Good Diets Fight Bad Alzheimer Genes

Diets high in fish oil have a beneficial effect in patients at risk

Scientists today agree that there are five molecules that are known to affect or cause Alzheimer’s disease, which plagues an estimated five million Americans. The potency of these molecules is linked to environmental factors such as diet and lifestyle.

Professor Daniel Michaelson of Tel Aviv University’s Department of Neurobiologyat the George S. Wise Faculty of Life Sciences has illuminating news about one of these five molecules — APOE, created by the apolipoprotein E gene found in all of our bodies.

Professor Michaelson says APOE comes in two forms, a “good” APOE gene and a “bad” APOE gene, called APOE4. He has developed animal models to investigate the effects of diet and environment on carriers of APOE4, the presence of which is a known risk factor for Alzheimer’s. It appears in 50% of all Alzheimer’s patients, and in 15% of the general population which due to APOE4 is the population which is at risk of getting the disease.

The good news? A diet high in Omega 3 oils and low in cholesterol appears to significantly reduce the negative effects of the APOE4 gene in mouse models.

Exercise is not enough — and may be worse

Prof. Daniel Michaelson

In differentiating between the good and bad variants of the APOE gene, Professor Michaelson and his team studied many variables. They determined that while a rich and stimulating environment is good for carriers of “good” APOE, the same environment has a negative effect on those at risk for Alzheimer’s because they carry the APOE4 gene. While this environment stimulated the formation of new neuronal connections in the “good APOE” mice, it caused the death of brain neurons in the “bad APOE” mice. The stimulating environment included running wheels and tubes for hiding and sliding, as well as ropes and other toys for the mice to play on, replaced and updated with new toys weekly. Those in a non-stimulating environment had access to no toys at all.

“Conditions that are generally considered good can be harmful if the mouse is a carrier of the APOE4 gene. Extrapolating this to the human population, individuals with the bad APOE4 gene are more susceptible to stress caused by an environment that stimulates their brain,” says Professor Michaelson.

The following is an abstract of a study by the research group of Professor Michaelson. The study is published in Journal of Alzheimer’s Disease (2012; 28 (3): 667-83):

“Apolipoprotein E4 (apoE4) is the most prevalent genetic risk factor for Alzheimer’s disease (AD). Epidemiological studies revealed that consumption of docosahexaenoic acid (DHA: 22 : 6 (ω3)), a major brain polyunsaturated fatty acid, is protective for AD and that elevated cholesterol levels are an AD risk factor. We presently investigated the extent to which the pathological effects of apoE4 in vivo can be prevented by consuming fish oil (DHA) or can be modified by cholesterol. Accordingly, apoE3- and apoE4-targeted replacement mice were subjected, following weaning, to a fish oil dietenriched in DHA and to a cholesterol-containing diet under regular and enriched environments. Cholesterol metabolism in the hippocampus and the corresponding phospholipid and fatty acid levels were affected by fish oil (DHA) and cholesterol diets and by environmental stimulation. Importantly, cholesterol metabolism and the fatty acid levels were not affected by apoE4. The phospholipid levels were, however, affected by apoE4. This effect was most pronounced in the cholesterol-fed mice and was abolished by the fish oil (DHA) diet. ApoE4 elevated hippocampal intraneuronal amyloid-β levels under regular conditions and lowered them following environmental stimulation, relative to those of the apoE3 mice. ApoE4 also elevated the levels of the presynaptic transporters Vglut and Vgat, and decreased behavioral performance in an object recognition test. Importantly, all of these apoE4 phenotypes were abolished by the fish oil (DHA) diet, whereas the cholesterol diet modified them. These findings suggest that a fish oil (DHA)diet could be used to attenuate the effects of apoE4 in AD.”

When it’s good, it’s good

“The main take-away message here is that good diets can alleviate the effects of bad genes. Of course nutritionists have had this general idea for a while, but it’s nice to be able to show that this approach can be applied to specifically counteract the negative effects of Alzheimer’s disease-related genes,” says Professor Michaelson.



Kariv-Inbal Z, Yacobson S, Berkecz R, Peter M, Janaky T, Lütjohann D, Broersen LM, Hartmann T, Michaelson DM. The isoform-specific pathological effects of apoE4 in vivo are prevented by a fish oil (DHA) diet and are modified by cholesterol. J Alzheimers Dis 2012; 28 (3): 667-83.


Antioxidant may disrupt Alzheimer’s disease process

According to new study published in the Journal of Alzheimer’s Disease

Alzheimer’s disease (AD) is now the sixth leading cause of death among Americans, affecting nearly 1 in 8 people over the age of 65. There is currently no treatment that alters the course of this disease. However, an increasing amount of evidence suggests that changes in the way the body handles iron and other metals like copper and zinc may start years before the onset of AD symptoms. A new study shows that reducing iron levels in blood plasma may protect the brain from changes related to AD.

In the current study a group of investigators from led by Dr. Othman Ghribi, PhD, Associate Professor, Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota School of Medicine and Health Sciences, rabbits were fed a high-cholesterol diet which caused them to accumulate plaques of a small protein called beta-amyloid (Aβ). These plaques are toxic to neurons and central to the development of Alzheimer’s disease. The rabbits also developed changes in tau protein, which is part of the skeleton of neurons. When this protein becomes heavily phosphorylated, the ability of neurons to conduct electrical signals is disrupted. Following treatment with a drug called deferiprone (an iron chelator), the iron level in the rabbits’ blood plasma was reduced and the levels of both beta-amyloid and phosphorylated tau in the brain were returned to normal levels.

Another degenerative process in AD involves the production of reactive oxygen species (ROS) that can damage neurons in the brain. Deferiprone is also thought to suppress this reactive oxygen damage caused by free iron in the bloodstream, however in this study there was no difference in reactive oxygen species in the treated group. It appears that iron in the AD brain is located in the wrong places – in particular it accumulates to very high levels in the cores of beta-amyloid plaques and is very reactive in this setting.

According to Dr. Ghribi, “Our data show that treatment with the iron chelator deferiprone opposes several pathological events induced by a cholesterol-enriched diet…Deferiprone reduced the generation of Aβ and lowered levels of tau phosphorylation.” While there was no effect on ROS levels, he comments that “It is possible that a higher dose of deferiprone, or combination therapy of deferiprone together with an antioxidant to prevent ROS generation would more-fully protect against the deleterious effects of cholesterol-enriched diet that are relevant to AD pathology.”

Noted expert on metals metabolism research on AD Ashley Bush, MD, PhD, Mental Health Research Institute, Melbourne, Australia, adds that “this research highlights the role of metal ions as key modulators for the toxic interactions of risk factors for Alzheimer’s disease, in this case cholesterol. Drugs targeting these metal interactions hold promise as disease-modifying agents.”



Prasanthi JR, Schrag M, Dasari B, Marwarha G, Kirsch WM, Ghribi O. Deferiprone Reduces Amyloid-β and Tau Phosphorylation Levels but not Reactive Oxygen Species Generation in Hippocampus of Rabbits Fed a Cholesterol-Enriched Diet. J Alzheimers Dis. 2012 Mar 9. [Epub ahead of print]


Diabetes May Significantly Increase Your Risk of Dementia

People with diabetes appear to be at a significantly increased risk of developing dementia, according to a study published in the September 20, 2011, print issue of Neurology®, the medical journal of the American Academy of Neurology.

“Our findings emphasize the need to consider diabetes as a potential risk factor for dementia,” said study author Yutaka Kiyohara, MD, PhD, of Kyushu University in Fukuoka, Japan. “Diabetes is a common disorder, and the number of people with it has been growing in recent years all over the world. Controlling diabetes is now more important than ever.”

People with diabetes were more likely to develop Alzheimer’s disease and other types of dementia, such as vascular dementia, which occurs when there is damage to blood vessels that eventually deprive the brain of oxygen.

For the study, a total of 1,017 people who were age 60 and older were given a glucose (sugar) tolerance test after an overnight fast to determine if they had diabetes. Study participants were monitored for an average of 11 years and then tested for dementia. During the study, 232 people developed dementia.

The study found that people with diabetes were twice as likely to develop dementia as people with normal blood sugar levels. Of the 150 people with diabetes, 41 developed dementia, compared to 115 of the 559 people without diabetes who developed dementia.

The results remained the same after the researchers accounted for factors such as high blood pressure, high cholesterol and smoking. The risk of dementia was also higher in people who did not have diabetes, but had impaired glucose tolerance, or were “pre-diabetes.”

In addition, the study found the risk of developing dementia significantly increased when blood sugar was still high two hours after a meal.



Matsuzaki T, Sasaki K, Hata J, Hirakawa Y, Fujimi K, Ninomiya T et al. Association of Alzheimer disease pathology with abnormal lipid metabolism: The Hisayama Study. Neurology 2011; 77 (11): 1068-1075.


Study Identifies Chemical Changes In Brains Of People At Risk For Alzheimer’s Disease

Dr. Kejal Kantarci

A brain imaging scan identifies biochemical changes in the brains of normal people who might be at risk for Alzheimer’s disease, according to research published in the August 24, 2011, online issue of Neurology®, the medical journal of the American Academy of Neurology.

The study of 311 people in their 70s and 80s with no cognitive problems, from the population-based Mayo Clinic Study of Aging, used an advanced brain imaging technique called proton MR spectroscopy to see if they had abnormalities in several brain metabolites that may be biomarkers for Alzheimer’s disease. They also had PET scans to assess the level of amyloid-beta deposits, or plaques, in the brain that are one of the first signs of changes in the brain due to Alzheimer’s disease. The participants were also given tests of memory, language and other skills.

“There is increasing evidence that Alzheimer disease is associated with changes in the brain that start many years before symptoms develop,” said Jonathan M. Schott, MD, of the Dementia Research Centre, University College London in England and a member of the American Academy of Neurology, who wrote an editorial accompanying the study. “If we could identify people in whom the disease process has started but symptoms have not yet developed, we would have a potential window of opportunity for new treatments—as and when they become available—to prevent or delay the start of memory loss and cognitive decline.”

The study found that 33 percent of the participants had significantly high levels of amyloid-beta deposits in their brains. Those with high levels of amyloid-beta deposits also tended to have high levels of the brain metabolites myoinositol/creatine and choline/creatine. People with high levels of choline/creatine were more likely to have lower scores on several of the cognitive tests, regardless of the amount of amyloid-beta deposits in their brains.

“This relationship between amyloid-beta deposits and these metabolic changes in the brain are evidence that some of these people may be in the earliest stages of the disease,” said study author Kejal Kantarci, MD, MSc, of the Mayo Clinic in Rochester, Minn., and a member of the American Academy of Neurology. “More research is needed that follows people over a period of years to determine which of these individuals will actually develop the disease and what the relationship is between the amyloid deposits and the metabolites.” At the present time, MR spectroscopy cannot be used for diagnosis.



Kantarci K, Lowe V, Przybelski SA, Senjem ML, Weigand SD, Ivnik RJ, et al. Magnetic resonance spectroscopy, β-amyloid load, and cognition in a population-based sample of cognitively normal older adults. Neurology 2011 Aug 24 [Epub ahead of print].


Treatment With Vitamin C Dissolves Toxic Protein Aggregates In Alzheimer’s Disease

Katrin Mani, MD, PhD, Assistant Professor.

Researchers at Lund University in Sweden have discovered a new function for vitamin C. Treatment with vitamin C can dissolve the toxic protein aggregates that build up in the brain in Alzheimer’s disease. The research findings are now being presented in the Journal of Biological Chemistry.

The brains of people with Alzheimer’s disease contain lumps of so-called amyloid plaques which consist of misfolded protein aggregates. They cause nerve cell death in the brain and the first nerves to be attacked are the ones in the brain’s memory centre.

“When we treated brain tissue from mice suffering from Alzheimer’s disease with vitamin C, we could see that the toxic protein aggregates were dissolved. Our results show a previously unknown model for how vitamin C affects the amyloid plaques”, says Katrin Mani, reader in Molecular Medicine at Lund University.

“Another interesting finding is that the useful vitamin C does not need to come from fresh fruit. In our experiments, we show that the vitamin C can also be absorbed in larger quantities in the form of dehydroascorbic acid from juice that has been kept overnight in a refrigerator, for example”.

There is at present no treatment that cures Alzheimer’s disease, but the research is aimed at treatments and methods to delay and alleviate the progression of the disease by addressing the symptoms.

That antioxidants such as vitamin C have a protective effect against a number of diseases, from the common cold to heart attacks and dementia, has long been a current focus of research.

“The notion that vitamin C can have a positive effect on Alzheimer’s disease is controversial, but our results open up new opportunities for research into Alzheimer’s and the possibilities offered by vitamin C”, says Katrin Mani.



Cheng F, Cappai R, Ciccotosto GD, Svensson G, Multhaup G, Fransson LÅ, Mani K. Suppression of Amyloid β A11 Antibody Immunoreactivity by Vitamin C: POSSIBLE ROLE OF HEPARAN SULFATE OLIGOSACCHARIDES DERIVED FROM GLYPICAN-1 BY ASCORBATE-INDUCED, NITRIC OXIDE (NO)-CATALYZED DEGRADATION. J Biol Chem 2011; 286 (31): 27559-72.


Over Half Of Alzheimer’s Cases May Be Preventable, Say Researchers

Over half of all Alzheimer’s disease cases could potentially be prevented through lifestyle changes and treatment or prevention of chronic medical conditions, according to a study led by Deborah Barnes, PhD, a mental health researcher at the San Francisco VA Medical Center.

Analyzing data from studies around the world involving hundreds of thousands of participants, Barnes concluded that worldwide, the biggest modifiable risk factors for Alzheimer’s disease are, in descending order of magnitude, low education, smoking, physical inactivity, depression, mid-life hypertension, diabetes and mid-life obesity.

In the United States, Barnes found that the biggest modifiable risk factors are physical inactivity, depression, smoking, mid-life hypertension, mid-life obesity, low education and diabetes.

Together, these risk factors are associated with up to 51 percent of Alzheimer’s cases worldwide (17.2 million cases) and up to 54 percent of Alzheimer’s cases in the United States (2.9 million cases), according to Barnes.

“What’s exciting is that this suggests that some very simple lifestyle changes, such as increasing physical activity and quitting smoking, could have a tremendous impact on preventing Alzheimer’s and other dementias in the United States and worldwide,” said Barnes, who is also an associate professor of psychiatry at the University of California, San Francisco.

The study results were presented at the 2011 meeting of the Alzheimer’s Association International Conference on Alzheimer’s Disease in Paris, France, and published online on July 19, 2011 in Lancet Neurology.

Barnes cautioned that her conclusions are based on the assumption that there is a causal association between each risk factor and Alzheimer’s disease. “We are assuming that when you change the risk factor, then you change the risk,” Barnes said. “What we need to do now is figure out whether that assumption is correct.”

Senior investigator Kristine Yaffe, MD, chief of geriatric psychiatry at SFVAMC, noted that the number of people with Alzheimer’s disease is expected to triple over the next 40 years. “It would be extremely significant if we could find out how to prevent even some of those cases,” said Yaffe, who is also a professor of psychiatry, neurology and epidemiology at UCSF.

Natural Chemical Found In Grapes May Protect Against Alzheimer’s Disease

Researchers at Mount Sinai School of Medicine have found that grape seed polyphenols—a natural antioxidant—may help prevent the development or delay the progression of Alzheimer’s disease. The research, led by Giulio Maria Pasinetti, MD, PhD, The Saunder Family Professor in Neurology, and Professor of Psychiatry and Geriatrics and Adult Development at Mount Sinai School of Medicine, was published online in the current issue of the Journal of Alzheimer’s Disease.

This is the first study to evaluate the ability of grape-derived polyphenols to prevent the generation of a specific form of β-amyloid (Aβ) peptide, a substance in the brain long known to cause the neurotoxicity associated with Alzheimer disease. In partnership with a team at the University of Minnesota led by Karen Hsiao Ashe, MD, PhD, Dr. Pasinetti and his collaborators administered grape seed polyphenolic extracts to mice genetically determined to develop memory deficits and Aβ neurotoxins similar to those found in Alzheimer’s disease. They found that the brain content of the Aβ*56, a specific form of Aβ previously implicated in the promotion of Alzheimer’s disease memory loss, was substantially reduced after treatment.

Previous studies suggest that increased consumption of grape-derived polyphenols, whose content, for example, is very high in red wine, may protect against cognitive decline in Alzheimer’s. This new finding, showing a selective decrease in the neurotoxin Aβ*56 following grape-derived polyphenols treatment, corroborates those theories.

“Since naturally occurring polyphenols are also generally commercially available as nutritional supplements and have negligible adverse events even after prolonged periods of treatment, this new finding holds significant promise as a preventive method or treatment, and is being tested in translational studies in Alzheimer’s disease patients,” said Dr. Pasinetti.

The study authors emphasize that in order for grape-derived polyphenols to be effective, scientists need to identify a biomarker of disease that would pinpoint who is at high risk to develop Alzheimer’s disease.

“It will be critical to identify subjects who are at high risk of developing Alzheimer’s disease, so that we can initiate treatments very early and possibly even in asymptomatic patients,” said Dr. Pasinetti. “However, for Alzheimer’s disease patients who have already progressed into the initial stages of the disease, early intervention with this treatment might be beneficial as well. Our study implicating that these neurotoxins such as Aβ*56 in the brain are targeted by grape-derived polyphenols holds significant promise.”

This research was funded by a grant from the National Institutes of Health. Dr. Giulio Pasinetti is a named inventor of a pending patent application filed by Mount Sinai School of Medicine (MSSM) related to the study of Alzheimer’s disease. In the event the pending or issued patent is licensed, Dr. Pasinetti would be entitled to a share of any proceeds MSSM receives from the licensee.



Liu P, Kemper LJ, Wang J, Zahs KR, Ashe KH, Pasinetti GM.  Grape Seed Polyphenolic Extract Specifically Decreases Aβ*56 in the Brains of Tg2576 Mice.  J Alzheimers Dis. 2011 Jul 8. [Epub ahead of print].

High Blood Levels Of Vitamin E Reduces Risk Of Alzheimer’s

High levels of several vitamin E components in the blood are associated with a decreased risk for Alzheimer’s disease (AD) in advanced age, suggesting that vitamin E may help prevent cognitive deterioration in elderly people.

“Vitamin E is a family of eight natural components, but most studies related to Alzheimer’s disease investigate only one of these components, ±-tocopherol”, says Dr. Francesca Mangialasche, who led a study on AD and vitamin E. “We hypothesized that all the vitamin E family members could be important in protecting against AD. If confirmed, this result has implications for both individuals and society, as 70 percent of all dementia cases in the general population occur in people over 75 years of age, and the study suggests a protective effect of vitamin E against AD in individuals aged 80+.”

The study was conducted at the Aging Research Center (ARC), Karolinska Institutet, Stockholm, Sweden, in collaboration with the Institute of Gerontology and Geriatrics, University of Perugia, Italy. The study included a sample of 232 participants from the Kungsholmen Project, a population-based longitudinal study on aging and dementia in Stockholm (Kungsholmen parish). All participants were aged 80+ years and were dementia-free at the beginning of the study (baseline). After 6-years of follow-up, 57 AD cases were identified.

The blood levels of all eight natural vitamin E components were measured at the beginning of the study. Subjects with higher blood levels (highest tertile) were compared with subjects who had lower blood levels (lowest tertile) to verify whether these two groups developed dementia at different rates. The study found that subjects with higher blood levels of all the vitamin E family forms had a reduced risk of developing AD, compared to subjects with lower levels. After adjusting for various confounders, the risk was reduced by 45-54%, depending on the vitamin E component.

Dr Mangialasche notes that the protective effect of vitamin E seems to be related to the combination of the different forms. Another recent study indicated that supplements containing high doses of the E vitamin form ±-tocopherol may increase mortality, emphasizing that such dietary supplements, if not used in a balanced way, may be more harmful than previously thought.

“Elderly people as a group are large consumers of vitamin E supplements, which usually contain only ±-tocopherol, and this often at high doses”, says Dr Mangialasche. “Our findings need to be confirmed by other studies, but they open up for the possibility that the balanced presence of different vitamin E forms can have an important neuroprotective effect.”



Mangialasche F, Kivipelto M, Mecocci P, Rizzuto D, Palmer K, Winblad B, Fratiglioni L. High plasma levels of vitamin E forms and reduced Alzheimer’s disease risk in advanced age. J Alzheimers Dis. 2010; 20 (4): 1029-37.

Advances In Research Into Alzheimer’s Disease

Transporter proteins at the blood CSF barrier and vitamin D may help prevent amyloid beta build-up in the brain.

Advancing age is a major risk factor for Alzheimer’s disease and is associated with build- up of the peptide amyloid β in the brain. New research published in BioMed Central’s open access journal Fluids and Barriers of the CNS shows that removal of amyloid β from the brain depends on vitamin D and also on an age-related alteration in the production of transporter proteins which move amyloid β in and out of the brain.

Low levels of vitamin D are thought to be involved in age-related decline in memory and cognition and are also associated with Alzheimer’s disease. Researchers from Tohoku University, Japan, looked at the mechanism behind this and found that vitamin D injections improved the removal of amyloid β from the brain of mice.

Prof Tetsuya Terasaki said, “Vitamin D appears increase transport of amyloid β across the blood brain barrier (BBB) by regulating protein expression, via the vitamin D receptor, and also by regulating cell signaling via the MEK pathway. These results lead the way towards new therapeutic targets in the search for prevention of Alzheimer’s disease.”

The transport of amyloid β across the BBB is known to be orchestrated by transporter proteins such as LRP-1 and P-gp, which move amyloid β out of the brain, and RAGE, which controls influx. Looking at the transport of amyloid β from blood to cerebrospinal fluid (CSF), and from CSF to blood, researchers from Rhode Island Hospital and The Warren Alpert Medical School, found that LRP-1 and P-gp at the blood-cerebrospinal fluid barrier (BCSFB), increased with age so increasing removal of amyloid β from the CSF and brain.

Prof Gerald Silverberg said, “While increased production of transporter proteins at the blood CSF barrier may help amyloid β removal from the older brain, production of these proteins eventually fails. This failure may be an important event in brain function as we age and for people with Alzheimer’s disease.”


1. Ito S, Ohtsuki S, Nezu Y, Koitabashi Y, Murata S, Tetsuya Terasaki T. 1α,25-Dihydroxyvitamin D3 enhances cerebral clearance of human amyloid-β peptide(1-40) from mouse brain across the blood-brain barrier.  Fluids and Barriers of the CNS 2011, 8:20 (8 July 2011).

2. Pascale CL, Miller MC, Chiu C, Boylan M, Caralopoulos IN, Gonzalez L, Johanson CE and Silverberg GD. Amyloid-beta transporter expression at the blood-CSF barrier is age-dependent. Fluids and Barriers of the CNS 2011, 8:21 (8 July 2011).