‘Jumping Genes’ May Set Stage for Brain Cell Death in Alzheimer’s, Other Diseases

(Duke University) The latest round of failed drug trials for Alzheimer’s has researchers questioning the reigning approach to battling the disease, which focuses on preventing a sticky protein called amyloid from building up in the brain.

Duke University scientists have identified a mechanism in the molecular machinery of the cell that could help explain how neurons begin to falter in the initial stages of Alzheimer’s, even before amyloid clumps appear.

This rethinking of the Alzheimer’s process centers on human genes critical for the healthy functioning of mitochondria, the energy factories of the cell, which are riddled with mobile chunks of DNA called Alu elements.

If these “jumping genes” lose their normal controls as a person ages, they could start to wreak havoc on the machinery that supplies energy to brain cells — leading to a loss of neurons and ultimately dementia, the researchers say.

And if this “Alu neurodegeneration hypothesis” holds up, it could help identify people at risk sooner, before they develop symptoms, or point to new ways to delay onset or slow progression of the disease, said study co-author Peter Larsen, senior research scientist in biology professor Anne Yoder’s lab at Duke.

The dominant idea guiding Alzheimer’s research for 25 years has been that the disease results from the abnormal buildup of hard, waxy amyloid plaques in the parts of the brain that control memory. But drug trials using anti-amyloid drugs have failed, leading some researchers to theorize that amyloid buildup is a byproduct of the disease, not a cause.

The Duke study builds on an alternative hypothesis. First proposed in 2004, the “mitochondrial cascade hypothesis” posits that changes in the cellular powerhouses, not amyloid buildup, are what cause neurons to die.

Like most human cells, neurons rely on mitochondria to stay healthy. But unlike other cells, most neurons stop dividing after birth, so they can’t be replaced if they’re damaged.

Alzheimer’s disease causes neurons in the brain to stop working, lose connections with other neurons and die. Duke University researchers have identified a molecular mechanism that may be responsible for setting the damage in motion.

Alzheimer’s disease causes neurons in the brain to stop working, lose connections with other neurons and die. Duke University researchers have identified a molecular mechanism that may be responsible for setting the damage in motion.

In Alzheimer’s patients, the thinking goes, the mitochondria in neurons stop working properly. As a result they are unable to generate as much energy for neurons, which starve and die with no way to replenish them. But how mitochondria in neurons decline with age is largely unknown.

Most mitochondrial proteins are encoded by genes in the cell nucleus before reaching their final destination in mitochondria. In 2009, Duke neurologist and study co-author Allen Roses (now deceased) identified a non-coding region in a gene called TOMM40 that varies in length. Roses and his team found that the length of this region can help predict a person’s Alzheimer’s risk and age of onset.

Larsen wondered if the length variation in TOMM40 was only part of the equation. He analyzed the corresponding gene region in gray mouse lemurs, teacup-sized primates known to develop amyloid brain plaques and other Alzheimer’s-like symptoms with age. He found that in mouse lemurs alone, but not other lemur species, the region is loaded with short stretches of DNA called Alus.

Found only in primates, Alus belong to a family of retrotransposons or “jumping genes,” which copy and paste themselves in new spots in the genome. If the Alu copies present within the TOMM40 gene somehow interfere with the path from gene to protein, Larsen reasoned, they could help explain why mitochondria in nerve cells stop working.

“Alu elements are a double-edged sword,” Larsen said. Once dismissed as selfish or junk DNA, they are now recognized as contributors to the diversity and complexity of the human brain.

“They can provide new and beneficial gene functions,” Larsen said.

“They have helped humans evolve higher cognitive function, but perhaps at the cost of neuron vulnerability that increases with age.”

When the researchers looked across the human genome, they found that Alus were more likely to be lurking in and around genes essential to mitochondria than in other protein-coding genes.

Alus are normally held in check by clusters of atoms called methyl groups that stick to the outside of the DNA and shut off their ability to jump or turn genes on or off. But in aging brains, DNA methylation patterns change, which allows some Alu copies to re-awaken, Larsen said.

The TOMM40 gene encodes a barrel-shaped protein in the outer membrane of mitochondria that forms a channel for molecules — including the precursor to amyloid — to enter. Larsen used 3D modeling to show that Alu insertions within the TOMM40 gene could make the channel protein it encodes fold into the wrong shape, causing the mitochondria’s import machinery to clog and stop working.

Such processes likely get underway before amyloid builds up, so they could point to new or repurposed drugs for earlier intervention, said study co-author Michael Lutz, assistant professor of neurology at Duke.

The TOMM40 gene is one example, the researchers say, but if Alus disrupt other mitochondrial genes, the same basic mechanism could help explain the initial stages of other neurodegenerative diseases too, including Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis (ALS).

Alus within the TOMM40 gene could make the channel protein it encodes misfold.

Alus within the TOMM40 gene could make the channel protein it encodes misfold.

The researchers describe the Alu neurodegeneration hypothesis in a paper published online by Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.

“We need to start thinking outside of the box when it comes to treating neurological diseases like Alzheimer’s,” said Larsen, who has filed a provisional patent that focuses on preserving mitochondrial function by keeping Alus in check.



By Robin A. Smith

Other authors include Kelsie Hunnicutt, Mirta Mihovilovic and Ann Saunders of Duke. This research was supported by a seed grant from Allen Roses and Duke funds to Anne Yoder.

© Copyright 2016 Duke University.


Mayo Clinic Publishes Genetic Screen for Alzheimer’s in African-Americans

(Journal of Alzheimer’s Disease) A Mayo Clinic research team has found a new gene mutation that may be a risk factor for late-onset Alzheimer’s disease in African-Americans. This is the first time this gene has been implicated in the development of this disease in this population. Alzheimer’s disease has been understudied in African-Americans, despite the fact that the disease is twice as prevalent in African-Americans, compared to Caucasians and other ethnic groups.

This likely pathogenic variant may be unique to the African-American population, the researchers say. It has not been found in Caucasians with Alzheimer’s disease or in gene repositories from more than 60,000 subjects who are not African-Americans.

The findings, published in the February issue of the Journal of Alzheimer’s Disease, represent the first comprehensive genetic screening in African-Americans for potentially pathogenic variants in known Alzheimer’s genes.

Mayo Clinic Alzheimer’s research seeks to paint a more complete genetic picture of genes that confer risk for Alzheimer’s and genes that protect against that risk in different populations, says neurogeneticist Minerva Carrasquillo, Ph.D., who is the co-author.

“Currently, at least 5 million Americans are affected by Alzheimer’s disease, and the rate of this devastating dementia is expected to rise dramatically in the coming decades,” says Dr. Carrasquillo.

“By uncovering genetic factors that modify the risk of Alzheimer’s disease, there is the potential to identify druggable gene targets and genetic variants that could be used for early disease detection and prevention.”

The research team’s approach is to look at genetic factors known to be involved in early-onset Alzheimer’s disease — dementia that occurs before 65 and sometimes in people as young as 30-40 years of age. Up to 5 percent of Alzheimer’s disease has this early form, and a substantial number of these cases have been shown to be caused by genetic irregularities.

The investigators hypothesized that early-onset Alzheimer’s disease genes may also be involved in late-onset Alzheimer’s disease in African-Americans, although a comprehensive screen has not been done previously.

In this study, researchers looked for genetic mutations in three genes known to contribute to early-onset Alzheimer’s disease. The three genes ─ APP, PSEN1 and PSEN2 ─ are involved in producing and cutting apart proteins as part of normal brain function. But mutations in these genes can result in increasing the amount of the amyloid beta peptide (Abeta) that leads to the amyloid plaques that build up in the brain of Alzheimer’s patients. The rise in brain plaque quantity mirrors progression of Alzheimer’s dementia.

While 200 early-onset Alzheimer’s disease mutations in these three genes have been identified in Caucasians with Alzheimer’s disease, only three have been found in African-Americans with Alzheimer’s disease — one APP mutation in a single family and two PSEN1 mutations.

Of the two PSEN1 mutations, one was within a single African-American family, and one was in a female early-onset Alzheimer’s disease patient. Before this study, no PSEN2 mutations had been found in African-American patients.

In this study, the team sequenced the genome of 238 African-Americans participants. This group was divided between 131 patients with late-onset Alzheimer’s disease and 107 control participants. Investigators found six variants within the early-onset Alzheimer’s disease genes in the patients, but not in the control group.

Researchers then looked for these six gene variants in a second independent group of 300 African-Americans participants (67 with late-onset Alzheimer’s disease and 233 controls) and found that four of the variants were in the control group. That means two variants ─ one in a shorter form of PSEN1 and one in PSEN2 ─ may pose risk for late-onset Alzheimer’s disease in African-Americans.

PSEN1 variants had been found before in African-Americans with the disease, but this discovery of a likely pathogenic PSEN2 gene variant is new in this population, says Dr. Carrasquillo. “And as far as we know, it has not been found in other populations with late onset Alzheimer’s disease.”

“This study opens the door to further analysis of this gene variant ─ both in African-Americans with Alzheimer’s and in other populations,” she says.

“These findings, which require replication, represent an important step in expanding genetic research in Alzheimer’s disease to minority populations,” says the study’s senior investigator, neurogeneticist and neurologist Nilufer Ertekin-Taner, M.D., Ph.D.



This work was supported by the Florida Department of Health, the Ed and Ethel Moore Alzheimer’s Disease Research Program (AZ03), the Mentored New Investigator Research Grant to Promote Diversity Alzheimer’s Association grant, Mayo Clinic Office of Health Disparities Research, Mayo Alzheimer’s Disease Research Center (P50 AG0016574), National Institute on Aging (RF1 G051504 and U01 AG046139), and National Institute of Neurological Disorders and Stroke (R01 NS080820).

N’Songo A, Carrasquillo MM, Wang X, Nguyen T, Asmann Y, Younkin SG, Allen M, Duara R, Custo MT, Graff-Radford N, Ertekin-Taner N (2017) Comprehensive Screening for Disease Risk Variants in Early-Onset Alzheimer’s Disease Genes in African Americans Identifies Novel PSEN Variants. J Alzheimers Dis 56, 1215-1222.

Journal of Alzheimer’s Disease is published by IOS Press

Copyright © 2017


Autoimmune Conditions and Dementia: What’s the Link?

(MedicalNewsToday) A recent large-scale study concludes that individuals with autoimmune conditions may have an increased risk of developing dementia later in life. Although the effect size is relatively small, if the findings are replicated, they will have important clinical implications.

Dementias are a range of conditions, the most prevalent of which is Alzheimer’s. They are characterized by a progressive loss of memory function and other cognitive skills, eventually leading to an inability to perform everyday activities.

Currently, an estimated 47.5 million people are living with dementia, worldwide. Due to increasing lifespans, this figure is predicted to triple by the year 2050.

This steep rise in the number of cases is being referred to by some as a dementia epidemic, and for this reason, there is a great deal of focus on identifying the precise causes.

Certain factors are known to increase the risk of dementia. Advanced age, alcohol use, diabetes, and hypertension (high blood pressure) have all been said to contribute to this risk. However, there is still much to learn about how and why dementia arises.

Autoimmune Disease and Dementia

Over recent years, another potential risk factor has received some attention: autoimmune diseases.

Autoimmune diseases are conditions in which the body’s own immune system attacks healthy cells and tissues. Some evidence has shown that individuals with these types of diseases have an increased risk of developing dementia.

A research team from the University of Oxford in the United Kingdom set out to examine this question in more detail. Utilizing hospital admissions data taken from U.K. hospitals between 1998 and 2012, they investigated whether being admitted to a hospital with one of 25 autoimmune diseases was associated with an increased risk of a dementia admission later in time.

Across the 14-year time sample, there were more than 1.8 million admissions to hospitals because of an autoimmune disorder. This included more than 300,000 people with rheumatoid arthritis (RA) and around 1,000 with Goodpasture’s syndrome, a rare condition that attacks the lungs and kidneys.

Increased Dementia Risk Identified

Once the data were analyzed, the researchers found that an initial admission due to an autoimmune condition increased the risk of a later admission due to dementia by 20 percent.

Of the 25 autoimmune conditions analyzed, 18 were shown to be significantly associated with dementia. These include:

  • Addison’s disease – 48 percent increased risk
  • Polyarteritis nodosa – 43 percent increased risk
  • Multiple sclerosis – 97 percent increased risk
  • Psoriasis – 29 percent increased risk
  • Systemic lupus erythematosus – 46 percent increased risk
  • Thyrotoxicosis – 31 percent increased risk.

The majority of these associations were still significant 5 or more years after the initial admission for an autoimmune disease. In other words, the dementia was not picked up during the initial hospital examination.

Although the exact dementia diagnosis was not always noted, the risk was 6 percent higher for Alzheimer’s and 28 percent higher for vascular dementia.

The researchers believe that the higher risk associated with vascular dementia might be due to associations between autoimmune diseases and risk factors for cardiovascular and cerebrovascular diseases in general.

For instance, individuals with an autoimmune disease were more likely to receive a subsequent hospital admission for coronary heart disease and stroke (53 percent and 46 percent, respectively).

An interesting exception to these results was RA; in this case, a hospital admission for RA seemed to protect against Alzheimer’s disease. The researchers believe that this might be due to the nonsteroidal anti-inflammatory drugs often taken by individuals with RA, such as aspirin and paracetamol. These medications have previously been shown to reduce Alzheimer’s risk.

“If our findings are confirmed in other studies, clinicians and epidemiologists will wish to know that some people with some autoimmune diseases have an elevated risk of dementia.”

The study is observational and, therefore, cannot prove cause and effect. Furthermore, although the large sample size makes the interaction worthy of further study, as the authors emphasize, the effect size was small. The authors write that their

“findings should be considered as indicative rather than definitive.”



Written by Tim Newman

© 2004-2017 All rights reserved. MNT is the registered trade mark of Healthline Media.


New Approach to Treating Alzheimer’s Disease

(Ulsan National Institute of Science and Technology) Alzheimer’s disease (AD) is one of the most common form of dementia. In search for new drugs for AD, the research team, led by Professor Mi Hee Lim of Natural Science at UNIST has developed a metal-based substance that works like a pair of genetic scissors to cut out amyloid-β (Aβ), the hallmark protein of AD.

The study has been featured on the cover of the January 2017 issue of the Journal of the American Chemical Society (JACS) and has been also selected as a JACS Spotlight article.

Alzheimer’s disease is the sixth leading cause of death among in older adults. The exact causes of Alzheimer’s disease are still unknown, but several factors are presumed to be causative agents. Among these, the aggregation of amyloid-β peptide (Aβ) has been implicated as a contributor to the formation of neuritic plaques, which are pathological hallmarks of Alzheimer’s disease (AD).

As therapeutics for AD, Professor Lim suggested a strategy that uses matal-based complexes for reducing the toxicity of the amyloid beta (Aβ). Althought various metal complexs have been suggested as therapeutics for AD, none of them work effectively in vivo.

The research team has found that they can hydrolyze amyloid-beta proteins using a crystal structure, called tetra-N methylated cyclam (TMC). Hydrolysis is the process that uses water molecules to split other molecules apart. The metal-mediated TMC structure uses the external water and cut off the binding of amyloid-beta protein effectively.

In this study, the following four metals (cobalt, nickel, copper and zinc) were placed at the center of the TMC structure. When the double-layered cobalt was added to the center, the hydrolysis activity was at the highest.

The research team reported that the cobalt-based metal complex (Co(II)(TMC)) had the potential to penetrate the blood brain barrier and the hydrolysis activity for nonamyloid protein was low. Moreover, the effects of this substance on the toxicity of amyloid-beta protein were also observed in living cell experiments.

“This material has a high therapeutic potential in the treatment of Alzheimer’s disease as it can penetrate the brain-vascular barrier and directly interact with the amyloid-beta protein in the brain,” says Professor Lim.

This study has also attracted attention by the editor of the Journal of the American Chemical Society. “Not only do they develop new materials, but they have been able to propose details of the working principles and experiments that support them,” according to the editor.

“As a scientist, this is such a great honor to know that our recent publication in JACS was highlighted in JACS Spotlights,” says Professor Lim. “This means that our research has not only been recognized as an important research, but also has caused a stir in academia.”

This study has been conducted in collaboration with Professor Jaeheung Cho of Daegu Gyeongbuk Institute of Science and Technology (DGIST), Professor Kiyoung Park of Korea Advanced Institute of Science and Technology (KAIST), and Dr. Sun Hee Kim of Korea Basic Science Institute (KBSI). It has been also supporte by the National Research Foundation of Korea (NRF) and the Ministry of Science, ICT and Future Planning (MSIP).


http://news.unist.ac.kr/ new-approach-to-treating-alzheimers-disease/

By Joo Hyeon Heo

Journal Reference:

Jeffrey S. Derrick, Jiwan Lee, Shin Jung C. Lee, Yujeong Kim, Eunju Nam, Hyeonwoo Tak, Juhye Kang, Misun Lee, Sun Hee Kim, Kiyoung Park, Jaeheung Cho, Mi Hee Lim. Mechanistic Insights into Tunable Metal-Mediated Hydrolysis of Amyloid-β Peptides. Journal of the American Chemical Society, 2017; 139 (6): 2234 DOI: 10.1021/jacs.6b09681

Copyright Ulsan National Institute of Science and Technology


Alzheimer’s Disease and Alternative Treatments

(Alzheimer’s Association) A growing number of herbal remedies, dietary supplements and “medical foods” are promoted as memory enhancers or treatments to delay or prevent Alzheimer’s disease and related dementias. Claims about the safety and effectiveness of these products, however, are based largely on testimonials, tradition and a rather small body of scientific research. The rigorous scientific research required by the U.S. Food and Drug Administration (FDA) for the approval of a prescription drug is not required by law for the marketing of dietary supplements or “medical foods.”

Concerns About Alternative Therapies

Although some of these remedies may be valid candidates for treatments, there are legitimate concerns about using these drugs as an alternative or in addition to physician-prescribed therapy:

  • Effectiveness and safety are unknown. The rigorous scientific research required by the U.S. Food and Drug Administration (FDA) for the approval of a prescription drug is not required by law for the marketing of dietary supplements. The maker of a dietary supplement is not required to provide the FDA with the evidence on which it bases its claims for safety and effectiveness.
  • Purity is unknown. The FDA has no authority over supplement production. It is a manufacturer’s responsibility to develop and enforce its own guidelines for ensuring that its products are safe and contain the ingredients listed on the label in the specified amounts.
  • Dietary supplements can have serious interactions with prescribed medications. No one should take a supplement without first consulting a physician

Caprylic Acid (clinically tested as Ketasyn [AC-1202], marketed as a “medical food” called Axona®) and Coconut Oil

Caprylic acid is the active ingredient of Axona, which is marketed as a “medical food.” Caprylic acid is a medium-chain triglyceride (fat) produced by processing coconut oil or palm kernel oil. The body breaks down caprylic acid into substances called “ketone bodies.” The theory behind Axona is that the ketone bodies derived from caprylic acid may provide an alternative energy source for brain cells that have lost their ability to use glucose (sugar) as a result of Alzheimer’s. Glucose is the brain’s chief energy source. Imaging studies show reduced glucose use in brain regions affected by Alzheimer’s.

Axona’s development was preceded by development of the chemically similar Ketasyn (AC-1202). Ketasyn was tested in a Phase II clinical study enrolling 152 volunteers with mild to moderate Alzheimer’s. Most participants were also taking FDA-approved Alzheimer’s drugs. The manufacturer of Axona reports that study participants who took Ketasyn performed better on tests of memory and overall function than those who received a placebo (a look-alike, inactive treatment).

The chief goal of Phase II clinical studies is to provide information about the safety and best dose of an experimental treatment. Phase II trials are generally too small to confirm that a treatment works. To demonstrate effectiveness under the prescription drug approval framework, the FDA requires drug developers to follow Phase II studies with larger Phase III trials enrolling several hundred to thousands of volunteers.

The manufacturer of Ketasyn decided not to conduct Phase III studies to confirm its effectiveness. The company chose instead to use Ketasyn as the basis of Axona and promote Axona as a “medical food.” Medical foods do not require Phase III studies or any other clinical testing. The Alzheimer’s Association Medical and Scientific Advisory Council has expressed concern that there is not enough evidence to assess the potential benefit of medical foods for Alzheimer’s disease. For more information, please see the Medical and Scientific Advisory Council statement about medical foods.

Some people with Alzheimer’s and their caregivers have turned to coconut oil as a less expensive, over-the-counter source of caprylic acid. A few people have reported that coconut oil helped the person with Alzheimer’s, but there’s never been any clinical testing of coconut oil for Alzheimer’s, and there’s no scientific evidence that it helps.

Coenzyme Q10

Coenzyme Q10, or ubiquinone, is an antioxidant that occurs naturally in the body and is needed for normal cell reactions. This compound has not been studied for its effectiveness in treating Alzheimer’s.

A synthetic version of this compound, called idebenone, was tested for Alzheimer’s disease but did not show any benefit. Little is known about what dosage of coenzyme Q10 is considered safe, and there could be harmful effects if too much is taken.

Coral Calcium

“Coral” calcium supplements have been heavily marketed as a cure for Alzheimer’s disease, cancer and other serious illnesses. Coral calcium is a form of calcium carbonate claimed to be derived from the shells of formerly living organisms that once made up coral reefs.

Coral calcium differs from ordinary calcium supplements only in that it contains traces of some additional minerals incorporated into the shells by the metabolic processes of the animals that formed them. It offers no extraordinary health benefits. Most experts recommend that individuals who need to take a calcium supplement for bone health take a purified preparation marketed by a reputable manufacturer.

The Federal Trade Commission (FTC) and the Food and Drug Administration (FDA) have filed formal complaints against the promoters and distributors of coral calcium. The agencies state that they are aware of no competent and reliable scientific evidence supporting the exaggerated health claims and that such unsupported claims are unlawful.

Ginkgo Biloba

Ginkgo biloba is a plant extract containing several compounds that may have positive effects on cells within the brain and the body. Ginkgo biloba is thought to have both antioxidant and anti-inflammatory properties, to protect cell membranes and to regulate neurotransmitter function. Ginkgo has been used for centuries in traditional Chinese medicine and currently is being used in Europe to alleviate cognitive symptoms associated with a number of neurological conditions.

However, results of a large, multicenter Phase 3 clinical trial conducted by several branches of the National Institutes of Health showed that ginkgo was no better than a placebo in preventing or delaying Alzheimer’s disease.

The Ginkgo Evaluation and Memory (GEM) Study enrolled 3,000 individuals age 75 or older who had no signs of dementia or had mild cognitive impairment (MCI). Participants were randomly assigned to receive twice daily doses of either a placebo or 120 milligrams of ginkgo biloba extract. They were followed up every six months for six years.

Researchers found no statistical difference in rates of dementia or Alzheimer’s disease between the ginkgo and placebo groups. For more information about the GEM study results, click here

Huperzine A

Huperzine A (pronounced HOOP-ur-zeen) is a moss extract that has been used in traditional Chinese medicine for centuries. It has properties similar to those of cholinesterase inhibitors, one class of FDA-approved Alzheimer’s medications. As a result, it is promoted as a treatment for Alzheimer’s disease.

The Alzheimer’s Disease Cooperative Study (ADCS) conducted the first large-scale U.S. clinical trial of huperzine A as a treatment for mild to moderate Alzheimer’s disease. Participants taking huperzine A experienced no greater benefit than those taking a placebo.

Because currently available formulations of huperzine A are dietary supplements, they are unregulated and manufactured with no uniform standards. Taking these unregulated preparations could increase the risks of serious side effects, especially if used in combination with FDA-approved Alzheimer’s drugs.

Omega-3 Fatty Acids

Omega-3s are a type of polyunsaturated fatty acid (PUFA). Research has linked certain types of omega-3s to a reduced risk of heart disease and stroke.

The U.S. Food and Drug Administration (FDA) permits supplements and foods to display labels with “a qualified health claim” for two omega-3s called docosahexaneoic acid (DHA) and eicosapentaenoic acid (EPA). The labels may state, “Supportive but not conclusive research shows that consumption of EPA and DHA omega-3 fatty acids may reduce the risk of coronary heart disease,” and then list the amount of DHA or EPA in the product. The FDA recommends taking no more than a combined total of 3 grams of DHA or EPA a day, with no more than 2 grams from supplements.

Research has also linked high intake of omega-3s to a possible reduction in risk of dementia or cognitive decline. The chief omega-3 in the brain is DHA, which is found in the fatty membranes that surround nerve cells, especially at the microscopic junctions where cells connect to one another.

Theories about why omega-3s might influence dementia risk include their benefit for the heart and blood vessels; anti-inflammatory effects; and support and protection of nerve cell membranes.

Two studies reported at the 2009 Alzheimer’s Association International Conference on Alzheimer’s Disease (AAICAD) found mixed results for the possible benefits of DHA:

  • The first study was a large federally funded clinical trial conducted by the Alzheimer’s Disease Cooperative Study (ADCS). In the ADCS study, participants with mild to moderate Alzheimer’s disease taking 2 grams of DHA daily fared no better overall than those who took a placebo (inactive, lookalike treatment). The data indicated a “signal” (preliminary but not conclusive evidence) that participants without the APOE-e4 Alzheimer’s risk gene might have experienced a slight benefit. More research is needed to confirm whether that preliminary signal is valid. Results of this study also appeared in the Nov. 3, 2010, issue of the Journal of the American Medical Association.
  • The second study—Memory Improvement with DHA (MIDAS)—enrolled older adults with normal age-related cognitive decline. Those who took 900 milligrams of DHA daily scored slightly better on a computerized memory test than those receiving the placebo. MIDAS was conducted by Martek Biosciences, the manufacturer of the DHA used in both studies.

Experts agree that more research is needed, and there is not yet sufficient evidence to recommend DHA or any other omega-3 fatty acids to treat or prevent Alzheimer’s disease


Phosphatidylserine (pronounced FOS-fuh-TIE-dil-sair-een) is a kind of lipid, or fat, that is the primary component of the membranes that surround nerve cells. In Alzheimer’s disease and similar disorders, nerve cells degenerate for reasons that are not yet understood. The theory behind treatment with phosphatidylserine is its use may shore up the cell membrane and possibly protect cells from degenerating.

The first clinical trials with phosphatidylserine were conducted with a form derived from the brain cells of cows. Some of these trials had promising results. However, most trials were with small samples of participants.

This line of investigation came to an end in the 1990s over concerns about mad cow disease (bovine spongiform encephalopathy), a fatal brain disorder believed to be caused by consuming foods or other products from affected cattle. Supplements containing phosphatidylserine are now derived from soy extracts. The FDA permits supplements containing very high-quality soy-derived phosphatidylserine to display a “qualified health claim” stating that “Very limited and preliminary scientific research suggests that phosphatidylserine may reduce the risk of dementia in the elderly. FDA concludes that there is little scientific evidence supporting this claim.” For more information about FDA qualified health claims, please click here. Experts agree that more research is needed, and do not currently recommend use of phosphatidylserine.

Tramiprosate (clinically tested as Alzhemed, marketed as a “medical food” called ViviMind™)

Tramiprosate is a modified form of taurine, an amino acid found naturally in seaweed. Amino acids are the chemical building blocks of proteins. Tramiprosate was tested in a large Phase 3 clinical study as a possible Alzheimer’s treatment. Analysis of the Phase 3 trial data was initially inconclusive for a variety of reasons. Investigators tried to work with the FDA to obtain clearer results, but the manufacturer decided to abandon development of tramisprosate as a prescription drug and market it over the Internet a “medical food.” Tramiprosate currently has no proven benefits, and “medical foods” are not subject to the same level of FDA regulation as prescription drugs. For more information, please see the statement of the Alzheimer’s Association Medical and Scientific Advisory Council on medical foods.



Copyright © 2017  Alzheimer’s Association®. All rights reserved.


Putting Exercise to The Test in People at Risk for Alzheimer’s

(National Institute on Aging) Can exercise slow or prevent cognitive decline in older people who are at increased risk for Alzheimer’s disease? A new clinical trial led by NIA-supported scientists in collaboration with the YMCA aims to find out whether exercise may be an effective nondrug treatment for staying cognitively fit.

The trial, called EXERT, will enroll 300 people, age 65 to 89, with mild cognitive impairment (MCI), a condition of mild memory problems that often leads to Alzheimer’s dementia. Based on the trial’s results, the researchers hope to develop an evidence-based “prescription” that will tell people the type and frequency of exercise needed to support memory and thinking skills.

“We want to design a real-life program that can be implemented in the community and prescribed by healthcare providers,” said Laura D. Baker, Ph.D., of Wake Forest Baptist Medical Center in Winston-Salem, N.C., who is leading the study with Carl W. Cotman, Ph.D., of the University of California, Irvine.

Laurie Ryan, Ph.D., chief of the Dementias of Aging branch in NIA’s Division of Neuroscience, added,

“The EXERT trial builds on previous evidence that associates aerobic physical activity with preservation of cognitive function. It will expand what we know about the benefits of aerobic exercise on memory, executive function, and other thinking abilities, as well as on the brain itself.”

The trial, to take place at 13 U.S. sites, is coordinated by the NIA-supported Alzheimer’s Disease Cooperative Study, a consortium of universities and research centers in the United States and Canada.

Wanted: Older Non-exercisers

The jury is still out on whether exercise can delay or prevent dementia. Some studies suggest that exercise has such a benefit, but others do not. Clinical trials have been small, and their results can be hard to compare because of differences in the types of people and exercise studied and, in some cases, the trials’ relatively short duration.

Researchers hope that EXERT—a longer trial with more people than previous trials—will definitively show whether exercise guards against cognitive decline in people with MCI.

Researchers are targeting people with MCI who are generally sedentary. That’s because people who are physically fit may already be at peak brain function and might not show much improvement, Dr. Baker said.

To qualify for the trial, participants may have engaged in casual, low-intensity physical activity but not rigorous exercise.

“Light gardening, walking the dog, and the like, that’s OK,” she explained.

All trial participants will receive a free membership at a participating YMCA, where they will work closely with a personal trainer for 1 year, then exercise on their own for an additional 6 months. The trainers will ensure participants’ physical safety and encourage them to stick with the EXERT exercise program.

Participants will be randomly assigned to one of two groups. The “high-intensity” group will walk on a treadmill and take exercise classes that raise their heart rate to 75 percent of capacity. The “low-intensity” group will do stretching, balance, and range-of-motion exercises. All participants will work out in four 45-minute sessions per week.

In addition, they will undergo tests and procedures at the beginning of the trial and then every 6 months, including:

  • Memory and other tests to measure changes in thinking and memory
  • Magnetic resonance imaging (a type of brain scan) to measure changes in brain blood flow and brain size and structure
  • Collection of blood and cerebrospinal fluid to measure Alzheimer’s-related changes

Walking fitness tests and sleep studies are also part of the trial. Researchers will examine whether exercise’s effects on walking and sleep might explain its effects on memory and thinking abilities.

A Window of Opportunity

Previous research has shown that Alzheimer’s disease begins in the brain years before symptoms appear. Its slow progression offers a chance to stall or even prevent full-blown dementia in people who are most likely to develop debilitating symptoms such as trouble with memory, planning, and organization. Many Alzheimer’s clinical trials are testing new drugs, while others are testing nondrug interventions like exercise and diet.

This 18-month trial won’t last long enough to determine if exercise can prevent dementia, Dr. Baker said. But it seeks to determine if exercise can slow disease progression and cognitive decline by altering biological signs of Alzheimer’s in the brain.

Investigators hypothesize that to make a difference in brain structure and function—and, in turn, memory and other cognitive functions—exercise must be physically challenging and sustained. What specific “dose” is effective remains to be seen. (Current federal guidelines recommend that adults engage in at least 150 minutes per week of moderate physical activity, 75 minutes of vigorous activity, or a combination of the two.)

Early Evidence That Exercise Helps the Brain

Years of animal and human observational studies—in which researchers observed behavior but did not influence or change it—suggest the possible benefits of exercise for the brain.

“Overall, exercise restores the aged brain to a more youthful state, as shown most directly in animal models,” Dr. Cotman said.

He added, “In animals, remarkable changes happen in the brain after exercise. Brain cells are less vulnerable to injury and toxicity. There’s also growth in connections between cells and an increase in growth factors in the brain.”

Studies in mice have also shown that exercise leads to an increase in new neurons, larger and healthier existing neurons, and new blood vessels—which together result in an increase in the size of the hippocampus, a brain region important for memory and learning.

Observational studies in cognitively normal humans have shown that those who exercise have a lower risk of cognitive decline than those who do not. Effects of exercise on the brain range from increased hippocampal volume (or a reduced shrinkage rate) to improved energy use. Exercise has also been associated with fewer Alzheimer’s plaques and tangles in the brain and better performance on certain cognitive tests.

In EXERT, Dr. Baker said, “we’ll be looking at specific regions of the brain that support memory and thinking and also regions first affected by Alzheimer’s disease.”

Laying the Groundwork

Dr. Baker and her research team laid promising groundwork for EXERT with PACE-2, or Piedmont Aging, Cognition, and Exercise, Study 2. In PACE-2, 65 volunteers with MCI and prediabetes, age 50 to 89, were randomly assigned to do either high-intensity aerobic exercise or stretching and balance exercise at local YMCAs. The first group exercised hard enough to get to 70 to 80 percent of their maximum heart rate. The second group kept their heart rate at 35 percent of maximum or lower. All participants worked out 45 minutes per day, 4 days per week, for 6 months.

Researchers found that the aerobic group had better executive function—the ability to plan and organize—than the stretching/balance group, but not better short-term memory. Blood flow increased in brain regions affected by aging and Alzheimer’s disease. Levels of the protein tau in cerebrospinal fluid, which normally rise with age and are associated with cognitive decline, fell in participants age 70 and older.

Why did executive function improve but not memory? According to Dr. Baker, it’s possible that people need to exercise for longer than 6 months to see memory benefits, or that the cognitive tests were not sensitive enough to detect changes.

“In EXERT, the tests are harder and more sensitive to changes in episodic memory,” she noted.

Dr. Baker added, “We are excited to get this trial up and running, so to speak, to contribute to the effort to find effective therapies, including nondrug treatments, that may help delay or even prevent cognitive decline and dementia.”

For more information about EXERT, contact the Alzheimer’s Disease Cooperative Study at brainlink@ucsd.edu.

To learn more about exercise for older adults, visit Go4Life from NIA. Find exercises, tips for getting started, Spanish-language resources, and more.




Alzheimer’s Drug Donezpezil Prescribed Off-Label Could Pose Risk for Some

(University of California – Los Angeles Health Sciences) Donepezil, a medication that is approved to treat people with Alzheimer’s disease, should not be prescribed for people with mild cognitive impairment without a genetic test. UCLA School of Nursing researchers discovered that for people who carry a specific genetic variation — the K-variant of butyrylcholinesterase, or BChE-K — donezpezil could accelerate cognitive decline.

Mild cognitive impairment is a transitional state between normal age-related changes in cognition and dementia. Because many people with the condition display symptoms similar to those caused by Alzheimer’s disease, some physicians prescribe donepezil, which is marketed under the brand name

Aricept and is the most-prescribed medication for Alzheimer’s.

Donepezil was tested as a possible treatment for mild cognitive impairment in a large, federally funded study published in 2005, but it was not approved by the FDA. Still, doctors have often prescribed the drug “off-label” — meaning that it is not approved for that specific disorder — for their patients with mild cognitive impairment.

From data collected during the 2005 trial, the researchers looked at the association between BChE-K and changes in cognitive function. Using two tests that measure cognitive impairment, the Mini-Mental State Examination and the Clinical Dementia Rating Sum of Boxes, they found that people with the genetic variation who were treated with donepezil had greater changes in their scores than those who took placebos. They also found that those who took donepezil had a faster cognitive decline than those who took the placebo.

Physicians are increasingly using personalized medicine, including pharmacogenetics — the study of how genetics affect a person’s response to a drug — to tailor their patients’ care. The findings reinforce the importance of physicians discussing the possible benefits and risks of this treatment with their patients.

The study was published in the Journal of Alzheimer’s Disease.



Journal Reference:

Louis De Beaumont, Sandra Pelleieux, Louise Lamarre-Théroux, Doris Dea, Judes Poirier. Butyrylcholinesterase K and Apolipoprotein E-ɛ4 Reduce the Age of Onset of Alzheimer’s Disease, Accelerate Cognitive Decline, and Modulate Donepezil Response in Mild Cognitively Impaired Subjects. Journal of Alzheimer’s Disease, 2016; 54 (3): 913 DOI: 10.3233/JAD-160373

Copyright 2017 UCLA


Be­ne­fits of Cog­nit­ive Train­ing in De­men­tia Pa­tients Un­clear

(University of Helsinki) Positive effects of cognitive training in healthy elderly people have been reported, but data regarding its effects in patients with dementia is unclear.

“The effects of cognitive training in dementia patients have been studied actively during recent decades but the quality and reliability of the studies varies,” says licenced neuropsychologist Eeva-Liisa Kallio. She reviewed 31 randomized controlled trials on cognitive training in dementia patients.

Kallio’s reserch paper “Cognitive Training Interventions for Patients with Alzheimer’s Disease: A Systematic Review” was published in Journal of Alzheimer’s Disease.

Some of the studies in the review focused primarily on cognitive training and in others cognitive training was part of broader cognitive or multi-component intervention.

“Many of the studies reported effects on cognitive functions immediately after the intervention but only few studies included follow-up of the patients or showed improvement in cognitive functions that were not directly linked to the skills trained in the intervention,” Kallio says.

In the studies, cognitive functioning was measured before and after the intervention. Also questionnaires on psychological wellbeing, quality of life and activities of daily living were used.

According to Kallio’s review, the data from the previous studies is not adequate to give any recommendations on the use of cognitive training in the treatment of dementia patients. Even though the scientific evidence remains scarce, the studies do suggest that the training should be intensive or focus primarily on a particular aspect of cognitive functions.

“Healthy adults can get limited benefits from cognitive training but we need more high quality trials to confirm cognitive training as an effective treatment option in dementia,” Kallio says.

She belongs to the University of Helsinki’s FINCOG research group, led by professor Kaisu Pitkälä. The next step in the project is to study the effects of intensive, 3-month cognitive training on the community-dwelling older persons with dementia participating in adult day care activities organised by the City of Helsinki.

In this randomized controlled trial, part of the participants attend systematic cognitive training while their control group participates in the normal day care activities.

In addition to cognitive functions, also indicators of quality of life and activities of daily living are used and the measurements are repeated six months after the intervention. The research also includes a 24-month health register follow-up.

“Cognitive training is quite easy to implement. If our research suggests that the participants benefit from it, cognitive training can be easily included in the adult day care activities,” Kallio says.


Journal Reference:

Eeva-Liisa Kallio, Hanna Öhman, Hannu Kautiainen, Marja Hietanen, Kaisu Pitkälä. Cognitive Training Interventions for Patients with Alzheimer’s Disease: A Systematic Review. Journal of Alzheimer’s Disease, 2017; 56 (4): 1349 DOI: 10.3233/JAD-160810

Copyright University of Helsinki 2017