19 September 2009

Fighting a Losing War That Must Be Won

Once the “war on cancer” was declared in 1971 by Congress, researchers have sought to defeat it (1), but after losses of many knights in shining armor, a newfound respect has come around for this dragon of a disease (1). In the 1990s and 2000s, however, a new sense of hope had come about.

“End cancer by the year 2015” was the message shared in 2003 by Andrew C. von Eschenbach, MD, director of the National Cancer Institute (NCI). And although he’s had many critics saying it couldn’t be done, others joined him in saying it could. Just two years afterward, in 2005, NCI modified it’s lofty goal to a softer “alleviate pain, suffering and death associated with cancer” (2). The change meant a new direction of “controlling” but not “curing” the disease .

The same year, 2005, one Eschenbach supporter put forward a plan for a victory (3). His name was Mikhail V Blagosklonny, MD, PhD, and his approach was by combining strategies that target cancerous cells directly while protecting normal cells in targeted tissues (3). Blagosklonny’s three-pronged attack (as suggested cures tend to be) may appear relatively simple, but so far scientists are finding the goal nothing more than elusive.

At cancer’s core there is a only one etiology, which strikes like sabotage at the core of the human body’s own blueprint: mutation. Genetic instability is why cancer has proved to be a more formidable enemy than diabetes or heart disease. The disease is completely unpredictable, arising any number of tissues, with more than 100 possible etiologies (1), and by the time you know its there, it’s an army of cancerous cells reproducing faster than rabbits, using healthy cells to shield itself from attacks, and ultimately making its final blow in a battle of attrition.

Can the 2015 goal be sustained? And, more curiously, will there ever be a cure? As always judgment will be left up to science leaving all with a need for patience, but over the years since the ‘70s much has been learned thanks to thousands of studies on cancer. Marching onward it is progressive understanding and creativeness in treatments that present hope that researchers will eventually prevail.

Reference List

1. Hesse BW. Harnessing the power of an intelligent health environment in cancer control. Stud Health Technol Inform 2005;118:159-76.
2. Conrads TP, Hood BL, Petricoin EF, III, Liotta LA, Veenstra TD. Cancer proteomics: many technologies, one goal. Expert Rev Proteomics 2005;2:693-703.
3. Blagosklonny MV. How cancer could be cured by 2015. Cell Cycle 2005;4:269-78.

18 September 2009

Anti-Soy Fiction

I just read a citizen's petition to FDA by Gail Elbek calling for the removal of soy because of antinutrients (trypsin inhibitors and phytates) and endocrine disruptors. Gave me a bit of a laugh, but I expect it will scare a lot of unwitting people.

The outrageous claims Ms. Elbek makes are not grounded in any science. Soy phytotoxicity is going to “kill our children”? Please. I’m not about to throw out my soy milk, tofu and soy sauce. What’s next? Spinach. Spinach contains a lot of phytates. Many raw foods like raw soybeans contain all sorts of anti-nutrients, but that’s why we dehull, cook, or ferment these raw foods. Most anti-nutrients are eliminated just by the processing.

There is a point to be made about high amounts of concentrated phytoestrogens (soy isoflavones) in a few dietary supplements, which are often marketed to women as natural hormonal therapy. These are basically drugs of which we don’t know enough about. The research is still out on whether or not they’re beneficial or if they can do harm.

But, again, there’s really not really anything raise eyebrows regarding levels of isoflavones in tofu or other soy products. The low levels of isoflavones that are in them are probably even good for you. So even if we ever did offer a soy protein shake, I don’t think I’d be too worried. We mustn’t forget that there have been more than 40 human clinical studies on soy protein’s health benefits. Not to mention that an entire, but relatively insignificant, country called China pretty much subsists on soy.

15 September 2009

Boron and Disease

Boron's ability to induce sex hormone levels give it a role preventing chronic disease. For example, adequate dietary boron may potentially reduce risk of lung cancer (1). The effects also explain why boron supplementation may support bone density guarding against osteoporosis (2).

However, caution should be exercised before supplementation with boron. Greater estrogen levels due to boron supplementation may potentially increase risk of breast cancer (1;2). Thus, boron should not be taken by women with high risk of breast cancer or who've had breast cancer.

Reference List

1. http://www.pccnaturalmarkets.com/health/2813008/
2. http://www.osteopenia3.com/Boron-Osteoporosis.html

13 September 2009

Nickel toxicity

Nickel is a known carcinogen. When in the diet in toxic amounts it contributes to oxidative stress, just as mercury and cadmium do, by reducing glutathione thereby interfering with cell membrane integrity and increasing lipid peroxidation (1). The oxidative damage, like from free iron or copper, can cause DNA damage (2).

Reference List

1. Valko M, Morris H, Cronin MT. Metals, toxicity and oxidative stress. Curr Med Chem 2005;12:1161-208.

2. Tkeshelashvili LK, Reid TM, McBride TJ, Loeb LA. Nickel induces a signature mutation for oxygen free radical damage. Cancer Research; 53, 4172-4174, September 15, 1993.

Flouride and the World

As one travels around the world, especially in developing countries, the state of oral health stands out as an issue that needs attention. Fluoride treatment of drinking water can be an important step in improving oral health (1), but some populations may find it's not necessary because they may already be consuming adequate or even too much fluoride daily.
Careful review of fluoride exposure must be evaluated region by region before deciding to treat local water with fluoride (2). According to the World Health Organization (WHO), flouride intake can vary depending fluoride already in water, on diet and other variables such as local pollution (2).

Areas of greater volcanic activity, for example, tend have highest concentrations of fluoride in groundwater (2). The act of tea drinking can provide significant amounts of fluoride (1). In parts of China where high-fluoride coal is burned, the ash that pollutes crops may be providing fluoride (2). And in Tanzania, the use of contaminated trona to tenderize vegetables contributes fluoride can easily result in excess amounts of fluoride ingested daily (2).

Reference List
1. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.3.
2. World Health Organization. Fluoride in Drinking Water. Available at http://www.who.int/water_sanitation_health/publications/fluoride_drinking_water_full.pdf

Molybdenum and Gout

A young electrician with a painful gouty arthritis in 2005 became the first case observed of occupational exposure of toxic amounts of molybdenum (1). Molybdenum is an activator of xanthine oxidase, which oxidizes xanthine producing uric acid (2). Too much produced hyperuricemia (1). The electrician can be thankful that his doctors found the cause of the gout because of previous men afflicted with gout by having consumed 10 to 15 mg of molybdenum daily (3;4). Tolerable uptake limits are set at 2 mg (2).

Reference List
1. Selden AI, Berg NP, Soderbergh A, Bergstrom BE. Occupational molybdenum exposure and a gouty electrician. Occup Med (Lond) 2005;55:145-8.2. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.3. http://lpi.oregonstate.edu/infocenter/minerals/molybdenum/4. http://www.crnusa.org/safetypdfs/027CRNSafetyMolybdenum.pdf

Manganese as a Neurotoxin

Toxicity of manganese is more common than its deficiency (1), which unfortunately cause damage to the brain. Manganese appears to cause neurogeneration by activating microglia and causing them to release neurotoxins such as reactive oxygen and nitrogen species, which produce oxidative damage (2). The neurotoxins are also thought to possibly alter influence of neurotransmitters such as dopamine or gamma-aminobutyric acid (GABA) (1). According to a studies on non-human primates exposed to high doses of manganese, the mineral can lead to deficits in working memory performance and even induce an increase of beta-amyloid production linking manganese to Alzheimer's disease (3;4).

Reference List
1. Anderson JG, Fordahl SC, Cooney PT, Weaver TL, Colyer CL, Erikson KM. Manganese exposure alters extracellular GABA, GABA receptor and transporter protein and mRNA levels in the developing rat brain. Neurotoxicology 2008;29:1044-53.
2. Zhang P, Wong TA, Lokuta KM, Turner DE, Vujisic K, Liu B. Microglia enhance manganese chloride-induced dopaminergic neurodegeneration: role of free radical generation. Exp Neurol 2009;217:219-30.
3. Schneider JS, Decamp E, Clark K, Bouquio C, Syversen T, Guilarte TR. Effects of chronic manganese exposure on working memory in non-human primates. Brain Res 2009;1258:86-95.
4. Burton NC, Guilarte TR. Manganese neurotoxicity: lessons learned from longitudinal studies in nonhuman primates. Environ Health Perspect 2009;117:325-32.

Mutagenic Metals

The biochemical mechanism by which metals are mutagenic is by their effects on DNA. The main pathway shared by iron, copper, chromium, vanadium and cobalt is by redox-cycling reactions and mercury, cadmium and nickel by depleting glutathione and bonding to sulfihydryl groups (1). Free iron, in particular, can cause oxidative damage on DNA that can cause cancer in the spleen (2). Arsenic, in particular binds directly to critical thiols producing DNA damage (1). Cadmium interferes with and inhibits DNA repair (3;4).

Reference List
1. Valko M, Morris H, Cronin MT. Metals, toxicity and oxidative stress. Curr Med Chem 2005;12:1161-208.
2. Wu X, Kannan S, Ramanujam VM, Khan MF. Iron release and oxidative DNA damage in splenic toxicity of aniline. J Toxicol Environ Health A 2005;68:657-66.
3. Slebos RJ, Li M, Evjen AN, Coffa J, Shyr Y, Yarbrough WG. Mutagenic effect of cadmium on tetranucleotide repeats in human cells. Mutat Res 2006;602:92-9.
4. Giaginis C, Gatzidou E, Theocharis S. DNA repair systems as targets of cadmium toxicity. Toxicol Appl Pharmacol 2006;213:282-90.

Ca and Mg balance

Calcium (Ca) and magnesium (Mg) are non-heavy metals with the same valence charge that are both critical for physiologic function, yet overlap each other in their mechanisms. For example, they both use the same transport systems in kidney competing with each other for absorption. They also oppose one another in blood coagulation, smooth muscle contraction and PTH release.

The relationship between Ca and Mg is important as it promotes a balance in given biological systems for proper function of the body. Deficiency either mineral could result in an improper balance leading to problems.

Vanadium treatment of type 2 diabetes enhanced by organic ligands

Vanadyl ions can act in an insulin-like manner in the body. Thus, when taken orally they may potentiate insulin’s effects, which can potentially improve situations of type 2 diabetes (1).

Bioavailability of vanadyl compounds, however, can depend on whether of organic or inorganic nature (2). The organic bis-ligand oxovanadium appear to be far more bioavailable and efficacious than inorganic vanadyl sulfate (2).

According to a couple of trials performed earlier this year in Canada, the organic version taken in doses of 10-90mg has no adverse effects (2). Further, it was found to help reduce fasting blood glucose levels and improves glucose tolerance (2).

Reference List
1. Conconi MT, DeCarlo E, Vigolo S et al. Effects of some vanadyl coordination compounds on the in vitro insulin release from rat pancreatic islets. Horm Metab Res 2003;35:402-6. 2. Thompson KH, Lichter J, LeBel C, Scaife MC, McNeill JH, Orvig C. Vanadium treatment of type 2 diabetes: a view to the future. J Inorg Biochem 2009;103:554-8.

12 September 2009

Life Depends on Arsenic?

As Gropper, Smitth and Groff tell it, arsenic "conjures an image of toxicity" unlike any other ultratrace mineral (1), but there are good things that come of arsenic and its story is worth discussion.

Without arsenic, DNA synthesis couldn't happen. This is because arsenic is needed for normal metabolism. Specifically, the mineral is required for forming and using methyl groups to S-adenosylmethionine (SAM) (1). SAM is used for methylation to form DNA compounds (1).

Arsenic, in fact, may have once been part of DNA itself. The mineral is very similar to phosphorus, which is currently the backbone of nucleic acids. Because this is is so it has been suggested that arsenic may have served as an alternate element early on, although not possible in modern biochemistry (3).

According to scientists Felisa Wolfe-Simon, Paul Davies and Ariel Anbar, there may even be possibility that organisms may still be using arsenic in their DNA today, but simply not yet found (3).

Reference List

1. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
2. Emsley J. Nature's Building Blocks: An A-Z Guide to the Elements. Oxford University Press, 2003.
3. Wolfe-Simon F, Davies PCW, Anbar A. Did nature also choose arsenic? Nature Precedings, Jan 2008.

06 September 2009

Estrogen & Osteoporosis

Estrogen appears to directly influence bone turnover. Its mechanism is byacting on estrogen receptors in bone cells (1). The hormone influencesvitamin D metabolism by increasing conversion of 25-hydroxyvitamin D(25OHD) to 1,25-(0H)2D as it does in birds (2).

The increase of 1,25-(0H)2D then enhances calcium absorption in the bones(2). Estrogen, thereby, contributes to bone density by slowing down boneloss and its absence can lead to lower bone density and predispose forosteoporosis (1;2).

This biochemistry supports evidence that already exists that estrogenreplacement therapy (ERT) combined with adequate calcium and vitamin Dintake as well as exercise may help prevent osteoporosis (3;4).

Despite the effects, however, I have the same opinion about using long-term estrogen replacement therapy (ERT) in postmenopausal women for osteoporosis as I do about estrogen for reducing risk of cardiovascular disease in postmenopausal women.

While there are benefits outlined suggesting that future research on long-term estrogen therapy is merited, the side risks involved may be too serious for estrogen for prescription at this time. Side risks, which include higher risk of breast cancer and other cancers, generally outweigh benefits of ERT.

Short-term ERT, however, may have its place. According to WebMD and Women's Health Initiative authors and those of WebMD, short-term ERT in low doses may reduce or eliminate risks associated with long-term ERT (5;6). More research is needed to explore use of short-term ERT.

Reference List

1. Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ. Modern Nutritionin Health and Disease. Baltimore, MD: Lippincott Williams & Wilkins, 2009.

2. Gallagher JC, Riggs BL, DeLuca HF. Effect of estrogen on calciumabsorption and serum vitamin D metabolites in postmenopausal osteoporosis.J Clin Endocrinol Metab 1980;51:1359-64.

3. Gallagher JC, Fowler SE, Detter JR, Sherman SS. Combination treatmentwith estrogen and calcitriol in the prevention of age-related bone loss. JClin Endocrinol Metab 2001;86:3618-28.

4. Gallagher JC. Role of estrogens in the management of postmenopausalbone loss. Rheum Dis Clin North Am 2001;27:143-62.

5. Banks E, Canfell K. Invited Commentary: Hormone therapy risks and benefits--The Women's Health Initiative findings and the postmenopausal estrogen timing hypothesis. Am J Epidemiol 2009;170:24-8.

6. WebMD. Women's Health Initiative (WHI): Risks and benefits of hormone replacement therapy (HRT) and estrogen replacement therapy (ERT). Available at: http://www.webmd.com/hw-popup/womens-health-initiative-whi-risks-and-benefits-of-hormone-replacement-therapy-hrt-and-estrogen.

05 September 2009

Chromium and Glucose Tolerance

Because of chromium’s known ability to potentiate action of insulin, an adequate chromium status is important especially for people with diabetes, insulin resistance and hypoglycemia to maintain glycemic control (1;2).

According to an evaluation of 15 randomized clinical trials, amounts of about 200 mcg per day appear to improve use of glucose (3). In addition, a placebo-controlled trial of 180 Chinese patients found that doses at 200 mcg and as high as 1,000 mcg of chromium taken per day lowered blood glucose levels by 15-19% (3).

Dose may depend on form of chromium since one form may be more bioavailable than another. Chromium picolinate appears to be the most bioavailable and, thus, the most potent (3).

The amount of chromium taken, however, should not exceed 1,000 mcg per day due to potential toxicity (1). Chromium picolinate, in addition, should not be taken in amounts over 600 mcg because of association with renal failure and hepatic dysfunction (1).

Reference List

1. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
2. Pohl M, Mayr P, Mertl-Roetzer M et al. Glycemic control in patients with type 2 diabetes mellitus with a disease-specific enteral formula: stage II of a randomized, controlled multicenter trial. JPEN J Parenter Enteral Nutr 2009;33:37-49.
3. Linus Pauling Institute. Chromium. Micronutrient Information Center. Available at: http://lpi.oregonstate.edu/infocenter/minerals/chromium/.

Chromium nicotinate, but not picolinate may improve body composition

Advertisements that suggest chromium picolinate may help consumers lose fat or gain muscle mass are largely overstated.

A double-blind, randomized, placebo-controlled 12-week trial in 2001 found that chromium picolinate offered moderately obese women participating in an exercise program no significant changes to body composition, resting metabolic rate, plasma glucose, serum insulin, plasma glucagon, serum C-peptide or serum lipid concentrations (1).

The 2001 study’s results supported at least three previous studies of which had also shown that chromium picolinate had been ineffective in changing body composition in obese women, in military personnel and in weight-lifting football players (2-4).

A 12-week randomized, placebo-controlled trial in 2008 combined chromium picolinate with conjugated linoleic acid and evaluated effects on body composition changes of young, overweight women for 12 weeks (5).; still, no significant changes were found (5).

Lastly, because of chromium’s known effects on enhancing insulin signaling and glucose uptake, a randomized, placebo-controlled clinical trial in 2006 investigated effects of chromium picolinate on glycogen synthesis on overweight men after intense exercise (cycling) and high-carbohydrate feeding (6). Chromium picolinate did not appear to augment glycogen synthesis, but did appear to lower activity of phosphoinositol-3-kinase, an enzyme involved in regulating glucose uptake (6).

Chromium nicotinate, however, does appear to have effects on body composition.

One study on young, obese women who were given either chromium picolinate or chromium nicotinate found that chromium picolinate while "resulted" in weight gain for subjects, it also found that chromium nicotinate, when combined with exercise, did produce weight loss and lower insulin response (2).

Another randomized, double-blinded, placebo-controlled, crossover study on African American women gave 200mcg chromium nicotinate for over 2 months (2). The study did find significant fat loss and "sparing of muscle" in the women taking chromium nicotinate when combined with moderate exercise (7).

Reference List

1. Volpe SL, Huang HW, Larpadisorn K, Lesser II. Effect of chromium supplementation and exercise on body composition, resting metabolic rate and selected biochemical parameters in moderately obese women following an exercise program. J Am Coll Nutr 2001;20:293-306.
2. Grant KE, Chandler RM, Castle AL, Ivy JL. Chromium and exercise training: effect on obese women. Med Sci Sports Exerc 1997;29:992-8.
3. Trent LK, Thieding-Cancel D. Effects of chromium picolinate on body composition. J Sports Med Phys Fitness 1995;35:273-80.
4. Clancy SP, Clarkson PM, DeCheke ME et al. Effects of chromium picolinate supplementation on body composition, strength, and urinary chromium loss in football players. Int J Sport Nutr 1994;4:142-53.
5. Diaz ML, Watkins BA, Li Y, Anderson RA, Campbell WW. Chromium picolinate and conjugated linoleic acid do not synergistically influence diet- and exercise-induced changes in body composition and health indexes in overweight women. J Nutr Biochem 2008;19:61-8.
6. Volek JS, Silvestre R, Kirwan JP et al. Effects of chromium supplementation on glycogen synthesis after high-intensity exercise. Med Sci Sports Exerc 2006;38:2102-9.
7. Crawford V, Scheckenbach R, Preuss HG. Effects of niacin-bound chromium supplementation on body composition in overweight African-American women. Diabetes Obes Metab 1999;1:331-7.

Selenium and Prostate Cancer

Prostate cancer has been associated with low serum selenium concentration. To investigate the mechanisms by which selenium affects gene expression prostate tissue, researchers set out to measure activity of glutathione peroxidase in men with relatively high serum selenium concentration (1).

The researchers measured serum selenium concentration in 98 men using atomic absorption spectrometry. Afterward, 12 men were selected for having the highest serum selenium concentration and another 12 were identified as having the lowest serum selenium concentration. Fresh prostate tissue samples were taken of the selected men to measure selenium concentration and glutathione peroxidase activity.

The study, which was published in July 2007, reported a positive correlation found between a higher serum selenium concentration and a prostate tissue concentration. However, there was no significant increase of glutathione peroxidase activity associated with the higher concentration of selenium concentration.

Discussion: Because the subjects of this study were already were identified as having high serum selenium concentrations, the results indicate simply that glutathione peroxidase activity is not increased by greater concentration of selenium beyond a certain requirement. The data suggest selenium dietary intake exceeding established amounts to correct deficiency do not present any additional benefit in prevention of prostate cancer.

Reference List

1. Takata Y, Morris JS, King IB, Kristal AR, Lin DW, Peters U. Correlation between selenium concentrations and glutathione peroxidase activity in serum and human prostate tissue. Prostate 2009.

02 September 2009

DHA May Assist in Preventing Alzheimer's Disease


Complementary preventive therapy for Alzheimer’s disease should include DHA for its biochemical implications, especially in apoE4-genotype obese-diabetic patients. DHA mechanisms involve reducing adiposity and secretions, improving insulin sensitivity, guarding against oxidative stress, and guarding against beta-amyloid plaque, neurofibrillary tangles and advanced glycation end-products.

Background: Urgent Call for Alzheimer’s Disease Preventive Therapies

Foresight warns that the present epidemic of obesity and diabetes in the United States of America will lead to future medical epidemics and among them will be Alzheimer’s disease (AD), the most common neurodegenerative disease seen in aging. AD is seriously debilitating and at present time has no cure. Current treatments are limited to cholinesterase inhibitors to improve function of signaling pathways in memory, but are not intended to prevent or slow further brain damage. Preventive strategies are currently being studied to assist in avoiding Alzheimer-type dementia in the population. Obese-diabetic persons are predisposed to AD, particularly if they are of the apoE4 genotype (Luchsinger & Gustafson, 2009). ApoE4-genotype obese-diabetic individuals, at high risk for AD, represent an ideal population for testing AD-prevention therapies. The last decade has witnessed popularity of researching fish-derived omega-3 fatty acids, notably docosahexaenoic acid (DHA), and their relationship with brain health. New research has begun to associate the use of fish oil with less cognitive decline and lowered risk of AD (Martin, 2008). Along with dieting and exercise directed at improving insulin sensitivity, DHA intake in apoE4-genotype obese-diabetic subjects may reduce the progression of AD. The following are four potential mechanisms that could explain how DHA operates: (a) improving insulin sensitivity to reduce continual hyperglycemia, hyperinsulinemia, and hypertension (b) inhibition of beta-amyloid (Abeta) and plaque production, (c) inhibition of hyperphosphorylation of tau protein, which leads to neurofibrillary tangle formation, and (d) reduction of oxidative stress and advanced glycation end-product (AGE) formation and cross-linking. This paper will discuss the literature supporting this hypothesis.

Biochemistry of AD

The underlying condition seen with AD is impairment of memory and learning, or dementia. It is primarily caused by Abeta plaques. At the core of the plaques is amyloid protein. Autopsy of AD brains shows that plaques are widely distributed over the cerebral cortex. The Abeta aggregates when under oxidative stress, which worsens the AD (Carr, Goate, Phil, & Morris, 1997). The Abeta protein binds to proteases inhibitors suppressing the normal catabolism of proteases, which allows them to damage neurons and other proteins. Neurofibrillary tangles are a secondary factor induced by Abeta. They become localized mainly in the hippocampus, entorhinal cortex and amygdala. The tangles are made up of the tau protein. Tau protein is one of the microtubule associated proteins used to stabilize microtubules and for providing attachment to other cells. The tangles are produced by abnormal hyperphosphorylation of the tau protein. The protein when hyperphosphorylated, also called “paired helical filaments,” becomes aggregated. Neurons affected by plaques and tangles eventually die (Carr et al., 1997). As described before, the tangled up mess causes considerable interference and attenuates damage in the brain. The tangles are susceptible to glycation. Advanced glycation end-products (AGEs) and cross-linking occur. The AGEs are formed by nonenzymatic Maillard reactions, when glucose molecules open and attach to lysine in proteins producing Schiff bases, which form Amadori products. The Amadori products—as also found in glycated hemoglobin—are more stable, but when attacked by free radicals produce oxoaldehydes, otherwise called AGEs. Glycations alter function of proteins causing their degradation. The Maillard reactions also lead to production of reactive oxygen species, which, in turn, promote more glycation (Kikuchi et al., 2003). Glycation on tau protein enhances formation of tangles and is thought to enhance aggregation of Abeta (Sasaki et al., 1998). The AGEs also activate glia producing inflammation and dysfunction as well as fragmentation into glyoxal and methylglyoxal (Kuhla et al., 2005). Thereby, AGEs are implicated as a cause of inflammation, oxidative stress, neuronal dysfunction (Yan et al., 1995). The Abeta aggregation, tangles and AGE cross-linking are ultimately cause for AD pathogenesis.

ApoE4 Genotype

Apolipoproteins are proteins that form lipoproteins to transport fats in the blood stream. They are produced in the liver and their amount in the bloodstream is reflective of dietary fats. An apolipoprotein involved with chylomicron transport across the blood-brain barrier is apolipoprotein E (apoE). These apoE proteins are also found along with Abeta in plaques and along with tau proteins in neurofibrillary tangles. Genetic variations of ApoE are associated with risk of AD. The allele variation episilon2 (E2) appears to be protective while episilon3 is protective to a lesser extent; however, the variant epsilon4 (E4) allele or two alleles has been found to increase AD risk 2.5-fold and 5.6-fold, respectively (Martins, Oulhaj, de Jager, & Williams, 2005; Scarmeas et al., 2002). The E4 allele is not a cause of AD, but predisposes individuals to risk.ApoE4 genotype individuals have increased susceptibility to developing Abeta plaques and neurofibrillary tangles. The mechanism is thought to be dependent on lipidated apoE4. It binds to a specific receptor, apoER2, in brain cells more easily than the other alleles. The receptor allows endocytosis of apoE4 as well as amyloid precursor protein and beta-secretase. Beta- and gamma-secretases then fragment the proteins (He, Cooley, Chung, Dashti, & Tang, 2007). The amyloid precursor protein is fragmented to Abeta. Presence of ApoE4 is also thought to slow clearance of occurring Abeta in the brain. Lipoprotein receptor-related protein-1 (LRP1) is an Abeta-binding molecule that clears Abeta at the blood-brain barrier. Abeta-apoE2 or Abeta-apoE3 complexes are cleared at a much faster rate than Abeta-apoE4 complexes (Deane et al., 2008). These factors lead to risk of “early onset” AD, which is defined as those with AD before age 65. ApoE4 genotype can lead to development of AD as early as ages 30 and 40, especially if obese and diabetic. The apoE4-genotype obese-diabetic population represent ideal candidates for study of AD preventive strategies.

AD Risk Increased by Adiposity and Hyperinsulinemia

Obesity has been consistently linked to the development of dementia and AD (Salihu, Bonnema, & Alio, 2009; Razay, Vreugdenhil, & Wilcock, 2006). Elevated adiposity promotes insulin resistance, an increase of adipokines (cytokines produced from adipocytes) including resistin and tumor necrosis factor-alpha (TNF╬▒). The insulin resistance exacerbates the process leading to metabolic syndrome and diabetes. When obesity is combined with diabetes, the risk of AD increases more than four-fold (Pasinetti et al., 2007). Diabetes and glucose intolerance occurs once the amount of insulin is not enough to overcome elevated plasma glucose. The pancreas secretes more insulin to abnormally high levels to maintain adequate glucose levels in the blood. Abnormal insulin signaling in the brain leads to prolonged elevated insulin levels. Normally insulin would bind to insulin receptors. Under conditions of AD, however, neurons have few insulin receptors and are resistant to insulin. Elevated insulin in the brain that is unable to bind to neurons accumulates in the serum. Hyperinsulinemia stimulation of inflammation is thought to induce formation of Abeta plaques. The loss of appropriate insulin signaling alters activity of phosphorylation leading to increased phosphorylation of tau proteins (Schubert et al., 2004). Prolonged levels of elevated insulin was also suggested by at least one study to peripherally stimulate abnormal signal transduction pathways causing hyperphosphorylation of tau proteins (Freude et al., 2005). The hyperphosphorylation and formation of Abeta plaques caused by hyperinsulinemia in the brain are major factors leading to AD.

Elevated insulin interferes with Abeta degradation. Insulin-degrading enzyme (IDE) breaks down both insulin and Abeta. In addition, it breaks down amylin, which is another amyloidogenic peptide. With all three substrates—insulin, Abeta and amylin competing for the same enzyme—less Abeta and amylin is broken down (Qiu & Folstein, 2006). ApoE4 is also thought to possibly downregulate IDE expression in neurons because it binds to its receptor (Du, Chang, Guo, Zhang, & Wang, 2009). A present target for AD preventive therapy may be to help increase effectiveness of IDE with drugs or by preventing hyperinsulinemia.

Clearance of Abeta is also affected by elevated insulin. The abnormal insulin signaling and inappropriate neuron function causes reduced levels of transthyretin. Transthyretin is a protein that normally supports transport of Abeta out of brain. Therefore, Abeta and amylin elevate in the plasma and becomes aggregated in the environment of inflammation forming plaques (Qiu & Folstein, 2006). In one prospective study, hyperinsulinemia was found to double the risk of AD in subjects ages 65 and older in Manhattan (Luchsinger, Tang, Shea, & Mayeux, 2004). Therefore, the indirect effects of elevated insulin on the brain is one more reason to closely monitor plasma glucose in both diabetics and metabolic syndrome.

Hyperinsulinemia also increases the risk of hypertension. Insulin stimulates sodium reabsorption in the kidneys and causes vasoconstriction that can lead to elevated blood pressure (Ritz, 2008). A seven-year longitudinal study found diabetics patients who had hypertension have a six-fold increased risk of AD (Posner et al., 2002). Hypertension may be involved mainly in progression of AD by producing dysfunction in the blood-brain barrier as well as increasing oxidative stress (Skoog, 1997). Increased permeability in the blood-brain barrier is thought to create greater transport of Abeta across the barrier and less to leave the brain. The oxidative stress presents additional effects by promoting glycation.

Hyperglycemia naturally increases glycation in the brain. Combined with oxidative stress, the excess glucose lead to rapid progression of AGEs (Sato et al., 2006), which can be attenuated by AGEs found in the diet (Gil & Bengmark, 2007). Increased glyoxal levels, resulting from fragments of amadori products, also inactivates enzymes such as superoxide dismutase, needed for neutralizing free radicals, promoting more aggregation, more glycation and more damage to cells (Jabeen, Saleemuddin, Petersen, & Mohammad, 2007). Formation of AGEs and occurrence of AGEs cross-linking neurofibrillary tangles and Abeta aggregates limits neuronal function, produces oxidative stress, increases susceptibility to oxidative stress, and leads to neuronal apoptosis.

Mechanisms of DHA Against AD

The human brain is made up of approximately 60 percent fatty acids. PUFAs make up a major portion of which DHA is in greatest amount followed by EPA. The greatest concentration of DHA in the nervous system is in the membrane phospholipids. Functionally, DHA is heavily involved in retinal and brain processes. Lack of DHA predisposes for neuron dysfunction and stress in various ways, of which some is discussed here, and not of which are all understood. Because DHA and EPA are omega-3 fatty acids, their occurrence in the body relies on dietary intake from fish, crustaceans or other animals, or, to a poorer extent, synthesis from dietary alpha-linolenic acid from plants. DHA is found in greatest amounts in cold-water fatty fish.

The last decade of research has revealed a strong association between DHA and AD. For example, one of the first studies to suggest a role of fish oil and cognitive decline was an observational, prospective study at Rush’s Institute for Healthy Aging. They found elderly subjects who ate fish at least once a week had 60 percent less risk of AD (Morris et al., 2003). Observational and clinical trials on DHA have yet to show benefit in reducing existing AD. According to a systemic review of 11 observational studies and four small clinical trials—of which most only used cognitive decline as an outcome—did not find convincing evidence for prevention or treatment of AD, only that fish-derived omega-3 fatty acids slowed cognitive decline in those without dementia (Fotuhi, Mohassel, & Yaffe, 2009). As a complementary therapy, however, omega-3 fatty acid biochemical nature (especially DHA) should not go ignored. In one large cohort in France involving three cities in 1999-2000, for example, it was found that omega-6 fatty acid intake that was not also met with omega-3 fatty acid intake increased risk of dementia and AD while a diet rich in omega-3 fatty acids from fish, and fruits and vegetables reduced risk of AD, particularly in ApoE4-genotype subjects (Barberger-Gateau et al., 2007). While dieting and exercise may still play the majority role in prevention, DHA’s biochemical implications suggest that there should be continued search for the right dosages of DHA for complementary AD preventive therapy.

DHA and Insulin Sensitivity

DHA as a polyunsaturated fat (PUFA) does not adversely affect insulin sensitivity. Unlike saturated and trans fats, PUFAs are not associated with insulin resistance. Research relating to PUFAs led to a commentary in J Am Diet Assoc recommending displacement of saturated fats with PUFAS, specifically 1 to 2 g of fish-derived omega-3-PUFAs, because of reports of lower glucose intolerance along with lower blood pressure, reduced triglyceride levels, and improved endothelial function (Nettleton & Katz, 2005). The mechanisms are various. PUFAs, particularly DHA and EPA, are thought to improve insulin sensitivity by more than one pathway. The mechanisms are beyond glycemic control (Kuda et al., 2009). In adipose tissue and the liver, PUFAs influence gene transcription to increase amount of proliferator-activated receptors, sterol regulatory element-binding proteins and liver X receptors (Al-Hasani & Joost, 2005). The greater presence of these proteins and receptors result in more sensitivity to various nutrients and insulin. PUFAs also improve lipid metabolism improving prevention of obesity an diabetes. Adipose tissue secretion of adipokines decreases improve insulin sensitivity. PUFAs stimulate mitochondrial beta-oxidation, thereby promoting reduced adiposity (Flachs, Rossmeisl, Bryhn, & Kopecky, 2009). The effects are independent of PUFAs role in eicosanoid synthesis. DHA, in particular, induces lipolysis while reducing lipogenesis in what appear to be various biochemical pathways in the liver and adipocytes. PUFAs regulate gene transcription of lipogenic enzymes—such as glucose-6 phosphate dehydrogenase and fatty acid synthase—and desaturatases—such as stearoyl-C desaturase (Riserus, 2008). DHA is thought to increase lipolytic gene expression and suppressing lipogenic gene expression (Wang et al., 2009). DHA enhances expression of serum amyloid A protein, involved in lipid metabolism, and increases lipases (Wang et al., 2009). All of these are biochemical changes effective for reducing adiposity, subsequent secretions, and the factors leading to insulin resistance.

DHA also improves insulin sensitivity through docosanoid pathways. DHA and EPA immunomodulatory effects are well-known because they inhibit pro-inflammatory cytokine production (Sijben & Calder, 2007). Apart from this role, they increase formation of EPA-derived eicosanoids and DHA-derived docosanoids, resolvins and protectins (Gonzalez-Periz et al., 2009; Pauwels, Volterrani, Mariani, & Kairemo, 2009). The resolvins and protectins then help guard against inflammation as well as insulin resistance. These effects all naturally lead to decreased hyperglycemia, hyperinsulinemia and resulting hypertension.

DHA Lowers Risk of Hypertension

Blood pressure levels are lowered by DHA in various ways. Reduced insulin reduces salt reabsorption in the kidney stemming hypertension. PUFAs such as DHA guard against hypertriacylglycerolemia associated with hypertension (Viljoen & Wierzbicki, 2009). DHA also may help to regulate aldosterone and corticosterone levels associated with hypertension (Engler et al., 1999). A dose of 5 g found to lower blood pressure (Dusing, 1989). In higher amounts (50g), fish oil quite effectively reduces diastolic blood pressure, lowers triglycerides and increases bleeding time, as shown in a six-week randomized, double-blind, parallel-group study on patients with mild hypertension (Levinson, Iosiphidis, Saritelli, Herbert, & Steiner, 1990). Without hypertension to attenuate oxidative stress in the brain, damage in AD may be reduced, but studies are unclear if omega-3 fatty acids would compensate for hyperinsulinemia-induced hypertension.

DHA can also protection against cardiogenic dementia, which can affect AD. Metabolic syndrome factors leading to atherosclerosis and possible thrombosis can result in major cardiac events. DHA improvement of endothelial function, its anti-inflammatory effects from adipokine andiponectin, its inhibition of tumor necrosis factor-alpha protect against factors, and blood platelet effects help protect against heart failure and myocardial infarction (Duda et al., 2009). Heart failure and myocardial infarction can cause cardiogenic dementia, which is a heavy burden on AD patients.

DHA Guards Against Inflammation and Oxidative Stress in the Brain

Depletion of DHA in older adults leads to greater oxidative stress in the brain. Older adults who have not consistently had DHA dietary intake slowly progress to DHA depletion. The depletion leaves membrane phospholipids at greatest risk for oxidative stress insults (Lukiw & Bazan, 2006). DHA-derived neuroprotectins have direct effects on oxidative stress. Because DHA is also involved directly in neuron-to-neuron signaling and in synaptic terminals, depletion and oxidative stress directly affects learning and memory (Lukiw & Bazan, 2006). Its involvement in brain and retinal function is combined with anti-inflammatory effects reducing oxidative damage to brain and retinal cells; thus, DHA may prevent brain damage through antioxidant properties (Farooqui, Horrocks, & Farooqui, 2007). Inhibition of inflammation and oxidative stress as well as antioxidant effects suggest a dual role of DHA protection. DHA antiflammatory properties act via anti-apoptotic and neurotrophic pathways (Orr & Bazinet, 2008).

The omega-3 fatty acid mechanisms are through DHA-derived resolvins, protectins, and neuroprotectins. Each act against the three greatest brain insults occurring in AD: neuroinflammation, oxidative stress and neuron apoptic death (Farooqui, Ong, Horrocks, Chen, & Farooqui, 2007; Farooqui et al., 2007). The effects of DHA depletion is highlighted in animals, which leads to learning and memory deficits with noticeable damage to neurons and synaptic defts; levels of cognitive function are somewhat corrected after DHA supplementation (Farooqui, Horrocks, & Farooqui, 2007). As noted earlier, humans must include DHA in the diet to effectively guard against depletion. DHA-derived neuroprotectin D1 (NPD1) offers main protection against oxidative stress. Along with sphingosine 1-phosphate, DHA inhibits cytokine-mediated cyclooxygenase-2 expression (Farooqui et al., 2007). Cyclooxygenase-2 is an enzyme that produces eicosanoids in the brain. NDP1 also triggers further neuroprotectins and gene-encoding for anti-apoptic proteins (Lukiw & Bazan, 2006). These new findings all point to preservation of DHA amounts during aging.

DHA Guards Against Abeta

DHA-derived protectins protect against Abeta formation and neurotoxicity. NDP1 protects against both. NDP1 synthesis is enhanced by Abeta occurrence. The production of NDP1 is stimulated through activation of growth factors and neurotrophins in the brain, a process that is affected directly by DHA deficits (Lukiw & Bazan, 2008). NDP1 is enhanced especially at times of oxidative stress and the lower the DHA levels, the lower the levels of NDP1 production (Lukiw & Bazan, 2008). NDP1’s effects on Abeta include regulatory interaction with gene-encoding for beta-amyloid precursor protein and Abeta formation. The reduced production of Abeta delays
AD progression by allowing more Abeta to be cleared.

NDP1 inhibits formation of Abeta, thereby against aggregation. NDP1 also displays anti-amyloidogenic effects and suppression of Abeta aggregation significantly in Abeta-infused AD-model rats (Hashimoto et al., 2008). In this way, NDP1 protects against against neurotoxicity and, in the retina, against retinal damage from aggregation and glycation from diabetes (Bazan, 2009). Protection of Abeta would be secondary benefits after DHA’s support for improving insulin sensitivity.

DHA Reduces Tangles and AGEs

DHA inhibits formation of neurofibrillary tangles. Two mechanisms are involved apart from improving helping to reduce risk of elevated insulin. Indirectly, DHA inhibition of Abeta formation reduces hyperphosphorylation. Abeta induces hyperphosphorylation by kinases, which lead to the production of the paired helical filaments that end up in tangles (Cole, Ma, & Frautschy, 2009). The second mechanism is by inhibiting hyperphosphorylation directly. DHA inhibits the enzyme c-Jun N-terminal kinase that leads to tau hyperphosphorylation (Ma et al., 2009). The inhibition of the kinases help keep in check hyperphosphorylation and help correct abnormal insulin signaling. In prolonged hyperinsulinemia, this may offer important protection to brain cells.

DHA antioxidant properties make an impact in suppressing AGE and cross-linking formation. Just as other antioxidants, DHA reduces susceptibility to free radicals. The reduced susceptibility to formation of AGEs while in presence of diabetes and hyperglycemia has been demonstrated in rats (El-seweidy, El-Swefy, Ameen, & Hashem, 2002). According to studies, the suppression of neurofibrillary tangles and AGEs cross-linking by DHA may be even more effective when used with other antioxidants from fruits and vegetables (Cole et al., 2009; Ono & Yamada, 2006). By reducing glycation, DHA suppresses AGEs cross-linking of neurofibrillary tangles and Abeta aggregation as well as inhibition of enzyme pathways. The stemming of Maillard reactions and production of free radicals contributes to less oxidative stress. Reduced glyoxal levels inhibit binding to superoxide dismutase, thereby increasing antioxidant protection. The cascade of benefits suggest DHA intake and suppression of AGEs may improve of protecting neurons from progression to dysfunction and death in AD. DHA Should Be Used

Complementary Therapy in AD

DHA has various biochemical implications that all assist in guarding against factors that lead to risk of AD. Its mechanisms involve docosanoid pathways and genetic expression that lead to reducing adiposity and secretions and improvement of insulin sensitivity. Increased insulin sensitivity helps to guard against hyperinsulinemia, hyperglycemia and hypertension, which lead to abnormal insulin signaling, glycation and oxidative stress, respectively. DHA also directly guards against AD progression through inhibition of formation of Abeta. Reduced Abeta combined with improved insulin sensitivity can lead to greater Abeta degradation from IDE and greater Abeta clearance from the brain across the blood-brain barrier. DHA also inhibits neurofibrillary tangles through suppression of Abeta formation and by modulation of tau phosphorylation. Lastly, DHA antiflammatory and antioxidant effects in the brain reduce glycation, inhibit oxidative stress from glycation and reduce advanced glycation end-product cross-linking. All of these effects support DHA’s role in assisting prevention of AD.In light of epidemiological studies and clinical trials, dieting and exercise combined with DHA should be used in the therapy of obese-diabetes patients, especially those of apoE4-genotype. The most recent of reports suggest patients adhere to a Mediterranean diet (with fish at least once a week) along with daily exercise such as walking (Scarmeas et al., 2009; Scarmeas, Luchsinger, Mayeux, & Stern, 2007). A symposium in 2008 announced the first-ever preventive trial using multi-domain interventions of which results will be available in 2013. The Multidomain Alzheimer Preventive Trial (MAPT) will examine effects of fish-derived omega-3 fatty acids in AD in a three-year, randomized, controlled study conducted in hospitals of four French cities (Gillette-Guyonnet et al., 2009). Four groups of 300 elderly subjects with specific criteria of memory complaints, slow walking speed and one instrumental activity of daily living, will be given either omega-3 fatty acid supplementation alone, multidomain intervention alone, omega-3 plus multidomain intervention, or a placebo (Gillette-Guyonnet et al., 2009). The trial will enlighten omega-3 fatty acid research further. However, more clinical studies are needed to determine effects of omega-3 fatty acids, specifically DHA, on apoE4-genotype obese-diabetic patients who are at highest risk of developing AD. DHA’s biochemical nature presents strong evidence that it will affect the elderly subjects and apoE4-genotype obese-diabetic patients positively.

Reference List

Al-Hasani, H. & Joost, H. G. (2005). Nutrition-/diet-induced changes in gene expression in white adipose tissue. Best.Pract.Res.Clin Endocrinol.Metab, 19, 589-603.
Barberger-Gateau, P., Raffaitin, C., Letenneur, L., Berr, C., Tzourio, C., Dartigues, J. F. et al. (2007). Dietary patterns and risk of dementia: the Three-City cohort study. Neurology, 69, 1921-1930.
Bazan, N. G. (2009). Neuroprotectin D1-mediated anti-inflammatory and survival signaling in stroke, retinal degenerations, and Alzheimer's disease. J Lipid Res., 50 Suppl, S400-S405.
Carr, D. B., Goate, A., Phil, D., & Morris, J. C. (1997). Current concepts in the pathogenesis of Alzheimer's disease. Am J Med., 103, 3S-10S.
Cole, G. M., Ma, Q. L., & Frautschy, S. A. (2009). Omega-3 fatty acids and dementia. Prostaglandins Leukot.Essent.Fatty Acids.
Deane, R., Sagare, A., Hamm, K., Parisi, M., Lane, S., Finn, M. B. et al. (2008). apoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain. J Clin Invest, 118, 4002-4013.
Du, J., Chang, J., Guo, S., Zhang, Q., & Wang, Z. (2009). ApoE 4 reduces the expression of Abeta degrading enzyme IDE by activating the NMDA receptor in hippocampal neurons. Neurosci.Lett..
Duda, M. K., O'Shea, K. M., Tintinu, A., Xu, W., Khairallah, R. J., Barrows, B. R. et al. (2009). Fish oil, but not flaxseed oil, decreases inflammation and prevents pressure overload-induced cardiac dysfunction. Cardiovasc.Res., 81, 319-327.Dusing, R. (1989). [Hemodynamic effect of unsaturated fatty acids. Do fish oils have an antihypertensive effect?]. Fortschr.Med., 107, 701-704.
El-seweidy, M. M., El-Swefy, S. E., Ameen, R. S., & Hashem, R. M. (2002). Effect of age receptor blocker and/or anti-inflammatory coadministration in relation to glycation, oxidative stress and cytokine production in stz diabetic rats. Pharmacol.Res., 45, 391-398.
Engler, M. M., Engler, M. B., Goodfriend, T. L., Ball, D. L., Yu, Z., Su, P. et al. (1999). Docosahexaenoic acid is an antihypertensive nutrient that affects aldosterone production in SHR. Proc.Soc.Exp.Biol.Med., 221, 32-38.
Farooqui, A. A., Horrocks, L. A., & Farooqui, T. (2007). Interactions between neural membrane glycerophospholipid and sphingolipid mediators: a recipe for neural cell survival or suicide. J Neurosci.Res., 85, 1834-1850.
Farooqui, A. A., Horrocks, L. A., & Farooqui, T. (2007). Modulation of inflammation in brain: a matter of fat. J Neurochem., 101, 577-599.
Farooqui, A. A., Ong, W. Y., Horrocks, L. A., Chen, P., & Farooqui, T. (2007). Comparison of biochemical effects of statins and fish oil in brain: the battle of the titans. Brain Res.Rev., 56, 443-471.
Flachs, P., Rossmeisl, M., Bryhn, M., & Kopecky, J. (2009). Cellular and molecular effects of n-3 polyunsaturated fatty acids on adipose tissue biology and metabolism. Clin Sci.(Lond), 116, 1-16.
Fotuhi, M., Mohassel, P., & Yaffe, K. (2009). Fish consumption, long-chain omega-3 fatty acids and risk of cognitive decline or Alzheimer disease: a complex association. Nat.Clin Pract.Neurol., 5, 140-152.
Freude, S., Plum, L., Schnitker, J., Leeser, U., Udelhoven, M., Krone, W. et al. (2005). Peripheral hyperinsulinemia promotes tau phosphorylation in vivo. Diabetes, 54, 3343-3348.Gil, A. & Bengmark, S. (2007). [Advanced glycation and lipoxidation end products--amplifiers of inflammation: the role of food]. Nutr Hosp., 22, 625-640.
Gillette-Guyonnet, S., Andrieu, S., Dantoine, T., Dartigues, J. F., Touchon, J., & Vellas, B. (2009). Commentary on "A roadmap for the prevention of dementia II. Leon Thal Symposium 2008." The Multidomain Alzheimer Preventive Trial (MAPT): a new approach to the prevention of Alzheimer's disease. Alzheimers.Dement., 5, 114-121.
Gonzalez-Periz, A., Horrillo, R., Ferre, N., Gronert, K., Dong, B., Moran-Salvador, E. et al. (2009). Obesity-induced insulin resistance and hepatic steatosis are alleviated by omega-3 fatty acids: a role for resolvins and protectins. FASEB J, 23, 1946-1957.
Hashimoto, M., Shahdat, H. M., Yamashita, S., Katakura, M., Tanabe, Y., Fujiwara, H. et al. (2008). Docosahexaenoic acid disrupts in vitro amyloid beta(1-40) fibrillation and concomitantly inhibits amyloid levels in cerebral cortex of Alzheimer's disease model rats. J Neurochem., 107, 1634-1646.
He, X., Cooley, K., Chung, C. H., Dashti, N., & Tang, J. (2007). Apolipoprotein receptor 2 and X11 alpha/beta mediate apolipoprotein E-induced endocytosis of amyloid-beta precursor protein and beta-secretase, leading to amyloid-beta production. J Neurosci., 27, 4052-4060.
Jabeen, R., Saleemuddin, M., Petersen, J., & Mohammad, A. (2007). Inactivation and modification of superoxide dismutase by glyoxal: prevention by antibodies. Biochimie, 89, 311-318.
Kikuchi, S., Shinpo, K., Takeuchi, M., Yamagishi, S., Makita, Z., Sasaki, N. et al. (2003). Glycation--a sweet tempter for neuronal death. Brain Res.Brain Res.Rev., 41, 306-323.
Kuda, O., Jelenik, T., Jilkova, Z., Flachs, P., Rossmeisl, M., Hensler, M. et al. (2009). n-3 fatty acids and rosiglitazone improve insulin sensitivity through additive stimulatory effects on muscle glycogen synthesis in mice fed a high-fat diet. Diabetologia, 52, 941-951.
Kuhla, B., Luth, H. J., Haferburg, D., Boeck, K., Arendt, T., & Munch, G. (2005). Methylglyoxal, glyoxal, and their detoxification in Alzheimer's disease. Ann.N.Y.Acad.Sci., 1043, 211-216.
Levinson, P. D., Iosiphidis, A. H., Saritelli, A. L., Herbert, P. N., & Steiner, M. (1990). Effects of n-3 fatty acids in essential hypertension. Am J Hypertens., 3, 754-760.
Luchsinger, J. A. & Gustafson, D. R. (2009). Adiposity and Alzheimer's disease. Curr.Opin.Clin Nutr Metab Care, 12, 15-21.
Luchsinger, J. A., Tang, M. X., Shea, S., & Mayeux, R. (2004). Hyperinsulinemia and risk of Alzheimer disease. Neurology, 63, 1187-1192.
Lukiw, W. J. & Bazan, N. G. (2006). Survival signalling in Alzheimer's disease. Biochem.Soc.Trans., 34, 1277-1282.
Lukiw, W. J. & Bazan, N. G. (2008). Docosahexaenoic acid and the aging brain. J Nutr, 138, 2510-2514.
Ma, Q. L., Yang, F., Rosario, E. R., Ubeda, O. J., Beech, W., Gant, D. J. et al. (2009). Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: suppression by omega-3 fatty acids and curcumin. J Neurosci., 29, 9078-9089.Martin, C. M. (2008). Omega-3 fatty acids: proven benefit or just a "fish story"? Consult Pharm., 23, 210-221.
Martins, C. A., Oulhaj, A., de Jager, C. A., & Williams, J. H. (2005). APOE alleles predict the rate of cognitive decline in Alzheimer disease: a nonlinear model. Neurology, 65, 1888-1893.
Morris, M. C., Evans, D. A., Bienias, J. L., Tangney, C. C., Bennett, D. A., Wilson, R. S. et al. (2003). Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease. Arch.Neurol., 60, 940-946.
Nettleton, J. A. & Katz, R. (2005). n-3 long-chain polyunsaturated fatty acids in type 2 diabetes: a review. J Am Diet.Assoc., 105, 428-440.
Ono, K. & Yamada, M. (2006). Antioxidant compounds have potent anti-fibrillogenic and fibril-destabilizing effects for alpha-synuclein fibrils in vitro. J Neurochem., 97, 105-115.
Orr, S. K. & Bazinet, R. P. (2008). The emerging role of docosahexaenoic acid in neuroinflammation. Curr.Opin.Investig.Drugs, 9, 735-743.
Pasinetti, G. M., Zhao, Z., Qin, W., Ho, L., Shrishailam, Y., Macgrogan, D. et al. (2007). Caloric intake and Alzheimer's disease. Experimental approaches and therapeutic implications. Interdiscip.Top.Gerontol., 35, 159-175.
Pauwels, E. K., Volterrani, D., Mariani, G., & Kairemo, K. (2009). Fatty acid facts, Part IV: Docosahexaenoic acid and Alzheimer's disease. A story of mice, men and fish. Drug News Perspect., 22, 205-213.
Posner, H. B., Tang, M. X., Luchsinger, J., Lantigua, R., Stern, Y., & Mayeux, R. (2002). The relationship of hypertension in the elderly to AD, vascular dementia, and cognitive function. Neurology, 58, 1175-1181.
Qiu, W. Q. & Folstein, M. F. (2006). Insulin, insulin-degrading enzyme and amyloid-beta peptide in Alzheimer's disease: review and hypothesis. Neurobiol.Aging, 27, 190-198.
Qiu, W. Q. & Folstein, M. F. (2006). Insulin, insulin-degrading enzyme and amyloid-beta peptide in Alzheimer's disease: review and hypothesis. Neurobiol.Aging, 27, 190-198.
Razay, G., Vreugdenhil, A., & Wilcock, G. (2006). Obesity, abdominal obesity and Alzheimer disease. Dement.Geriatr.Cogn Disord., 22, 173-176.
Riserus, U. (2008). Fatty acids and insulin sensitivity. Curr.Opin.Clin Nutr Metab Care, 11, 100-105.
Ritz, E. (2008). Metabolic syndrome and kidney disease. Blood Purif., 26, 59-62.
Salihu, H. M., Bonnema, S. M., & Alio, A. P. (2009). Obesity: What is an elderly population growing into? Maturitas, 63, 7-12.
Sasaki, N., Fukatsu, R., Tsuzuki, K., Hayashi, Y., Yoshida, T., Fujii, N. et al. (1998). Advanced glycation end products in Alzheimer's disease and other neurodegenerative diseases. Am J Pathol., 153, 1149-1155.
Sato, T., Shimogaito, N., Wu, X., Kikuchi, S., Yamagishi, S., & Takeuchi, M. (2006). Toxic advanced glycation end products (TAGE) theory in Alzheimer's disease. Am J Alzheimers.Dis.Other Demen., 21, 197-208.
Scarmeas, N., Brandt, J., Albert, M., Devanand, D. P., Marder, K., Bell, K. et al. (2002). Association between the APOE genotype and psychopathologic symptoms in Alzheimer's disease. Neurology, 58, 1182-1188.
Scarmeas, N., Luchsinger, J. A., Mayeux, R., & Stern, Y. (2007). Mediterranean diet and Alzheimer disease mortality. Neurology, 69, 1084-1093.
Scarmeas, N., Stern, Y., Mayeux, R., Manly, J. J., Schupf, N., & Luchsinger, J. A. (2009). Mediterranean diet and mild cognitive impairment. Arch.Neurol., 66, 216-225.
Schubert, M., Gautam, D., Surjo, D., Ueki, K., Baudler, S., Schubert, D. et al. (2004). Role for neuronal insulin resistance in neurodegenerative diseases. Proc.Natl.Acad.Sci.U.S.A, 101, 3100-3105.
Sijben, J. W. & Calder, P. C. (2007). Differential immunomodulation with long-chain n-3 PUFA in health and chronic disease. Proc.Nutr Soc., 66, 237-259.
Skoog, I. (1997). The relationship between blood pressure and dementia: a review. Biomed.Pharmacother., 51, 367-375.
Viljoen, A. & Wierzbicki, A. S. (2009). Potential options to treat hypertriglyceridaemia. Curr.Drug Targets., 10, 356-362.
Wang, Y. C., Kuo, W. H., Chen, C. Y., Lin, H. Y., Wu, H. T., Liu, B. H. et al. (2009). Docosahexaenoic acid regulates serum amyloid A protein to promote lipolysis through down regulation of perilipin. J Nutr Biochem.
Yan, S. D., Yan, S. F., Chen, X., Fu, J., Chen, M., Kuppusamy, P. et al. (1995). Non-enzymatically glycated tau in Alzheimer's disease induces neuronal oxidant stress resulting in cytokine gene expression and release of amyloid beta-peptide. Nat.Med., 1, 693-699.