s disease: Systemic review and meta-analysis. Alzheimer’s and Dementia, Volume 10, 2014, p 485-502.
  4. Reynolds E. Vitamin B12, folic acid and the nervous system. Lancet Neurology 2006; 5: 949-60.
  5. Smith PJ et al, Diet and Neurocognition: review of evidence and methodological considerations. Current Aging Science 2010; 3: 57-66
  6. Kamphuis PJ et al, Can nutrients prevent or delay onset of Alzheimer’s disease? Journal Alzheimer’s Disease 2010; 20: 765-775
  7. Guerin O. et al, Nutritional status assessment during Alzheimer’s disease: results after one year (the REAL French study group). Journal of Nutrition Health and Aging. 2005; 9: 81-84
  8. Sandman PO et al. Nutritional Status and dietary intake in institutionalized patients with Alzheimer’s disease and multiinfarct dementia. Journal of American Geriatric Society 1987 ;35: 31-8.
  9. Astarita G. et al, Deficient liver biosynthesis of Docosahexaenoic acid correlates with cognitive impairment in Alzheimer’s disease. PLoS One 2010; 5: e 12538
  10. Bouedel-Marchasson et al, Antioxidant defences and oxidative stress markers in erythrocytes
  11. Scheltens P. et al. Efficacy of Souvenaid in Mild Alzheimer’s Disease ;: results from a randomized study controlled trial. Journal of Alzheimer’s Disease 2012; 31: 225-36
  12. Kamphuis PJ et al, Efficacy of a medical food on cognition in Alzheimer’s disease : results from secondary analysis of a randomized controlled trial. Journal of Nutrition Health and Aging 2011; 15: 720-4.
  13. Fotuhi M. et al. Better cognitive performance in elderly taking antioxidant vitamin E and C supplements in combination with NSAIDS: the Cache county study. Alzheimer’s and Dementia 2008 ; 4(3): 223-27.
  14. Sano M et al, Controlled trial of Selegeline, alph-tocopherol, or both as treatment for Alzheimer’s disease. The Alzheimer’s Disease Cooperative study. NEJM 1997. ; 336(17): 1216-22.
  15. Dysken MW, Effect of Vitamin E and Memantine on Functional Decline in Alzheimer’s disease. JAMA January 1/2014 volume 311, number 1, pages 33-44.
  16. Peterson R.C. et al, Vitamin E and Donepezil for the treatment of MCI. Alzheimer’s disease cooperative study group. NEJM 2005; 352 (23): 2379-2388.
  17. Miller ER III et al, Meta-analysis: high dosage vitamin E supplementation may increase all cause mortality. Annals Internal Medicine 2005; 142 (1): 37-46.
  18. Blasko I et al, Conversion from MCI to dementia: influence of folic acid and vitamin B12 in the VITA cohort. Journal of Nutritional Health and Aging. 2012 ;16(8): 687-94.
  19. Vance JE. Et al, Metabolism and Functions of Phosphatidylserine. Progress Lipid Research 2005, 44(4): 207-34
  20. Crook TH. Et al, Effects of Phosphatidylserine Serine in age associated memory impairment. Neurology 1991, 41(5):644-49.
  21. Vakhapova V. et al, Safety of Phosphatidylserine containing Omega-3 fatty acids in non- demented elderly : A double blind placebo controlled trial followed by an open label extension. BMC Neurology 2011, 11: 79
  22. Vakhapova V. et al Phosphatidylserine containing omega 3 fatty acids may improve memory abilities in nondemented elderly with memory complaints: A double blind placebo-controlled study. Dementia and Geriatric Cognitive Disorders 2010; 29: 467-474.
  23. Devere R. Cognitive consequences of Vitamin D deficiency. Practical Neurology Jan/Feb 2014 volume 13 (1): pages 25-28.
  24. Toffanelo ED. Et al, Vitamin D deficiency predicts cognitive decline in older men and women. Neurology Nov 5/2014 published on line before Print.
  25. Wilson VK> et al, Relationship between 25 hydroxy Vitamin D and cognitive function in older adults. : The health, aging and body composition study. Journal of the American Geriatric Society 2014; 62(4): 636.
  26. Frechette JD. Et al, Role of Nutrition in the Prevention of Cognitive Decline. Annals of long term care. February 2014 Pages 41-48
  27. Obulesu M. et al, Carotenoids and Alzheimer’s disease: an insight into the therapeutic role of retinoids in animal models. Neurochem Int. 2011; 59(5): 535-541.
  28. Scapagnini G. et al, Modulation of Nrf2/ARE pathway by food polyphenols: a nutritional neuroprotective strategy for cognitive neurodegenerative disorders. Molecular Neurobiology 2011; 44(2): 192-201.
  29. Ho L. et al, Heterogeneity in red wine polyphenolic contents differently influences Alzheimer’s disease type neuropathology and cognitive deterioration. Journal of Alzheimer’s disease 2009; 16(1):59-72.
  30. Stranahan AM. Et al, Impact of energy intake and expenditure on neuronal plasticity. Neuromolecular Medicine 2008; 10 (4) : 209-18.
  31. Mattson MP. et al. The impact ofdietary energy intake on cognitive aging. Front Aging Neuroscience 2010;2: 5
  32. Vining EP. Et al, Clinical Efficacy of the Ketogenic diet. Epilepsy Research 1999; 37(3): 181-90.
  33. Witte AV et al, Caloric Restriction improves memory in elderly humans. Proc Natl. Acad Sci.
  34. Isaacson RS., Ochner CN., The Alzheimer Diet. Step by step nutritional approach for memory loss prevention and treatment. 2013 Publisher: AD education consultants Inc. Miami Beach FL.
  35. Small G., Vorgan G., The Alzheimer Prevention Program 2012 Workman Publishing. New York.
  36. Perlmutter D., Grain Brain 2013 Little Brown and Company
  37. Polimeni G. et al, Role of Melatonin supplementation in Neurodegenerative disorders.. Front Bioscience (Landmark Ed.), 2014; 19:429-446
  38. Smith GE. Et al, A cognitive training program based on principles of brain plasticity: results from the improvement in memory with plasticity based Adaptive Cognitive Training (IMPACT) study. J American geriatric society 2009; 57:594-603.
  39. disease: S longitudinal study. Neurology 2010; 75: 1408-14.
  40. Bredesen DE. Et al, Next generation therapeutics for Alzheimer’s disease. EMBO Molecular Medicine 2013; 5: 795-98.
  41. Yaffee K. et al, Estrogen Use, APOE and cognitive decline: evidence of gene-environment interaction Neurology 2000 54: 1949-54
  42. Begum AN. et al, Curcumin structure-function, bioavailability, and efficacy in models of neuro-inflammation and Alzheimer’s disease. J. Pharmacol Exp Ther 2008; 326: 196-208
  43. MA QL. et al, Curcumin suppresses soluble Tau dimers and corrects molecular chaperone, synaptic and behavioral deficits in aged human Tau transgenic mice. J Biol Chem 2013: 288: 4056-4065.
  44. Zanotta D. et al, Cognitive effects of a dietary supplement made from extract of Bacopa monnieri, astaxanthin, phosphatidylserine and Vitamin E in subject with Mild Cognitive Impairment: A non-comparative exploratory clinical study. Neuropsychiatric Dis Treat. 2014; 10: 225-30.
  45. Li W. et al, Elevation of Brain magnesium prevents and reverses cognitive deficits and synaptic loss in Alzheimer’s disease mouse model. Journal of Neuroscience 2013; 33: 8423-41.
  46. Littlejohns TJ et al, Vitamin D and the risk of dementia and Alzzheimer’s disease. Neurology 2014.
  47. Taglialatela G. et al, L Acetyl-L-carnitine treatment increases nerve growth factor levels and choline acetyl-transferase activity in the central nervous system of aged rats. Exp Gerontology 1994; 29: 55-56.
  48. Cansev M. et al, Oral administration of circulating precursors for membrane phosphatides can promote the synthesis of new brain synapses. Alzheimer’s Dementia 2008; 4: S153-168.
  49. Parachikova A. et al, Formulation of a medical food food cocktail for Alzheimer’s disease: Beneficial effects on cognition and neuropathology in a mouse model of the disease. PLoSOne. 2010; 5: e14015.
  50. Brewer GJ. Et al, Zinc deficiency and zinc therapy efficiency with reduction of serum free copper in Alzheimer’s disease. International Journal of AD 2013; 2013: 586365
  51. Troussiere AC. Et al, Treatment of sleep apnea syndrome decreases cognitive decline in patients with AD. JNNP 2014
  52. Bland J. The Disease Delusion: Conquering the causes of illness for a Healthier, Longer and Happier Life. 2014; United States: Harper Wave.
  53. Henderson ST. et al, Study of the Ketogenic agent AC-1202 in mild to moderate AD; A randomized double blind placebo controlled multicenter trial. Nutritional Metabolism (London). 2009; 6: 31.