The rate of formation of amyloid-beta in Alzheimer's disease brains is not the problem. Too slow removal of the peptide plaques in brains might be the real problem.
Neurologists finally have an answer to one of the most important questions about Alzheimer's disease: Do rising brain levels of a plaque-forming substance mean patients are making more of it or that they can no longer clear it from their brains as effectively?
"Clearance is impaired in Alzheimer's disease," says Randall Bateman, MD, assistant professor of neurology at Washington University School of Medicine in St. Louis. "We compared a group of 12 patients with early Alzheimer's disease to 12 age-matched and cognitively normal subjects. Both groups produced amyloid-beta (a-beta) at the same average rate, but there's an average drop of about 30 percent in the clearance rates of the group with Alzheimer's."
The measured slower rate of clearance would cause accumulation up to a level that causes disease state in about 10 years.
Scientists calculate this week in Science Express that it would take 10 years for this decrease in clearance to cause a build-up of a-beta equal to those seen in the brains of Alzheimer's patients.
This explanation might be compatible with some of the other hypotheses for Alzheimer's. For example, poorer brain blood circulation due to atherosclerosis or other blood vessel diseases could starve brain metabolism of the oxygen and sugar it needs to power the trash removal mechanisms. Also, a problem with insulin receptors similarly might starve the neurons for nutrients. Alzheimer's might be a special kind of brain diabetes disease.
Update: What is the root cause of the slow trash removal? This report does not tell us. It is an important question because the nature of the root cause may determine how hard it is to cure Alzheimer's Disease. If the root cause is a nutrient supply problem that is easier to fix than if accumulations of genetic mutations with age are the root cause. If accumulation of genetic mutations degrades the energy production machinery or plaque removal machinery in the cell then curing Alzheimer's will be a lot harder.
SAN FRANCISCO, CA—November 21, 2010— Scientists at the Gladstone Institute of Neurological Disease (GIND) in San Francisco have discovered a new strategy to prevent memory deficits in a mouse model of Alzheimer's disease (AD). Humans with AD and mice genetically engineered to simulate the disease have abnormally low levels of an enzyme called EphB2 in memory centers of the brain. Improving EphB2 levels in such mice by gene therapy completely fixed their memory problems. The findings will be published in the November 28 issue of the journal Nature.
Just for the sake of argument imagine that a gene therapy delivered to every brain cell could raise levels of EphB2 and thereby prevent Alzheimer's Disease. Okay, will this even be practical to do anything in the next few decades?
Sound easy? Hold on. The human brain has about 100 billion neurons (to be fair some estimates are down in the range of 10's of billions of neurons). Well, okay, how to deliver exactly 1 copy of a gene to 100 billion cells all sitting behind barriers designed to protect them? Even if we could get thru the barriers how to prevent some cells from getting dozens or hundreds of copies of a gene before other cells get any? That's not just a rhetorical question (though rhetorical questions are great and I encourage their use). I'd like to know how to approach the problem.
One can break this up: How to package the genes so they can get into cells? How to structure the inner portion of the package so the delivered genes will either integrate into the host genome without causing damage or otherwise situate themselves to function well for an extended period of time? How to get the genes into neurons that are, for whatever reason, harder to reach? Finally, how to prevent overdosing? Is overdosing the hardest and most serious problem? Maybe a delivered package could include code for machinery that would break down a newly arriving second package. But that would take a lot of work to make such a specific extra bit of functionality and might make the delivered package too big.
As I always bring up when I read debates about when we will be able to rejuvenate our bodies and greatly extend human lifespans, brain rejuvenation is the hardest part. We can't replace our nerves without replacing who we are. We need to fix them in place. Gene therapy, nano repair bots, and helper cell therapies (e.g. new glial cells) will all be needed for this purpose. I do not think that gene therapy and helper cell therapy by themselves will be sufficient in the long run. But if we are lucky then we can extend our brains for, say, an extra 50 years to give time for the nanobots to be developed. If we are not so lucky then we'll become a society of young bodies and senile minds.
Turning on a blood-brain barrier protein known as P-glycoprotein lowers the level of beta amyloid of Alzheimer's mice to levels seen in normal mouse brains. Could avoidance of Alzheimer's be avoided just by turning on a gene to make a protein that transports beta amyloid protein out of the brain?
"What we've shown in our mouse models is that we can reduce the accumulation of beta-amyloid protein in the brain by targeting a certain receptor in the brain known as the pregnane X receptor, or PXR," said Miller.
The researchers from NIEHS and the University of Minnesota Duluth demonstrated that when 12-week-old genetically modified mice expressing human beta-amyloid protein are treated with a steroid-like chemical that activates PXR, the amount of beta-amyloid protein in the brain is reduced. The activation of the PXR was found to increase the expression of a blood-brain barrier protein known as P-glycoprotein. This protein transports beta-amyloid out of the brain.
"Our results show several new findings. We now know that P-glycoprotein plays a pivotal role in clearing beta-amyloid from the brain. Secondly, we know P-glycoprotein levels are reduced in the blood-brain barrier, and that the Alzheimer's mice treated with the chemical to activate PXR were able to reduce their beta-amyloid levels to that of mice without Alzheimer's," said Bjorn Bauer, Ph.D., assistant professor at the University of Minnesota and senior author on the paper.
Alzheimer's disease sits at the top of my list of diseases I do not want to get. It amounts to slow motion brain death. All of your accumulated knowledge, wisdom, experience, learning, and relationships just gradually disappear. It amounts to the destruction of self.
Measurement of P-glycoprotein levels in the blood-brain barrier might provide a much earlier indicator that Alzheimer's is starting to develop. More time to launch a pharmacological counter-attack before you lose too many brain cells and memories.
Anika Hartz, Ph.D., lead author on the study, added that it is also likely that reduced P-glycoprotein expression at the blood-brain barrier may be an early indicator of Alzheimer's disease, even before the cognitive symptoms appear.
Aging is not dignified. Aging is not sacred or exalted. Aging is not pretty or nice. Aging is destruction. Aging of the brain is destruction of the brain.
After years of reports aimed at looking for a causal relationship between cell phone use and brain cancer a new report finds that in mice genetically engineered to get Alzheimer's exposure to electromagnetic waves is protective.
Tampa, FL (Jan. 6, 2010) – The millions of people who spend hours every day on a cell phone may have a new excuse for yakking. A surprising new study in mice provides the first evidence that long-term exposure to electromagnetic waves associated with cell phone use may actually protect against, and even reverse, Alzheimer's disease. The study, led by University of South Florida researchers at the Florida Alzheimer's Disease Research Center (ADRC), was published today in the Journal of Alzheimer's Disease.
"It surprised us to find that cell phone exposure, begun in early adulthood, protects the memory of mice otherwise destined to develop Alzheimer's symptoms," said lead author Gary Arendash, PhD, USF Research Professor at the Florida ADRC. "It was even more astonishing that the electromagnetic waves generated by cell phones actually reversed memory impairment in old Alzheimer's mice."
The researchers showed that exposing old Alzheimer's mice to electromagnetic waves generated by cell phones erased brain deposits of the harmful protein beta-amyloid, in addition to preventing the protein's build-up in younger Alzheimer's mice. The sticky brain plaques formed by the abnormal accumulation of beta amyloid are a hallmark of Alzheimer's disease. Most treatments against Alzheimer's try to target beta-amyloid.
I'm picturing a future where people are assigned to periodically swap in freshly charged batteries in cell phones strapped on to granny's head.
You know that (probably wrong saying) "starve a cold, feed a fever"? People who get Alzheimer's Disease are less likely to get cancer and vice versa.
People who have Alzheimer’s disease may be less likely to develop cancer, and people who have cancer may be less likely to develop Alzheimer’s disease, according to a new study published in the December 23, 2009, online issue of Neurology®, the medical journal of the American Academy of Neurology.
Anyone care to explain this?
During the study, 478 people developed dementia and 376 people developed invasive cancer. For people who had Alzheimer’s disease at the start of the study, the risk of future cancer hospitalization was reduced by 69 percent compared to those who did not have Alzheimer’s disease when the study started. For Caucasian people who had cancer when the study started, their risk of developing Alzheimer’s disease was reduced by 43 percent compared to people who did not have cancer at the start of the study, although that finding was not evident in minority groups.
I would expect a stronger immune system to protect against both diseases. But might inflammation contribute to the development of Alzheimer's while at the same time stimulating the immune system to attack cancer cells?
A protein implicated in as a cause of Alzheimer's Disease increases in mice while they are away and declines while they are asleep. The implication here is that people who do not get enough sleep may be at increased risk of Alzheimer's.
While the occasional all-nighter to cram for exams or finish a grant proposal may seem like no big deal, losing sleep night after night could take its toll on brain health in later life, two new studies suggest. Based on microdialysis experiments in live mice, Dave Holtzman, Washington University, St. Louis, Missouri, and colleagues report in the current issue of Science that extracellular amyloid-beta levels in the brain fall during slumber and rise with wakefulness. They discovered that these Abeta dynamics rely on the hormone orexin, and that forcing animals to sleep or stay awake decreases or increases Abeta plaque formation accordingly in a mouse model for Alzheimer disease.
Lack of sleep increases inflammation and inflammation is also implicated in Alzheimer's. Lack of sleep also puts on the weight and increases obesity. This accelerates aging. So get lots of sleep. It is good for your brain.
The study found that people who had respiratory, gastrointestinal or other infections or even bumps and bruises from a fall were more likely to have high blood levels of tumor necrosis factor-α, a protein involved in the inflammatory process, and were also more likely to experience memory loss or other types of cognitive decline than people who did not have infections and who had low levels of the protein.
The blood levels and cognitive abilities of 222 people with Alzheimer's disease with an average age of 83 were measured at the beginning of the study and three more times over six months. Caregivers were interviewed to determine whether the participants had experienced any infections or accidental injury that could lead to inflammation.
A total of 110 people experienced an infection or injury that led to inflammation during the study. Those people experienced memory loss that was at twice the rate of those who did not have infections or injuries.
People who had high levels of the protein in their blood at the beginning of the study, which may indicate chronic inflammation, had memory loss at four times the rate of those with low levels of the protein at the start of the study. Those who had high levels of the protein at the start of the study who also experienced acute infections during the study had memory loss at 10 times the rate of those who started with low levels and had no infections over the six-month period.
"Two recent advances in neuroimaging now allow us to explore the early, asymptomatic phase of AD, the ability to measure amyloid distribution in living humans and the identification of sensitive markers of brain dysfunction in AD," explains lead study author, Dr. Reisa Sperling from the Center for Alzheimer's Research and Treatment at Brigham and Women's Hospital in Boston. In addition to amyloid accumulation, AD has been associated with functional alterations in a specific network of brain regions that are intimately linked with memory formation.
These scientists may be watching early stage AD.
Dr. Sperling and colleagues combined amyloid imaging with an associative memory functional brain imaging paradigm to study older humans who did not exhibit significant memory impairment. Importantly, the researchers found that a significant number of nondemented older individuals exhibited amyloid deposition and abnormal neural activity in key areas of the brain network thought to be involved in successful memory function. These results demonstrate for the first time that amyloid pathology in asymptomatic older humans is linked with aberrant neural responses during the process of memory formation.
"Longitudinal studies are certainly needed, but our findings are consistent with the premise that cognitively intact older individuals with amyloid pathology may already be in the early stages of AD," explains Dr. Sperling. "The combination of molecular and functional imaging techniques may prove useful in monitoring disease progression prior to significant clinical symptoms, as well as the response to amyloid-modifying therapeutic agents in subjects at-risk for developing AD."
What I'd like to see in a follow-up study: do the brain scans on elderly people and measure the plaque build-up. Then try various dietary and drug interventions followed by another round of brain scans to see if any of these interventions reverse the plaque build-up when it is found in early stages. In theory brain scan technology that detects early stage AD ought to allow faster checking of the efficacy of interventions and therefore the ability to try out a lot more interventions to find ones that work.
Not all blood pressure drugs are equal in protection provided against brain function decline with age. The angiotensin-converting enzyme (ACE) inhibitors are better for the brain than other blood pressure reducing drugs. But not all ACE inhibitors are equal either. The centrally acting ACE inhibitors provide the benefit.
WINSTON-SALEM, N.C. – A particular class of medication used to treat high blood pressure could protect older adults against memory decline and other impairments in cognitive function, according to a newly published study from Wake Forest University School of Medicine.
Research suggests that some of the drugs classified as angiotensin-converting enzyme (ACE) inhibitors, specifically those types of ACE inhibitors that affect the brain by crossing the blood-brain barrier, may reduce inflammation that could contribute to the development of Alzheimer's disease, a major cause of dementia.
The study appears in the current issue of Archives of Internal Medicine.
"High blood pressure is an important risk factor for Alzheimer's disease and vascular dementia," said Kaycee Sink, M.D., M.A.S., lead author of the study, geriatrician and an assistant professor of internal medicine – gerontology. "Our study found that all blood pressure medications may not be equal when it comes to reducing the risk of dementia in patients with hypertension."
Inflammation as an agent of accelerated aging is a recurring theme in a lot of research on aging mechanisms. Dietary and drug factors that reduce inflammation tend to slow aging and lower disease risks.
ACE inhibitors that can cross the blood-brain barrier get into the brain and dampen inflammation.
The study found an association between taking centrally-active ACE inhibitors and lower rates of mental decline as measured by the Modified Mini-Mental State Exam, a test that evaluates memory, language, abstract reasoning and other cognitive functions. The research showed that participants who were exposed to ACE inhibitors that cross the blood-brain barrier saw an average 65 percent less cognitive decline per year of exposure compared to participants taking other blood pressure medications.
What I would like to know: For people who do not have high blood pressure (knock on wood) which drugs or dietary elements will best lower brain inflammation? Anyone have insights on this?
Non-centrally active ACE inhibitors definitely do not help.
Researchers also found that non-centrally active ACE inhibitors were associated with an increased risk of dementia and the people taking them were more likely to develop difficulty performing daily activities. Specifically, participants who, for three years, took ACE inhibitors that do not cross the blood-brain barrier were at a 73 percent greater risk of developing dementia than were the individuals taking other anti-hypertensive drugs.
Okay, those of you with high blood pressure are wondering: which ACE inhibitors are centrally acting? Here's your list:
Centrally-acting ACE inhibitors include captropril (Capoten®), fosinopril (Monopril®), lisinopril (Prinivil® or Zestri®), perindopril (Aceon®), ramipril (Altace®) and trandolapril (Mavik®).
Anyone going to get their high blood pressure drug changed as a result of this news?
A novel test that detects enzymes that are dysfunctional in patients with Alzheimer's disease--and that are found both in the brain and in skin cells--is about to undergo large clinical trials. Researchers at the Blanchette Rockefeller Neurosciences Institute (BRNI), in Morgantown, WV, who developed the diagnostic have also garnered approval from the Food and Drug Administration to test in humans an experimental drug that activates the enzymes--a mechanism that represents a new therapeutic approach to Alzheimer's.
One likely consequence of such a test: It will increase the number of people who support the developmetn of therapies to stop the disease. If millions of people can be told a few years earlier than they are about to develop Alzheimer's symptoms then they'll form a bigger political interest group demanding a cure before they lose their memories.
If all goes well, the first commercial version of the test could be available in 12 to 18 months, possibly enabling patients to try to slow progression of the increasingly common disease, said Dr. Daniel Alkon, scientific director of the Blanchette Rockefeller Neurosciences Institute.
"The patients who had the typical changes in biomarker profile of the cerebrospinal fluid had a risk of deterioration that was 27 times higher than the control group. We could also see that all patients with mild cognitive impairment who deteriorated and developed Alzheimer's disease had these changes in the biomarker profile of their cerebrospinal fluid", says Kaj Blennow.
The scientists were also able to show a relationship between the profile of biomarkers and other typical signs of the disease, such as the presence of the gene APOE e4 and atrophy of the hippocampus, which is the part of the brain cortex that controls memory.
Here is more evidence for the theory that Alzheimer's is due to a special form of insulin-insensitive diabetes of the brain. Insulin blocks toxic proteins from damaging nerve cells.
EVANSTON, Ill. --- A Northwestern University-led research team reports that insulin, by shielding memory-forming synapses from harm, may slow or prevent the damage and memory loss caused by toxic proteins in Alzheimer's disease.
The findings, which provide additional new evidence that Alzheimer's could be due to a novel third form of diabetes, will be published online the week of Feb. 2 by the Proceedings of the National Academy of Sciences (PNAS).
In a study of neurons taken from the hippocampus, one of the brain's crucial memory centers, the scientists treated cells with insulin and the insulin-sensitizing drug rosiglitazone, which has been used to treat type 2 diabetes. (Isolated hippocampal cells are used by scientists to study memory chemistry; the cells are susceptible to damage caused by ADDLs, toxic proteins that build up in persons with Alzheimer's disease.)
The researchers discovered that damage to neurons exposed to ADDLs was blocked by insulin, which kept ADDLs from attaching to the cells. They also found that protection by low levels of insulin was enhanced by rosiglitazone.
Diabetics have a significantly greater risk of dementia, both Alzheimer's disease — the most common form of dementia — and other dementia, reveals important new data from an ongoing study of twins. The risk of dementia is especially strong if the onset of diabetes occurs in middle age, according to the study.
"Our results . . . highlighted the need to maintain a healthy lifestyle during adulthood in order to reduce the risk of dementia late in life," explained Dr. Margaret Gatz, who directs the Study of Dementia in Swedish Twins.
In a study published in the January 2009 issue of Diabetes, Gatz and researchers from Sweden show that getting diabetes before the age of 65 corresponds to a 125 percent increased risk for Alzheimer's disease. Nearly 21 million people in the United States have diabetes, according to the American Diabetes Association, which publishes the journal.
Eating less to remember more might become a new prescription for some elderly people, German researchers say.
They found that memory and thinking skills improved among healthy, overweight subjects who cut their calorie intake by 30 percent over a three-month period.
If further research supports this conclusion, "from a public health point of view, you could actually do something for the prevention of cognitive decline from aging," said lead researcher Dr. Agnes Floel, assistant professor of neurology at the University of Munster.
CHICAGO --- A slow, chronic starvation of the brain as we age appears to be one of the major triggers of a biochemical process that causes some forms of Alzheimer's disease.
A new study from Northwestern University's Feinberg School of Medicine has found when the brain doesn't get enough sugar glucose -- as might occur when cardiovascular disease restricts blood flow in arteries to the brain -- a process is launched that ultimately produces the sticky clumps of protein that appear to be a cause of Alzheimer's.
Robert Vassar, lead author, discovered a key brain protein is altered when the brain has a deficient supply of energy. The altered protein, called elF2alpha, increases the production of an enzyme that, in turn, flips a switch to produce the sticky protein clumps. Vassar worked with human and mice brains in his research.
The study is published in the December 26 issue of the journal Neuron.
"This finding is significant because it suggests that improving blood flow to the brain might be an effective therapeutic approach to prevent or treat Alzheimer's," said Vassar, a professor of cell and molecular biology at the Feinberg School.
This is good news and bad news. The good news is that a rejuvenating therapy for the vascular system will probably prevent Alzheimer's Disease. The bad news is that we might need a rejuvenating therapy for the vascular system to prevent Alzheimer's Disease.
Of course there are many things we can do dietarily and otherwise to slow the rate of decay of our veins and arteries. But all those good things to do just slow the decay. Very worth doing. But we still need the rejuvenating stem cells and gene therapy to fix up our piping.
Also, short of a rejuvenated circulatory system we can expect to see the development of therapies that block various steps involved in Alzheimer's development. But this result is an example of how the best strategy for attacking most of the diseases of old age is to reverse the aging process.
A team at U Rochester is chasing down what they think is a mechanism by which poor circulation turns on two proteins which block the removal of toxic amyloid beta.
"To some, it might seem odd that a cardiovascular group would intersect with a neuroscience group to study Alzheimer's disease," Miano said. "But there's a great deal of evidence to suggest that Alzheimer's disease is a problem having much to do with the vascular plumbing. And Rochester is the type of institution where partnerships like these are easy to strike up."
For 15 years Zlokovic's laboratory has focused on the molecular mechanisms regulating blood supply and the role of the blood-brain barrier in the development of Alzheimer's disease. It's not simply that reduced blood supply hurts brain cells by causing a shortage of oxygen and other nutrients. Rather, deterioration of blood flow seems to gum up the brain's ability to remove toxic amyloid beta.
These researchers have previously published results which suggest that a drug that blocks the proteins SRF and myocardin might improve brain blood circulation.
Two years ago, Zlokovic and Miano published a study showing that the two proteins are much more active in the blood vessels of brains of people with Alzheimer's disease than in people who do not have the disease. They showed that when they reduced the activity of the proteins, blood flow in the brain increased, and when the genes were more active, blood flow decreased.
The latest report goes further, implicating the molecular duo in the slowed removal of amyloid beta. The team found that SRF and myocardin working together turn on a molecule known as SREBP2. That protein inhibits a molecule known as LRP-1, which helps the body remove amyloid beta. In other words, when SRF and myocardin are active, toxic amyloid beta accumulates.
Now the team has turned its attention to studying the role of hypoxia, which seems to play a role in turning on myocardin, as well as searching for molecules that block the hookup between SRF and myocardin.
Even if these mechanisms become well understood and toxic protein accumulation becomes blockable with drugs our brains still need a circulatory system that works well enough to deliver sufficient sugar, oxygen, and other nutrients. Drugs that improve circulation are certainly within the realm of the plausible. But ultimately we still need rejuvenated circulatory systems.
The only known genetic risk factor for Alzheimer's disease slows down the brain's ability to export a toxic protein known as amyloid-beta that is central to the damage the disease causes, scientists have found.
The research, published Nov. 13 by the Journal of Clinical Investigation, provides new clues into the workings of a protein known as apolipoprotein E4, or ApoE4. People who carry two copies of the gene have roughly eight to 10 times the risk of getting Alzheimer's disease than people who do not.
The new results mark a step toward resolving a longstanding question that scientists have had about exactly how ApoE4 increases a person's risk for the disease. The findings point to differences in the way that amyloid-beta is removed from the brain depending on which ApoE protein is involved.
Scientists found that when ApoE4 is present, the brain is less efficient at ridding itself of the toxic material, because a molecule that is much slower at removing the substance becomes much more involved.
Biogerontologist Aubrey de Grey argues that one of the major causes of cellular aging is the accumulation of toxic junk inside of aging cells. The body lacks enzymes to break down some kinds of intracellular junk. Therefore Aubrey argues for development of therapies to transplant into aging human cells the genes for enzymes that break down intracellular junk in other species. This report that Alzheimer's risk is boosted by a gene involved in intracellular trash removal underscores the importance of intracellular trash accumulation in brain aging. If we could remove more of the trash that accumulates in cells as we age then we wouldn't age as rapidly.
An over-the-counter vitamin in high doses prevented memory loss in mice with Alzheimer’s disease, and UC Irvine scientists now are conducting a clinical trial to determine its effect in humans.
Nicotinamide, a form of vitamin B3, lowered levels of a protein called phosphorylated tau that leads to the development of tangles, one of two brain lesions associated with Alzheimer’s disease. The vitamin also strengthened scaffolding along which information travels in brain cells, helping to keep neurons alive and further preventing symptoms in mice genetically wired to develop Alzheimer’s.
“Nicotinamide has a very robust effect on neurons,” said Kim Green, UCI scientist and lead author of the study. “Nicotinamide prevents loss of cognition in mice with Alzheimer’s disease, and the beauty of it is we already are moving forward with a clinical trial.”
Nicotinamide even boosted cognitive abilities in normal mice. Hmmm...
The nicotinamide, in fact, slightly enhanced cognitive abilities in normal mice. “This suggests that not only is it good for Alzheimer’s disease, but if normal people take it, some aspects of their memory might improve,” said LaFerla, UCI neurobiology and behavior professor.
Scientists also found that the nicotinamide-treated animals had dramatically lower levels of the tau protein that leads to the Alzheimer’s tangle lesion. The vitamin did not affect levels of the protein beta amyloid, which clumps in the brain to form plaques, the second type of Alzheimer’s lesion.
Nicotinamide is pretty low toxicity. So it is worth consideration for Alzheimer's sufferers.
ST. PAUL, Minn. – Long-term use of ibuprofen and other drugs commonly used for aches and pains was associated with a lower risk of Alzheimer’s disease, according to a study published in the May 6, 2008, issue of Neurology®, the medical journal of the American Academy of Neurology. Previous studies have shown conflicting results, but this is the longest study of its kind.
For the study, researchers identified 49,349 US veterans age 55 and older who developed Alzheimer’s disease and 196,850 veterans without dementia. The study examined over five years of data and looked at the use of several non-steroidal anti-inflammatory drugs (NSAIDs). The veterans received medical care and prescriptions through the VA Health Care system.
The study found people who specifically used ibuprofen for more than five years were more than 40 percent less likely to develop Alzheimer’s disease. Results also showed that the longer ibuprofen was used, the lower the risk for dementia. In addition, people who used certain types of NSAIDs for more than five years were 25 percent less likely to develop Alzheimer’s disease than non-users.
While other NSAIDs such as indomethacin may also have been associated with lower risks, others such as celecoxib did not show any impact on dementia risk.
My guess is that the NSAIDs do this risk cutting. The fact that some have stronger risk reduction effects suggests the drugs themselves make the difference. Also, lots of research finds chronic inflammation increases risk of a variety of diseases of old age.
But long term NSAIDs might not reduce all cause mortality. They might increase risks of other diseases. Safer bets for Alzheimer's disease risk reduction include fruit and vegetable juices, tea, the Mediterranean Diet, fish oils, and curcumin.
A drug commonly used to treat arthritis caused a dramatic and rapid improvement in patients with Alzheimer's disease, according to physicians in California. However, scientists and others not involved in the work worry that the report, which was based on trials in a few patients and hasn't been independently confirmed, may offer little more than false hope for Alzheimer's sufferers and their families.
Alzheimer's patients injected with the anti-inflammatory drug etanercept--marketed as Enbrel--showed dramatic improvements in their functioning within minutes, according to Edward Tobinick, director of the Institute for Neurological Research, a private medical facility in Los Angeles where the patients were treated, and an assistant clinical professor of medicine at the University of California, Los Angeles.
"The patients improve literally before your eyes," says Tobinick, who began using etanercept in Alzheimer's patients three years ago. He uses an unconventional method to administer the drug; he injects it near patients' spines.
Will affluent Alzheimer's sufferers seek out doctors capable of delivering this treatment? Will it spread even without big clinical trials to check its effectiveness? Think about it. If you had early stage Alzheimer's would you try something like this? I would.
Suppose this turns out to work really well. If the relief from this treatment is long lasting then the methods under development to detect beta amyloid plaque years before disease diagnosis will end up getting used in routine screenings of people in their 40s and 50s. One way or another early detection will get used to trigger the use of preventive treatments against Alzheimer's once such treatments become available.
Will trying to make yourself more conscientious slow your brain's aging? Or is conscientiousness a genetically caused trait? What is the mechanism fort this effect?
Individuals who are more conscientious—in other words, those with a tendency to be self-disciplined, scrupulous and purposeful—appear less likely to develop Alzheimer’s disease, according to a report in the October issue of Archives of General Psychiatry, one of the JAMA/Archives journals.
Conscientiousness refers to a person’s tendency to control impulses and be goal-directed, and is also known as will, work and dependability, according to background information in the article. It has been associated with a wide range of mental and physical disorders, disability and death, suggesting it may be important for maintaining overall health.
Robert S. Wilson, Ph.D., of Rush University Medical Center, Chicago, and colleagues studied 997 older Catholic nuns, priests and brothers who did not have dementia when the study began in 1994. Participants underwent evaluations that included medical history, neurologic examinations and cognitive testing. Conscientiousness was measured with a 12-item inventory, where participants rated agreement with each item (for example, “I am a productive person who always gets the job done”) on a scale of one to five. Scores ranged from zero to 48, with higher scores indicating more conscientiousness. The researchers conducted follow-up examinations annually through 2006, with an average of 7.9 evaluations per person.
The participants had an average conscientiousness score of 34 out of 48. Through a maximum of 12 years of follow-up, 176 individuals developed Alzheimer’s disease. Those who had conscientiousness scores in the 90th percentile (40 points) or higher had an 89 percent lower risk of developing Alzheimer’s disease than those whose scores ranked in the 10th percentile (28 points) or lower. Controlling for known Alzheimer’s disease risk factors did not substantially change these results. Conscientiousness also was associated with a slower rate of cognitive decline and a lower risk of mild cognitive impairment, a condition that may precede Alzheimer’s disease.
Maybe conscientious people take better care of themselves and eat better food. The Mediterranean diet appears to lower Alzheimer's risk for example. So do conscientious driven people adopt the best dietary advice at a higher rate than do less conscientious and less goal-oriented people? Seems highly plausible.
Or maybe being driven they stimulate their minds harder their entire lives. build up more neurons, and therefore have more cognitive reserves to lose before the symptoms of Alzheimer's becomes apparent.
Or maybe the genetic variants that make people driven also somehow protect the body against brain aging?
What is the most important thing to know about Alzheimer's Disease? You don't want to get it and you don't want anyone you care about to get it either. You want cures for it sooner rather than later. We should try to stop and reverse brain aging.
EVANSTON, Ill. --- Insulin, it turns out, may be as important for the mind as it is for the body. Research in the last few years has raised the possibility that Alzheimer’s memory loss could be due to a novel third form of diabetes.
Now scientists at Northwestern University have discovered why brain insulin signaling -- crucial for memory formation -- would stop working in Alzheimer’s disease. They have shown that a toxic protein found in the brains of individuals with Alzheimer’s removes insulin receptors from nerve cells, rendering those neurons insulin resistant. (The protein, known to attack memory-forming synapses, is called an ADDL for “amyloid ß-derived diffusible ligand.”)
With other research showing that levels of brain insulin and its related receptors are lower in individuals with Alzheimer’s disease, the Northwestern study sheds light on the emerging idea of Alzheimer’s being a “type 3” diabetes.
Insulin serves multiple functions. The best known is that it binds on the surface of cells and causes the cells to pull sugar out of the bloodstream. But the lack of binding by insulin on neurons in Alzheimer's might wreak damage due to interference with other processes which insulin helps regulate.
Development of the ability to block the accumulation of these ADDL proteins might provide a way to stop Alzheimer's. But the research on insulin resistance in Alzheimer's suggests that treatments used for type 2 insulin resistant diabetes might help also. Or drugs could be developed to block ADDL binding to insulin receptors.
“We found the binding of ADDLs to synapses somehow prevents insulin receptors from accumulating at the synapses where they are needed,” said William L. Klein, professor of neurobiology and physiology in the Weinberg College of Arts and Sciences, who led the research team. “Instead, they are piling up where they are made, in the cell body, near the nucleus. Insulin cannot reach receptors there. This finding is the first molecular evidence as to why nerve cells should become insulin resistant in Alzheimer’s disease.”
ADDLs are small, soluble aggregated proteins. The clinical data strongly support a theory in which ADDLs accumulate at the beginning of Alzheimer’s disease and block memory function by a process predicted to be reversible.
Alzheimer's is a horrible disease. Your brain slowly dies while your body remains living. You know it is happening until you reach the point where you can't even remember that much.
Why do the ADDLs accumulate in the first place? We need treatments that will stop Alzheimer's by stopping the very earliest steps in the disease. Is toxic protein accumulation the earliest step? Or is the earliest step something that causes the toxic proteins to start accumulating?
Wisdom comes with age (doesn't it?), but not without a process that takes place in the brain called myelination. Myelin is the fatty sheath that coats the axons of the nerves, allowing for efficient conduction of nerve impulses. It is key to the fast processing speeds that underlie our higher cognitive functioning, including, yes, wisdom.
Myelination continues sheathing axons until we reach the age of about 50, but in these later stages, the myelin becomes more and more susceptible to damage. Now, in a report in the April issue of the journal Alzheimer's & Dementia, Dr. George Bartzokis, UCLA professor of neurology, suggests that it is the breakdown of this late-stage myelin that promotes the buildup of toxic amyloid-beta fibrils that eventually deposit in the brain and become the plaques which have long been associated with Alzheimer's disease.
These amyloid products in turn destroy more and more myelin, according to Bartzokis, disrupting brain signaling and leading to cell death and the classic clinical signs of Alzheimer's. If correct, the research suggests a broader approach to therapeutic interventions for the disease.
If myelin breakdown is behind Alzheimer's then that strongly suggests to me that brain rejuvenation therapies that repair and replace myelin would be most effective at preventing and stopping Alzheimer's.
Late stage added myelin is thinner and breaks down more easily.
"Myelination of the brain follows an inverted U-shaped trajectory, growing strongly until middle age. Then it begins to breakdown," Bartzokis said. "Before the advent of modern medicine, very few persons lived beyond age 50 and therefore, as a species, we evolved to continue myelinating over our entire natural life span."
As a result, the volume of myelinated white matter increases to a peak at about age 50, then slowly begins to reverse and decline in volume as we continue to age. The myelin that is deposited in adulthood ensheaths increasing numbers of axons with smaller axon diameters, and so spreads itself thinner and thinner, he said. As a result, it becomes more susceptible to the ravages of age in the form of environmental and genetic insults and slowly begins to break down.
Your myelin slowly breaks down after age 50. That, by itself, is thoroughly disgusting even before we consider the threat from Alzheimer's. The brain is our most powerful tool. Our brains become less powerful. In the process of its decay and aging we become less capable and lose parts of who we are. Shouldn't we try much harder with research funding to find ways to stop and reverse brain aging?
Dr. Bartzokis found that the areas of the brain with the latest myelin formation are the areas where amyloid plaques form.
Oligodendrocytes and myelin have the highest levels of iron of any brain cells, Bartzokis said, and circumstantial evidence supports the possibility that brain iron levels might be a risk factor for age-related neurodegenerative diseases like Alzheimer's. In the study, he suggests that myelin breakdown in the late-myelinating regions releases iron, which promotes the development of the toxic amyloid oligomers and plaques, which in turn destroy more myelin.
Bartzokis tested his hypothesis by examining published images of amyloid deposition acquired in living individuals; the images were made using radiolabeled ligands molecules that bind to amyloid plaques in the brains of Alzheimer's patients. Next, he compared the physical location of these plaques to much earlier work published in a the Lancet in 1901 that mapped the locations in the brain where late-stage myelination occurs. The two matched up perfectly.
Stem cells and gene therapy are both strong contenders to some day serve treatments to re-myelinate aging brains. We need faster rates of research into both approaches.
Treatments that stop and reverse nerve demyelination will some day boost worker productivity and increase the rate of economic growth. We should try 10 times harder to develop those treatments.
ST. PAUL, Minn – People who develop dementia or Alzheimer's disease experience brain structure changes years before any signs of memory loss begin, according to a study published in the April 17, 2007, issue of Neurology®, the scientific journal of the American Academy of Neurology. Researchers say these findings may help identify people at risk of developing mild cognitive impairment (MCI), which leads to Alzheimer's disease.
Researchers performed brain scans and cognitive tests on 136 people over the age of 65 who were considered cognitively normal at the beginning of the five-year study. Participants were then followed annually with neurologic examination and extensive mental status testing. By the end of the study, 23 people had developed MCI, and nine of the 23 went on to be diagnosed with Alzheimer's disease. The brain scans of the 23 people with memory loss were then compared to the 113 people who remained cognitively normal.
Compared to the group that didn't develop memory problems, the 23 people who developed MCI or Alzheimer's disease had less gray matter in key memory processing areas of their brains even at the beginning of the study when they were cognitively normal.
Your brain is aging. It is getting older every day. Alzheimer's Disease isn't something you just catch one day and start forgetting things the next day and get diagnosed a week later. Your brain accumulates damage over a period of years until finally the brain can't compensate for the losses.
Some people think aging is okay because it is graceful and you get old and wise and gray. But aging isn't nice. Aging is destruction, not wisdom. Brain aging will turn into Alzheimer's if you live long enough. A recent Plos One article states: Virtually the entire population has Alzheimer-related pathology (amyloid plaques and neurofibrillary tangles) by age 90 years .
We need brain rejuvenation therapies. Vascular stem cells will help repair decaying arteries, capillaries, and veins to improve brain cell food supplies. Gene therapies will conduct repairs on genomes of neurons. Gene therapies, drugs and immunotherapies will help to clear away accumulated debris. We need a much larger research effort to develop all the therapies we need to make our minds young again. The costs will get paid back many times over in increased productivity and more rapid economic growth.
Researchers at the University of Pennsylvania School of Medicine have shown that impaired function and loss of synapses in the hippocampus of a mouse form of Alzheimer’s disease (AD) is related to the activation of immune cells called microglia, which cause inflammation. These events precede the formation of tangles – twisted fibers of tau protein that build up inside nerve cells – a hallmark of advanced AD. The researchers report their findings in the February 1 issue of Neuron.
The microglia might cause the tau protein to get all bent out of shape. Then the tau proteins can't get transported to stabilize microtubules. That causes the loss of the transport mechanism and the nerves collapse since needed stuff isn't getting delivered.
So why do the microglia get activated in the first place? Even before the tau protein gets bent out of shape it accumulates. But why does the tau protein accumulate? This report does not answer that question but one potential answer is that aged nerve cells cease to make enough energy to run their internal transport and internal trash destruction mechanisms.
“Abolishing the inflammation caused by the accumulation of the tau protein might be a new therapy for treating neurodegenerative disorders,” says senior author Virginia Lee, PhD, Director of the Center for Neurodegenerative Disease Research. “This work points the way to a new class of drugs for these diseases.”
In addition, the immunosuppressant FK506 diminishes neuron loss and extends the life span of the transgenic Alzheimer’s mice. Normally only 20 percent of these mice survive by one year. With FK506, 60 percent of the mice were alive by one year.
But methods to suppress the immune response, while potentially useful for therapeutic purposes, probably won't get at the original cause of Alzheimers. Decreased blood flow might be the real cause of Alzheimer's Disease.
The latest findings from the University of Rochester Medical Center mesh not only with Dr. Azheimer's initial observations but also with new findings from today's best imaging technologies. While the first visible symptom of Alzheimer's may be a person forgetting names or faces, the very first physical change is actually a decline in the amount of blood that flows in the brain. Doctors have found that not only is blood flow within the brain reduced, but that the body's capacity to allocate blood to different areas of the brain on demand is blunted in people with the disease.
"A reduction in blood flow precedes the decline in cognitive function in Alzheimer's patients," said Berislav Zlokovic, M.D., Ph.D., professor in the Department of Neurological Surgery and a neurovascular expert whose research is causing scientists to consider the role of reduced blood flow in Alzheimer's disease.
"People used to say, well, the brain is atrophying because of the disease, so not as much blood as usual is needed. But perhaps it's the opposite, that the brain is dying because of the reduced blood flow," he added.
Perhaps this phenomenon is at work on a lesser scale with many people whose minds decay to a lesser extreme without getting diagnosed with Alzheimer's. If so then a treatment to prevent this would likely reduce the rate of cognitive decline even in people who never are going to get Alzheimer's.
Look at how they were able to make this discovery. It is only because gene array chips allow the measurement of the activity of thousands of genes that these scientists were able to get clues that the problem was in the vascular system.
The first step in the study came when Zlokovic's team compared the activity of genes in the brain from several people with Alzheimer's who had died, to that of several people without the disease who had died. It's a type of study widely done now by scientists looking at a host of diseases, using vast gene arrays that can tell how active thousands of genes are in a part of the body.
Scientists have been chasing after the cause of Alzheimer's Disease for decades. But now they have the technological tools to figure out the puzzle and they are coming up with answers that eluded them until now. Think about what that portends for the future of biomedical research into the causes of diseases. The gene chips, microfluidic chips (think "lab on a chip"), and other tools are going to keep getting better at a rapid rate.
The scientists were able to narrow their search down to two key genes that regulate contraction of muscle cells found in arteries.
As Zlokovic perused the list of genes whose activity differed depending on whether the person had Alzheimer's or not, he recognized that several play a role in constricting the arteries. He asked colleague Joseph Miano, Ph.D., a cardiovascular researcher and expert on the smooth muscle that makes up part of the arteries, to take a look.
Miano recognized the group as genes that are all controlled by one of two master regulators of gene activity in smooth muscle cells. Those proteins, myocardin and SRF (serum response factor), are well known for the control they exert on blood vessel walls. Working together, the two are the chief players that regulate how much the smooth muscle cells inside the arteries contract. The more the cells contract, the narrower the artery becomes, and the less blood that flows.
They discovered that SRF and myocardin are more active in Alzheimer's brains, that greater activity of SRF and myocardin causes blood vessels to contract, and that silencing SRF allowed blood to flow more freely. So we might be able to prevent Alzheimer's with a drug that turns down SRF or myocardin.
Now we need a way to detect at an early stage that SRF and myocardin are overactive. You do not want to lose a big chunk of your brain before getting diagnosed with Alzheimer's. We also need to know why these genes become overactive in the brains of some old people. With that knowledge scientists could develop ways to prevent the whole chain of events from ever getting started.
Thanks to Lou Pagnucco for the tip on the second article.
Want to know if you'll slowly lose all your memory and control of your body in your 70s and 80s? Probably not. Hopefully a cure for Alzheimer's won't take more than 10 or 15 years and any genetic risk you have for Alzheimer's will never get a chance to slowly destroy your mind. . But if you want to know if you are at risk a research team has identified yet another genetic variation that increases the risk of late-onset Alzheimer's Disease.
Researchers led by Howard Hughes Medical Institute (HHMI) international research scholar Peter St George-Hyslop have identified a new genetic risk factor associated with the most common form of Alzheimer's disease. The research implicates a gene called SORL1 in late-onset Alzheimer's, which usually strikes after age 65.
In an advance online publication in Nature Genetics on January 14, 2007, St George-Hyslop and colleagues connected the gene to the disease in six different groups of people, although they did not pinpoint the exact genetic mutations in SORL1 responsible for Alzheimer's. In their studies, the researchers used databases that include genetic information about people with and without Alzheimer’s disease. More than 6,800 individuals—45.8 percent of them affected with the disease—were included in the analysis, which is considered a large data set in the field, said St George-Hyslop..
These SORL1 variations join apolipoprotein E variation ApoE4 as known genetic risks for late onset Alzheimer's.
“We looked for variations of SORL1 in nine different groups of people and found those variations to be associated with an increased risk of Alzheimer's in six of them,” St George-Hyslop said. “That implies that SORL1 is not the only cause of Alzheimer's, but it's one of several. Some people with the disease will have a SORL1-related cause, and some won't.” St George-Hyslop is a professor in the department of medicine and director of the Center for Research in Neurodegenerative Disease at the University of Toronto and an HHMI international research scholar. Through its international research scholars program, HHMI supports leading scientists in 28 countries outside the United States.
The researchers studied several groups of Caucasians, one group of African Americans, one group of Hispanics from the Dominican Republic, and a group of Israeli Arabs. They tracked the SORL1 genes via single nucleotide polymorphisms, or SNPs, which are single-letter changes in a gene's sequence. They found that the Caucasians with Alzheimer's displayed a certain SNP signature at one end of the gene, while the African Americans, Hispanics, and Israeli Arabs with the disease displayed another SNP signature. “This implies that there are at least two, and possibly more, gene variants at work here,” said St George-Hyslop. “That's not unusual—in many diseases you see multiple variations that all impact a specific gene.”
So how can the scientists know that a gene has a genetic variation that contributes to a disease without knowing which particular genetic variation is responsible? See the mention of SNPs (single nucleotide polymorphisms) above. Those are locations in the genome where groups of people have single letter differences in their DNA as compared to all other groups of people. SNPs tend to occur in groups. Suppose at a particular location you have a letter A in your genome. Suppose other people have a G in that location and those who have a G have greater risk of Alzheimer's. That G usually will occur along with a group of other SNPs in nearby locations. The A at the same location will occur with letters at the same nearby SNP locations. The puzzle is to figure out which of other other nearby SNPs is the one that contributes to a disease risk.
The cost of testing for SNPs in genes is declining because chips are coming to market that can test for the presence of hundreds of thousands of SNPs at a time. The decline in SNP testing costs is enabling a growing flood of successful searches for genetic variations that contribute to disease risks. Within 5 years time I expect the number of discovered and easily testable genetic risk factors will become large enough to make personal DNA testing worthwhile.
But which risks will be worth testing for? Those you'll be able to do something about. Suppose a genetic variation makes Alzheimer's inevitable at middle age and that diet has little influence on when you'll get it. Well, I guess you could decide to avoid taking on family responsibilities that you won't be around to fulfill. But initially the biggest potential for doing something about a risk will involve risks that can be influenced by diet or exercise. What we need: genetic sample collection on big population studies of diets and lifestyles. Existing on-going longitudinal studies of diet and lifestyle risks could have their diet and lifestyle information compared against disease outcomes for those with high genetic disease risk to see if any dietary factors delayed or reduced the risk of major diseases.
What you should do when you discover 5 or 10 years hence that you have high genetic risk of a disease: Write your elected officials and argue for more research on the disease you are on course to get. Lobby for cures for diseases that will otherwise kill you and your loved ones.
Two geneticists at Massachusetts General Hospital, Lars Bertram and Rudolph Tanzi, have tried to bring order to this confused field by combining the data from many different studies. In an article in Nature Genetics earlier this month, they presented a group of 13 genes besides apolipoprotein E that have a statistically significant association with Alzheimer’s.
Dr. Tanzi said that he had run the numbers on SORL1 and that it would qualify at present for a place in his canon. “This is another gene worth paying attention to,” he added, “but we really have to wait for more replications.”
Over on the Gene Expression blog Amnestic points to evidence that APOE4 boosts episodic memory when young at the expense of greater Alzheimer's risk when you get old. APOE4 might be a variation worth having for someone being born now. The short term advantage might not cost you anything in the long run becaus 50 years from now Alzheimer's will be easily preventable.
We are going to find that many genetic variations which increase disease risks also provide benefits. The task of choosing ideal genetic variations for offspring will not be straightforward with a simple list of good genes and another list of bad genes. The best trade-offs will depend on guesses about the future availability of technologies, guesses about the shape of future societies, and one's values.
The ApoE-4 version of the ApoE gene which is associated with a higher Alzheimer's Disease risk probably increase the risk of Alzheimer's by doing a poorer job of suppressing the Herpes virus that causes cold sores.
A gene known to be a major risk factor for Alzheimer's disease puts out the welcome mat for the virus that causes cold sores, allowing the virus to be more active in the brain compared to other forms of the gene. The new findings, published online in the journal Neurobiology of Aging, add some scientific heft to the idea, long suspected by some scientists, that herpes somehow plays a role in bringing about Alzheimer's disease.
The work links a form of the ApoE gene known as ApoE-4, which after advanced age is the leading known risk factor for getting Alzheimer's disease, with the form of herpes – herpes simplex 1 or HSV – that infects more than 80 percent of Americans and causes cold sores around the mouth. The findings from a group at the University of Rochester Medical Center show that the particular form of the gene that puts people at risk also creates a fertile environment for herpes in the brain, allowing the virus to be more active than other forms of the ApoE gene permit.
We need vaccines that will prevent Herpes virus infections. We also need drugs or perhaps gene therapies that'll suppress or kill Herpes in the brain and peripheral nerves.
Scientists have known for more than 15 years that the ApoE-4 gene is a player in Alzheimer's disease, but the idea that it works in concert with the herpes virus is new.
Note how we've known about the ApoE-4 link to Alzheimer's for 15 years without being able to do anything about it. That's true with many other genetic variations which have known roles in causing diseases. We lack the gene therapy technologies to intervene. Though the knowledge that specific genes play roles in development of diseases does allow many scientists to focus their attention on how those those operate and how their role may help cause diseases.
Different lines of evidence point toward an Apo-E4 plus Herpes connection with Alzheimer's.
Ruth Itzhaki of the University of Manchester has led the way with several studies showing a correlation between herpes and Alzheimer's. She has shown that Alzheimer's patients who have the ApoE-4 form of the gene have more herpes DNA in the brain regions that are affected by Alzheimer's, compared to Alzheimer's patients who also have herpes but who have a different form of the ApoE gene. And she has shown that people with the ApoE-4 version of the gene who are infected with herpes are more likely to get Alzheimer's disease than people infected with herpes who have a different form of the ApoE gene, or than people who have the ApoE-4 gene but who don't have herpes.
Other scientists have found that a herpes infection is active more often – causing the tell-tale cold sores around the mouth – in the 25 percent of people who have a copy of the ApoE-4 gene. In other words, people who are frequently troubled by cold sores are more likely to have the gene that makes them more vulnerable to Alzheimer's disease.
Every time you get a cold sore do you suffer mild brain damage? Seems plausible at least.
ApoE-4 does not increase the odds of infection but it does increase the amount of time time the virus is active.
The team found that the virus infiltrates brain cells about the same no matter which gene is involved. But they found that the subsequent activity level of the virus generally mirrored the disease-causing potential of the gene. They found that in animals with the ApoE-4 gene, the virus is less likely to be in the quiet, latent stage of its life cycle, suggesting it has more of an opportunity to replicate. In animals with the ApoE-2 gene, the virus was less active.
Brain aging is the form of aging I most want to slow down and delay. How to rejuvenate the 100 billion neurons in the brain is the hardest task facing rejuvenation medicine. We'll be able to reverse the aging of the rest of the body before we develop the ability to make the brain youthful once again. Therefore any treatments we can come up with to slow brain aging will provide great benefits and give us more time to develop brain rejuvenation therapies.
A team at University of British Columbia in Canada including Weihong Song has found that oxygen deprivation activated the gene BACE1 which causes beta anyloid production and therefore likely more plaque formation.
Song’s team found that oxygen deprivation triggers a greater activation of the BACE1 gene. More beta-amyloid means more plaques and, in turn, more neuron death. So getting enough oxygen to the brain may help stave off Alzheimer’s in people with known risk factors, says Song.
A diet that reduces your risk of heart disease will probably reduce your risk of Alzheimer's.
The link between low oxygen and plaque formation may be a gene called BACE 1, he added. This gene encodes a protein that converts the precursor amyloid molecule to the more dangerous beta-amyloid form. In their studies with mice, Song's group found that lower oxygen levels increased the activity of the gene.
Lower oxygen might also lead to Alzheimers by reducing the amount of energy available to dispose of plaque. Lower oxygen reduces the ability of cells to break down sugar for energy. The energy gets used to run many cellular processes including junk disposal. So oxygen deprivation could also work to cause brain diseases by reducing the ability of cells to take out the trash.
Eat a diet that is good for your heart and circulatory system. You'll also reduce your risk of stroke, dementia, Alzheimer's, and other degenerative diseases as well.
A long-term study of the elderly has revealed that their average rate of weight loss doubles in the year before symptoms of Alzheimer's-type dementia first become detectable. The finding may be useful to researchers seeking ways to detect and treat Alzheimer's before it causes irreversible brain damage.
The study is the first to confirm in precise detail a link between weight loss and dementia tentatively identified a decade ago. Researchers report in the September 2006 Archives of Neurology that one year before study volunteers were diagnosed with very mild dementia, their rate of weight loss doubled from 0.6 pounds per year to 1.2 pounds per year. The analysis used data from the Memory and Aging Project at the Alzheimer's Disease Research Center (ADRC) of Washington University School of Medicine in St. Louis.
Alzheimer's researchers are working hard to find biomarkers, indicators that can be used to detect the presence of Alzheimer's before clinical symptoms become obvious. Studies at the ADRC and elsewhere have strongly suggested that if Alzheimer's treatments will ever prevent lasting cognitive damage, they may have to be given to patients before memory loss and other disruptions caused by the disorder are evident.
When you read claims that being overweight is not correlated with shorter lifespans keep in mind that a number of illnesses cause weight loss before the illnesses are diagnosed. Cancer can cause weight loss. Unexpected weight loss is sometimes the reason people with undiagnosed cancer go to a doctor and end up with a cancer diagnosis. But cancer is not the only major disease common in old age that causes weight loss. As reported above, even Alzheimer's causes weight loss before diagnosis.
Botton line: People who keep their weight down as a conscious choice are mixed in with people who have lost weight due to illness. So reports which show similar risk of death in the overweight and regular weight are misleading unless they are carefully crafted to control for illness as a cause of weight loss.
A couple of recent studies did attempt to control for illness as a cause of weight loss. They used weight of their subjects before the subjects reached old age. This allowed them to reduce the bias caused by weight loss due to undiagnosed illnesses. They found that being overweight really does shorten life expectancy. See my post Two Studies Find Being Overweight Shortens Life Expectancy for the details.
Providence, RI – Stimulation of a receptor in the brain that controls insulin responses has been shown to halt or diminish the neurodegeneration of Alzheimer's disease, providing evidence that the disease can be treated in its early stages, according to a study by researchers at Rhode Island Hospital and Brown Medical School.
Researchers have found that peroxisome-proliferator activated receptor (PPAR) agonists prevent several components of neurodegeneration and preserve learning and memory in rats with induced Alzheimer's disease (AD). They found that an agonist for PPAR delta, a receptor that is abundant in the brain, had the most overall benefit.
"This raises the possibility that you can treat patients with mild cognitive impairment who have possible or probable Alzheimer's disease. This is really amazing because right now, there's just no treatment that works," says lead author Suzanne M. de la Monte, MD, MPH, a neuropathologist at Rhode Island Hospital and a professor of pathology and clinical neuroscience at Brown Medical School in Providence, RI.
The study appears in the September issue (Volume 10, Issue 1) of the Journal of Alzheimer's Disease (www.j-alz.com).
Alzheimer's looks to be a type of diabetes that is specific to the brain.
In previous studies, the researchers demonstrated that Alzheimer's is a brain-specific neuroendocrine disorder, or a Type 3 diabetes, distinct from other types of diabetes. They showed that insulin and IGF-I receptors are produced separately in the brain, and begin to disappear early in Alzheimer's and continue to decline as the disease progresses. As insulin signaling breaks down, it leads to increased oxidative stress, impaired metabolism and cell death – all causing neurodegeneration.
Scientists were also previously able to replicate Alzheimer's in rats with Streptozotocin (STZ), a compound that is known to destroy insulin producing cells in the pancreas and cause diabetes. When injected into the brains of rats, the compound mimicked the neurodegeneration of Alzheimer's disease – plaque deposits, neurofibrillary tangles, diminished brain size, impaired cognitive function, cell loss and overall brain deterioration.
Since PPAR gamma is already approved as a treatment for Type 2 (insulin resistant) diabetes in humans it would be pretty easy to try it out in early stage Alzheimer's patients. PPAR alpha and PPAR delta would also be useful against Alzheimer's.
Having created an animal model for Alzheimer's, researchers in this study induced Alzheimer's with STZ and then administered treatment with three classes of PPAR agonists – alpha, gamma and delta. All are found in various tissues and organs in the body, including the brain, and PPAR gamma is already FDA approved as a treatment for Type 2 diabetes, or adult-onset diabetes. The two other classes of PPAR agonists have not yet been approved for clinical use.
Following treatment, many of the abnormalities associated with Alzheimer's were reduced or nearly disappeared. The agonists affected different regions of the brain, with PPAR delta producing the most striking effect in preserving the hypothalamus and temporal lobes, areas of the brain responsible for memory, learning, and behavior. In these brain regions, PPAR alpha and PPAR gamma were effective in reducing amyloid gene expression. PPAR delta had the most benefit for reducing oxidative stress and improving learning and memory.
"That was the most spectacular," de la Monte says, "because everybody wants something for cognitive impairment, and that was the most improved with the PPAR delta agonist."
Researchers were not able to stop the deterioration of insulin and its receptors. However, by administering PPAR, they were able to bypass the defects in insulin signaling and preserve the cells that need insulin to thrive. PPAR molecules go directly to the nucleus of cells and tell DNA to turn on or off genes that are normally regulated by insulin, thus preventing them from dying and allowing them to communicate with each other. The major effects of the PPAR treatments were to increase brain size, preserve insulin and IGF-II receptor bearing neurons, and preserve learning and memory.
"The trigger for dementia is the loss of insulin and IGF producing cells. The cells that need those growth factors subsequently die. This study shows you can block the second phase, which is responsible for dementia. This is great news for patients since you treat early stages of disease," de la Monte says.
Another promising result for Alzheimer's patients is that these drugs could be given in the form of a pill, de la Monte says. In the study, the drugs were injected to control the amounts administered.
"One of the most exciting findings was that peripheral (intraperitoneal) injection of the PPAR agonists either partially or completely rescued the brains from neurodegeneration," the authors write.
Alzheimer's appears to be caused by parallel abnormalities – impaired insulin signaling and oxidative stress, which is regulated by the genes NOS and NOX. The PPAR agonists treatments target both problems. They preserve the cells regulated by insulin and IGF, and they decrease oxidative stress, resulting in fewer lesions in the brain.
"If the diagnosis is suspected or patients are in the early phases of AD, there's a good possibility they could get treatment that will help them. It's possible that in the moderate phase, treatment will also help, but more work needs to be done to show that," de la Monte says.
Treatment is not likely to work in the late stages of the disease, she says, because the cells have already died.
All the reports lately about much earlier stage tests for Alzheimer's will turn out to be very useful because periodic testing as we age might be used to determine when to start treatment for type 3 diabetes.
These results remind me of other studies on brain aging. As we age glucose concentrations drop more rapidly and rise more slowly when we do mental work. Basically, our brains can not get enough glucose for sustained concentration. Is the brain glucose shortage seen in normal aging just a milder manifestation of the Type 3 diabetes that these reseachers claim is the cause of Alzheimer's? As we age would we be better able to maintain sustained concentration by taking drugs developed to stimulate insulin receptors in the brain?
Also, is Alzheimer's caused by a glucose shortage that robs the neurons of enough energy to remove the junk (e.g. beta amyloid plaque) that accumulates? Or does the lack of stimulation of the insulin receptors reduce the signalling that tells intracellular machinery to break down the accumulated junk?
Thanks to Lou Pagnucco for the heads up.
In a large epidemiological study, researchers found that people who drank three or more servings of fruit and vegetable juices per week had a 76 percent lower risk of developing Alzheimer’s disease than those who drank juice less than once per week.
The study by Qi Dai, M.D., Ph.D., assistant professor of Medicine, and colleagues appears in the September issue of The American Journal of Medicine.
The researchers followed a subset of subjects from a large cross-cultural study of dementia, called the Ni-Hon-Sea Project, which investigated Alzheimer’s disease and vascular dementia in older Japanese populations living in Japan, Hawaii and Seattle, Wash.
For the current study, called the Kame Project, the researchers identified 1,836 dementia-free subjects in the Seattle population and collected information on their dietary consumption of fruit and vegetable juices. They then assessed cognitive function every two years for up to 10 years.
After controlling for possible confounding factors like smoking, education, physical activity and fat intake, the researchers found that those who reported drinking juices three or more times per week were 76 percent less likely to develop signs of Alzheimer’s disease than those who drank less than one serving per week.
The benefit appeared particularly enhanced in subjects who carry the apolipoprotein E ÿ-4 allele, a genetic marker linked to late-onset Alzheimer’s disease – the most common form of the disease, which typically occurs after the age of 65.
A diet that cuts Alzheimer's risk probably cuts stroke and heart disease risk as well.
Researchers have found that vitamins C, E, and beta carotene do not provide a neuroprotective effect against Alzheimer's. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) also have been found to provide little or no benefit. The researchers behind this study suspected that perhaps polyphenols in foods provide benefit.
Dai began to suspect that another class of antioxidant chemicals, known as polyphenols, could play a role. Polyphenols are non-vitamin antioxidants common in the diet and particularly abundant in teas, juices and wines. Most polyphenols exist primarily in the skins and peels of fruits and vegetables. Recent studies have shown that polyphenols (like resveratrol in wine) extend maximum lifespan by 59 percent and delay age-dependent decay of cognitive performance in animal models.
"Also, animal studies and cell culture studies confirmed that some polyphenols from juices showed a stronger neuroprotective effect than antioxidant vitamins. So we are now looking at polyphenols," Dai said.
The researchers intend to check blood polyphenol levels to see if high polyphenols correlate with low Alzheimer's risk.
The nomenclature here may seem confusing. Catechins in tea are both polyphenols and flavonoids. Polyphenols are a larger set of chemical compounds which includes flavonoids as a subset. Then within the subset called flavonoids exists the smaller subset catechins. Fruits have flavonoids called anthocyanins. Tea and wine (and presumably dark grape juice) contain flavonoids called catechins.
Obvious question: Was the protective effect against Alzheimer's seen in this study due to catechins from tea and grape juice or from anthocyanins found in fruits? Or perhaps from other flavonoids called flavones and flavonols? Or other polyphenols? Or some combination of the above? I'm sorry I do not have an answer for you.
One obvious question: Drink the juice or eat whole fruits and vegetables? Well, juices appear to work (see above) and are quicker to consume. But perhaps the people who consume more fruit and vegetable juices also eat more fruits and vegetables. It is not clear what confounding factors these researchers controlled for.
Writing in the article, Qi Dai, MD, PhD, states, “We found that frequent drinking of fruit and vegetable juices was associated with a substantially decreased risk of Alzheimer’s disease. This inverse association was stronger after adjustments for potential confounding factors, and the association was evident in all strata of selected variables. These findings are new and suggest that fruit and vegetable juices may play an important role in delaying the onset of Alzheimer’s disease”.
I find it really surprising that these researchers could find an influence from juices above the background of all the other factors that will influence polyphenol content of diet.
Enormous amounts of other research has been done on the health benefits of polyphenols including flavonoids. Green tea catechins might reduce the risk of prostate cancer.
Anaheim, Calif. – After a year's oral administration of green tea catechins (GTCs), only one man in a group of 32 at high risk for prostate cancer developed the disease, compared to nine out of 30 in a control, according to a team of Italian researchers from the University of Parma and University of Modena and Reggio Emilia led by Saverio Bettuzzi, Ph.D.
The 600 mg-per-day dosage of caffeine-free, total catechins (50 percent of which is EGCG) given to participants in the Italian study is one or two times the amount of green tea consumed daily in China, where ten to 20 cups a day is normal.
I do not want to drink 10, let alone 20, cups of green tea a day. I'd rather take some caffeine-free catechin capsules. Better yet, I'd rather figure out which fruits and vegetables would deliver the same benefits and eat them instead.
Green tea is very popular in Japan and its consumption there might be the cause of lower Alzheimer's in Japanese in Japan as compared to Japanese in America.
Another paper which reported a reduction in blood plasma peroxide free radicals with green tea extract found a higher concentration of catechin polyphenols per cup of green tea.
"We believe we have shown for the first time the course change of both green tea catechin levels in human plasma as well as human plasma lipid peroxide levels after oral green tea catechin supplementation, " said Teruo Miyazawa, Ph.D., biodynamic chemistry professor at the Tohoku University Graduate School of Life Science and Agriculture and the study's principal investigator.
In the study, 18 healthy male subjects between the ages of 23 and 41 ingested green tea extracts in tablet form (including 254 milligrams of catechins per subject - one cup of green tea contains about 100 to 150 milligrams of catechin). All of the subjects avoided tea and tea-related beverages for 12 hours prior to the testing. Blood samples were taken one hour before and after the catechin ingestion.
I'd love to see a massive comparison study of a wide range of fruits and vegetables, juices, teas, and cocoa (which also contains catechins) where the effects of each food on blood plasma peroxides, blood pressure, and other indicators were compared. What are the most potent foods to eat?
The 806 male participants, averaging age 71 in 1985, were followed until 1995, with complete dietary and medical examinations in 1985 and 1990. Epidemiological evaluation of the health effects of catechins has previously been difficult due to the lack of information on the exact catechin composition of foods. For this study, the authors measured the catechin content of 120 frequently consumed plant foods, using the data to divide the subjects into low, medium and high quintiles of catechin consumption.Among the men in the highest quintile, 87% of catechins in the diet came from black tea; whereas those in lower quintiles ate more foods in which catechins were less concentrated. High catechin intake was associated with other practices characteristic of a healthy lifestyle, such as refraining from smoking, eating more fruits and vegetables, and increased activity levels.
For examples of more on the health benefits of tea see these research reports: Tea Intake Is Inversely Related to Blood Pressure in Older Women and Black and Green Tea Polyphenols Attenuate Blood Pressure Increases in Stroke-Prone Spontaneously Hypertensive Rats.
Green tea is hardly the only food that can improve blood flow and reduce blood free radicals. For example, see the research paper: Wine Polyphenols Decrease Blood Pressure, Improve NO Vasodilatation, and Induce Gene Expression. The "NO" in the title refers to Nitric Oxide which is a naturally occurring vasodilator (i.e. it makes blood vessels widen which lowers blood pressure). Nitric oxide deficiency is, in all likelihood, a cause of high blood pressure. Some drugs release NO as their mechanism of action. Viagra and Cialis work by releasing NO to cause blood to flow in the right places for male sexual function. Minoxidil, the anti-hair loss drug, has the "nox" in its name because it too is an NO releaser. But better to raise your vascular NO by diet before resorting to drug use. The foods that'll improve NO will also deliver other benefits.
NEW YORK August 24, 2006 -- Researchers at Columbia University Medical Center have successfully restored normal memory and synaptic function in mice suffering from Alzheimer's disease. The study was published today on the website of the journal Cell.
Scientists at Columbia's Taub Institute for Research on Alzheimer's Disease and the Aging Brain have identified an enzyme that is required for normal cognition but that is impaired in a mouse model of Alzheimer's. They discovered that mice regained the ability to form new memories when the enzyme's function was elevated.
The research suggests that boosting the function of this enzyme, known as ubiquitin C-terminal hydrolase L1 (Uch-L1), may provide a promising strategy for battling Alzheimer's disease, and perhaps reversing its effects.
In the new study, the Columbia researchers discovered that the enzyme Uch-L1 is part of a molecular network that controls a memory molecule called CREB, which is inhibited by amyloid beta proteins in people with Alzheimer's. By increasing Uch-L1 levels in mice that had Alzheimer's, they were able to improve the animals' ability to create new memories.
"Because the amyloid beta proteins that cause Alzheimer's may play a normal, important physiological role in the body, we can't destroy them as a therapy," explained Ottavio Arancio, M.D., Ph.D., Assistant Professor of Pathology at Columbia University Medical Center and co-principal investigator of the study with Michael Shelanski, MD, Ph.D., Chairman of the Department of Pathology at the Columbia University College of Physicians and Surgeons. "What makes this newly discovered enzyme exciting as a potentially effective therapy is that it restores memory without destroying amyloid beta proteins."
We'll have effective cures for Alzheimer's before cancer becomes totally curable. Alzheimer's is an easier problem.
"While amyloid beta is certainly a key player in Alzheimer's disease--and efforts to reduce it remain a worthy goal--our results show that, even in the presence of the plaque, damage to memory can be reversed."
The findings suggest that neurons' protein-ridding machinery, the so-called ubiquitin/proteasomal pathway, may play an important early role in the pathogenesis of Alzheimer's disease, he added.
Ubiquitin is a "tag" that marks proteins for destruction by the cellular "garbage disposal" known as the proteasome, Shelanski explained. Uch-L1 acts as the proteasome's "gatekeeper," he added. Before proteins can be eliminated by the proteasome, Uch-L1 must remove their ubiquitin tag.
Earlier studies found that the brains of Alzheimer's disease patients show an accumulation of ubiquitin-tagged proteins, suggesting some defect of the protein degradation machinery, the researchers noted. Studies of the brains of humans with Alzheimer's after death found evidence that the proteasome remained intact but largely unable to degrade proteins.
Interestingly, Uch-L1--a protein found almost exclusively in nerve cells--was also found at reduced levels in the Alzheimer's brain. Unpublished studies by Shelanski's group found that cells treated with Aß exhibited a rapid drop in Uch-L1, he said.
Uch-L1 doesn't sound like it stops the underlying cause of Alzheimer's. But if boosting it delays Alzheimer's disease progression drugs that boost Uch-L1 will buy Alzheimer's sufferers valuable time while treatments are devised that fix the underlying causes of the disease.
We need gene therapies that will rejuvenate the mechanisms which brain cells use to break down and remove proteins that are no longer needed. The aging of junk removal mechanisms probably leads to accumulation of junk in and around cells. That junk causes damage to cells and interferes with their operations and communications.
Development of treatments to improve intracellular and extracellular junk removal are two of the rejuvenation Strategies for Engineered Negligible Senescence (SENS).
LA JOLLA, CA - Like most neurodegenerative diseases, Alzheimer's disease usually appears late in life, raising the question of whether it is a disastrous consequence of aging or if the toxic protein aggregates that cause the disease simply take a long time to form.
Now, a collaboration between researchers at the Salk Institute for Biological Studies and the Scripps Research Institute shows that aging is what's critical. Harmful beta amyloid aggregates accumulate when aging impedes two molecular clean-up crews from getting rid of these toxic species.
This finding opens the door for development of drugs preventing build-up of toxic protein aggregates in the brain. The study appears in the Aug. 10 issue of Science Express, the advanced online edition of the journal Science.
Biogerontologist Aubrey de Grey has repeatedly made the argument that biomedical science could do more to reduce death from assorted diseases of old age by reversing aging than by researching treatments for each disease. This paper provides evidence for his assertion. If brain cells could be rejuvenated they'd once more break down toxic proteins as well as they did when they were younger. Then the incidence of Alzheimer's diease would plummet.
The clearing out of beta amyloid protein fragments becomes less efficient as we age.
Throughout life, brain cells produce aggregation-prone beta-amyloid fragments that must be cleared. "This process is very efficient when we are young but as we get older it gets progressively less efficient," says Cohen. As the affected individual reaches the seventh decade of life the clearance machineries fail to degrade the continually forming toxic aggregates and the disease emerges. In individuals who carry early onset Alzheimer's-linked mutation, an increased "aggregation challenge" leads to clearance failure and the emergence of Alzheimer's much earlier – usually during their fifth decade.
Drugs that block steps in the formation of beta amyloid protein fragments might help. But we'd be better if we could get brain cells to once again effectively taking out the trash. We need Strategies for Engineered Negligible Senescence.
Old hippies who haven't toked for decades might come back to the stoner life. Marijuana active ingredient tetrahydrocannabinol blocks the formation of beta amyloid plaques which are suspected as a cause of Alzheimers disease.
LA JOLLA, CA, August 9, 2006 - Scientists at The Scripps Research Institute have found that the active ingredient in marijuana, tetrahydrocannabinol or THC, inhibits the formation of amyloid plaque, the primary pathological marker for Alzheimer's disease. In fact, the study said, THC is "a considerably superior inhibitor of [amyloid plaque] aggregation" to several currently approved drugs for treating the disease.
The study was published online August 9 in the journal Molecular Pharmaceutics, a publication of the American Chemical Society.
According to the new Scripps Research study, which used both computer modeling and biochemical assays, THC inhibits the enzyme acetylcholinesterase (AChE), which acts as a "molecular chaperone" to accelerate the formation of amyloid plaque in the brains of Alzheimer victims. Although experts disagree on whether the presence of beta-amyloid plaques in those areas critical to memory and cognition is a symptom or cause, it remains a significant hallmark of the disease. With its strong inhibitory abilities, the study said, THC "may provide an improved therapeutic for Alzheimer's disease" that would treat "both the symptoms and progression" of the disease.
The development of better tests for amyloid plaque formation probably will provide the ability to predict the development of Alzheimer's many years in advance of obvious symptoms. For people who face the threat of losing their memory 10 years hence if THC can prevent or delay that outcome use of THC might be worth it. Though quite a few people won't want to go through every day of their lives high on THC.
THC works better than commercial drugs currently on the market.
"When we investigated the power of THC to inhibit the aggregation of beta-amyloid," Janda said, "we found that THC was a very effective inhibitor of acetylcholinesterase. In addition to propidium, we also found that THC was considerably more effective than two of the approved drugs for Alzheimer's disease treatment, donepezil (Aricept ®) and tacrine (Cognex ®), which reduced amyloid aggregation by only 22 percent and 7 percent, respectively, at twice the concentration used in our studies. Our results are conclusive enough to warrant further investigation."
Alzheimer's is a terrible disease. It gradually robs you of your identity. People who face the prospect of losing their memories should be allowed a great deal of latitutde in terms of what they can do to protect themselves from that fate. I expect drugs, antibodies, and vaccines will all come to market in the next 10 years that stop and reverse beta amyloid plaque formation. Use of THC for this purpose will be transitory at best. But will any government even allow clinical trials of its effectiveness against Alzheimer's?
Animal research from the University of Massachusetts Lowell (UML) indicates that apple juice consumption may actually increase the production in the brain of the essential neurotransmitter acetylcholine, resulting in improved memory.
Neurotransmitters such as acetylcholine are chemicals released from nerve cells that transmit messages to other nerve cells. Such communication between nerve cells is vital for good health, not just in the brain, but throughout the body.
“We anticipate that the day may come when foods like apples, apple juice and other apple products are recommended along with the most popular Alzheimer’s medications,” says Thomas Shea, Ph.D., director of the UML Center for Cellular Neurobiology and Neurodegeneration Research.
The study will be published in the August issue of the international Journal of Alzheimer’s Disease. The abstract is now available online at http://www.j-alz.com/issues/9/vol9-3.html.
I'd like to see experiments like this one repeated with a wider range of fruits and vegetables at a range of doses to identify the foods that deliver the most benefit the least amount of calories consumed. Also, use of quercetin, other flavonoids, and other antioxidants by themselves would help tease out which compounds are delivering the benefits.
In this novel animal study at UML, adult (9-12 months) and old (2-2.5 years) mice, some specially bred to develop Alzheimer’s-like symptoms, were fed three different diets (a standard diet, a nutrient-deficient diet, and a nutrient-deficient diet supplemented with apple components (in this case, apple juice concentrate was added to their drinking water).
Among those fed the apple juice-supplemented diet, the mice showed an increased production of acetylcholine in their brains. Also, after multiple assessments of memory and learning using traditional Y maze tests, researchers found that the mice who consumed the apple juice-supplemented diets performed significantly better on the maze tests.
Diet optimization for aging brains could provide great personal and economic benefits for hundreds of millions of people.
In fact, the normal adults had the same acetylcholine levels regardless of diet.
However, the genetically engineered mice on the nutrient-poor diet had lower acetylcholine levels. But this drop was prevented in those given apple juice.
In the aged mice on a normal diet, acetylcholine levels were lower than in the normal adult mice; and their levels were even lower if placed on the nutrient-poor diet. But, again, this decline was prevented by the addition of apple juice to drink.
Eat apple sauce with your salmon dinner.
Update: Elderly people in Singapore who occasionally consume curry score higher on a standard test of cognitive function. The turmeric in curry and, in particular, the curcumin in the turmeric might be behind this effect. Those who benefitted did not even have to eat it once a month. Just occasional consumption is enough to produce a measurable benefit.
Building on their discovery that people with Alzheimer’s have ß-amyloid deposits that appear as unusual cataracts in the lens of the eye, Lee E. Goldstein, M.D., Ph.D., of Brigham & Women's Hospital and Harvard Medical School, Boston, and colleagues have developed a new, non-invasive, laser technology that may detect Alzheimer’s at its earliest stages.
Clumps of abnormal ß-amyloid protein (known as “plaques”) accumulate outside the brain’s nerve cells in people with Alzheimer’s. As Goldstein and colleagues previously reported in the British medical journal The Lancet, these same ß-amyloid clumps also collect in the lens of the eye as unusual “supranuclear cataracts.” These Alzheimer’s cataracts are different from common, age-related cataracts. This is the first evidence to date that Alzheimer’s-related amyloid pathology may occur outside the brain.
In their most recent experiments to be reported in Madrid, the researchers used genetically engineered Alzheimer’s mice to test a new, non-invasive molecular diagnostic technology. Goldstein and his team directed a brief pulse of infrared light – barely visible to humans – into the eye of each of four non-anesthetized Alzheimer mice and four age-matched normal mice every month starting at five months of age. Analysis of how the light bounced back from the lens completely separated the two types of mice by 10 months of age, when amyloid lesions were not detectable in the brain or eye by conventional means. The scientists believe that this technology, known as quasi-elastic light scattering (QLS), may detect the very earliest stages of ß-amyloid pathology, even in eyes that are completely clear.
“Amyloid in the lens can be detected using extremely sensitive, non-invasive optical techniques. This makes the lens an ideal window for early detection and disease monitoring in Alzheimer’s,” Goldstein said.
Early identification of developing Alzheimer's might extend back by literally decades the point at which a person can be diagnosed as developing Alzheimer's. Imagine being told at, say, age 45 that 20 or 25 years from now your memory will degrade far enough that you'll have clincal Alzheimer's. I hope such people so diagnosed will react by making loud demands of their elected officials (or the dictators who rule them as the case may be) to accelerate the development of treatments. People should treat early diagnosis as a wake-up call to become politically active and fight for much larger efforts to discover the causes and cures of their diseases.
Early diagnosis will also greatly speed up research on preventive therapies, whether those therapies be drugs, diet, or other techniques. Long longitudinal studes that watch for increased risks of diseases will be replaced by shorter studies that can watch people for several years to see what factors are associated with very early stage development of Alzheimer's and other diseases of aging. Also, people so diagnosed will be able to try new therapies and scientists will be able to find out whether each therapy works before memory has degraded by a substantial amount.
The article linked to above also reports on an fMRI (functional magnetic resonance imaging) technique that finds small blood vessel ruptures may cause dementia in the elderly. Better measurement methods for this problem will lead to better ways to test therapies in shorter periods of time.
Update: Once you get the diagnosis of very early stage Alzheimer's Disease you'll of course want an immediate cure before the brain deteriorates much. Well, some Australian researchers might have the ticket. A drug called PBT2 might stop and reverse the build-up of the plaque that probably causes Alzheimer's.
Professor Ashley Bush, MD, PhD, of the Mental Health Research Institute of Victoria (Australia) and co-founding scientist of Prana Biotechnology Limited (Nasdaq: PRAN, ASX: PBT) today presented data at the 10th International Conference on Alzheimer's Disease (ICAD) in Madrid demonstrating that in mouse models PBT2:
-- improved memory performance within five (5) days of oral dosing
-- rapidly reduced the levels of soluble beta-amyloid ("Abeta") in the brain, and
-- restored normal function to Abeta impaired synapses.
I'm expecting cures for Alzheimer's before cures for cancer. Preventing the build-up of a protein plaque seems a lot easier than stopping some of your own cells from dividing like mad.
The results sound promising.
In addition, Professor Bush referenced studies he and colleagues performed on 15-month old transgenic Alzheimer's mice treated with 30 mg/kg PBT2, which showed the drug reduced soluble Abeta40 and Abeta42 levels by 60 percent within 24 hours of oral PBT2 administration. Professor Bush also presented mechanistic findings showing that PBT2 blocks the copper-dependent formation of amyloid oligomers, considered by many to be the toxic chemical entity leading to brain damage in Alzheimer's disease. Professor Bush showed that, by this mechanism, PBT2 in the rodent brain blocks synaptotoxicity caused by soluble beta-amyloid oligomers and restores LTP (long-term potentiation) -- the neuronal electrical activity that underlies memory formation.
Another team has just reported preliminary results of a monoclonal antibody against Alzheimer's plaques. Drugs, vaccines, and monoclonal antibodies will all work against Alzheimer's eventually. We'd already have vaccines against Alzheimer's if the US Food and Drug Administration didn't demand excessively low levels of side effects. I'd rather run the risk of brain inflammation from a vaccine if I knew I was in the process of losing my memory and ability to think. But the FDA doesn't think we should be allowed to judge such trade-offs for ourselves.
Overall, each additional unit of the Mediterranean diet adherence score (a zero to nine-point scale) was associated with a 9% to 10% decreased risk for Alzheimer's, reported Nikolaos Scarmeas, M.D., of Columbia University here, and colleagues, in the April issue of the Annals of Neurology and published online.
Compared with participants who had the lowest adherence to the diet, the risk for those with the highest adherence was 39% to 40% lower, while those in the middle tertile had a decreased Alzheimer's risk of 15% to 21%. This, the investigators said, showing a significant dose response, and sensitivity analysis did not change these findings.
Scarmeas followed more than 2,000 cognitively normal elderly people from Manhattan, with an average age of 77 years, for about four years. Every 18 months the participants filled out a dietary questionnaire asking them about what they consumed and how often. In total, 262 of the participants developed Alzheimer's during the course of the study.
The changes that lead to Alzheimer's start happening decades before the full blown disease. Therefore following a better diet makes sense even if you are fairly young.
A new UCLA imaging study shows that age-related breakdown of myelin, the fatty insulation coating the brain's internal wiring, correlates strongly with the presence of a key genetic risk factor for Alzheimer disease.
The findings are detailed in the January edition of the peer-reviewed journal Archives of General Psychiatry and add to a growing body of evidence that myelin breakdown is a key contributor to the onset of Alzheimer disease later in life.
In addition, the study demonstrates how genetic testing coupled with non-invasive evaluation of myelin breakdown through magnetic resonance imaging (MRI) may prove useful in assessing treatments for preventing the disease.
The idea of losing the insulation of the nerves of one's brain with aging strikes me as thoroughly disgusting. We should heavily fund attempts to develop treatments to prevent and reverse brain aging.
A genetic variation in Apolipoprotein E causes the myelin insulating sheaths to break down more rapidly with age.
As the brain continues to develop in adulthood and as myelin is produced in greater and greater quantities, cholesterol levels in the brain increase and eventually promote the production of a toxic protein that attacks the brain. The protein attacks myelin, disrupts message transfer through the axons and eventually can lead to the brain/mind-destroying plaques and tangles visible years later in the cortex of Alzheimer patients.
The Apolipoprotein E (ApoE) genotype is the second most influential Alzheimer risk factor, after only advanced age. The study used MRI to assess myelin breakdown in 104 healthy individuals between ages 55 and 75 and determine whether the shift in the age at onset of Alzheimer disease caused by the ApoE genotype is associated with age-related myelin breakdown.
The results show that in later-myelinating regions of the brain, the severity and rate of myelin breakdown in healthy older individuals is associated with ApoE status. Thus both age, the most important risk factor for Alzheimer disease, and ApoE status, the second-most important risk factor, seem to act through the process of myelin breakdown.
Some people argue that aging is a natural process or a sacred process which we can experience with dignity. But where's the dignity of suffering from a progressive breakdown of the insulation on the nerves of your brain? One doesn't just become gray and wrinkly and move more slowly with age. One's brain goes. One loses the ability to think as well. One is more prone to confusion, less able to deal with the problems of life, less able to recall memories of past events or to remember what one has to accomplish on any given day. There's nothing the least bit dignified about brain decay. It does not bring wisdom. It takes away the ability to recall lessons learned.
New York University School of Medicine researchers have developed a brain scan-based computer program that quickly and accurately measures metabolic activity in a key region of the brain affected in the early stages of Alzheimer's disease. Applying the program, they demonstrated that reductions in brain metabolism in healthy individuals were associated with the later development of the memory robbing disease, according to a new study.
"This is the first demonstration that reduced metabolic activity in the hippocampus may be used to help predict future Alzheimer's disease," says Lisa Mosconi, Ph.D., a research scientist in the Department of Psychiatry, who developed the computer program and led the new study. "Although our findings need to be replicated in other studies," she says, "our technique offers the possibility that we will be able to screen for Alzheimer's in individuals who aren't cognitively impaired."
How would you like to get a brain scan and then be told that in 5 or 10 years you will start to lose your memory and eventually forget everything thing you know?
Dr. Mosconi and colleagues have recently published the technical details of the program, called "HipMask," in the June 2005 issue of the journal Neurology. She will present the new findings on June 20 at the Alzheimer's Association International Conference on Prevention of Dementia held in Washington.
The computer program is an image analysis technique that allows researchers to standardize and computer automate the sampling of PET brain scans. The NYU researchers hope the technique will enable doctors to measure the metabolic rate of the hippocampus and detect below-normal metabolic activity.
The technique grew out of years of research by Mony de Leon, Ed.D., Professor of Psychiatry and Director of the Center for Brain Health. His group was the first to demonstrate with CT and later with MRI scans that the hippocampus, a sea-horse shaped area of the brain associated with memory and learning, diminishes in size as Alzheimer's disease progresses from mild cognitive impairment to full-blown dementia.
Yet until now there has been no reliable way to accurately and quickly measure the hippocampal area of the brain on a PET scan. The hippocampus is small and its size and shape are affected greatly in individuals with Alzheimer's, making it difficult to sample this region. HipMask is a sampling technique that uses MRI to anatomically probe the PET scan.
MRI relies on electromagnetic energy to excite water molecules in the brain to create an anatomical map of the brain. The MRI was used in the study to determine the total volume of the hippocampus and then to define that portion (namely the HipMask) that was shared by all persons regardless of their disease status. PET employs radioactively labeled glucose to show the brain at work and the HipMask was applied to these scans to derive estimates of the hippocampal glucose metabolism.
The researchers followed 53 healthy, normal subjects between the ages of 54 and 80 for at least 9 years and in some cases for as long as 24 years. All subjects received two FDG-PET scans -- one at baseline and a follow-up after 3 years. Thirty individuals had a second follow-up scan after another seven years. Altogether there were 136 PET scans.
The researchers applied the HipMask to all 136 scans. The results showed that hippocampal glucose metabolism, as determined by the HipMask, was significantly reduced 15% to 40% on the first scan, compared to controls, of those 25 individuals who would later experience cognitive decline related to either mild cognitive impairment or to Alzheimer's. The researchers found that the baseline hippocampal glucose metabolism was the only brain or clinical measure that predicted the future cognitive decline.
"Right now, we can show with great accuracy who will develop Alzheimer's nine years in advance of symptoms, and our projections suggest we might be able to take that out as far as 15 years," says Dr. de Leon, whose longitudinal study is funded by the National Institutes of Health (NIH).
"Our basic results will need to be replicated in other studies and expanded to include PET data from diverse patient groups," adds Dr. De Leon. "But we're confident this is a strong beginning, demonstrating accurate detection of early Alzheimer's disease. Now we have a better tool to examine disease progression, and we anticipate this might open some doors to prevention treatment strategies."
Most people are not going to get brain PET scans. The greater value of this finding is in research on methods to prevent or delay the onset of Alzheimer's Disease.
Don't wait for that PET scan result to come back with bad news. Reduce your risk of Alzheimers.
People who drink fruit or vegetable juice at least three times a week seem four times less likely to develop Alzheimer's than nonjuice drinkers, according to a study of 1,800 elderly Japanese Americans. The theory is that juice contains high levels of polyphenols, compounds that may play a brain-protective role.
Less education, gum disease early in life, or a stroke were more important than genes in determining who got dementia, concluded a study of 100 dementia patients with healthy identical twins. Education stimulates neuronal growth; gum disease is a marker of brain-harming inflammation.
Middle-aged sons and daughters of people with Alzheimer's disease may be able to reduce their risk of getting the disorder through lifestyle measures such as exercise, avoiding gum disease, moderate alcohol consumption, and drinking fruit and vegetable juice, according to new research.
Keep your teeth clean. Drink some V-8 or pure fruit juice. Get regular exercise. They'll all protect your brain.
A new study of dementia in identical twins suggests that exposure to inflammation early in life quadruples one's risk of developing Alzheimer's disease.
Margaret Gatz, lead author and professor of psychology in the USC College of Letters, Arts and Sciences, is slated to present her findings at the first Alzheimer's Association International Conference on Prevention of Dementia, to be held June 18-21 in Washington, D.C.
If confirmed, the link would add inflammatory burden to the short list of preventable risk factors for Alzheimer's.
Previous studies by Gatz and others have shown that Alzheimer's is strongly genetic: If one twin has the disease, his or her identical twin has a 60 percent chance of developing it.
Stroke and a short period of formal education both increase the odds of dementia, but not of Alzheimer's specifically, the new study found.
Dementia is an umbrella term for many conditions, including Alzheimer's.
"People can plan a life span that will alter dementia risk," Gatz said. "And these aren't risk factors that are unique to dementia. Many of these are also risk factors for other disorders. This is good news."
Gatz's team, which included researchers from the Karolinska Institute in Stockholm, Sweden, sifted the 20,000 participants in the Swedish Twin Registry for the 109 "discordant" pairs where only one twin had been diagnosed with dementia.
Information about participants' education, activities and health history came from surveys they completed in the 1960s, when the registry was created, and from hospital discharge records.
The surveys included questions about loose or missing teeth. Gatz and colleagues used the answers to build a crude indicator of periodontal disease.
"We're talking about gum disease, but it was measured by teeth lost or loose," Gatz said. "It's not perfect. Given it's not perfect, it's even more striking that it's such a solid risk factor."
The conclusion is not that good oral health can prevent Alzheimer's, but that an inflammatory burden early in life, as represented by chronic gum disease, may have severe consequences later.
I think that previous sentence is poorly worded. Surely good oral health will reduce the risk of Alzheimer's. Poor oral health is not the only souce of inflammatory burden. But it is one big source.
Gatz was inspired to focus on inflammation by the work of USC gerontologists Caleb Finch and Eileen Crimmins, who published a paper in the journal Science linking today's record life spans to lower rates of childhood infectious diseases, such as gum disease, flu, rheumatic fever, tuberculosis and other illnesses.
Such diseases are often preventable, raising hope for prevention of Alzheimer's.
"If what we're indexing with periodontal disease is some kind of inflammatory burden, then it is probably speaking to general health conditions," Gatz said. "There was in our twins quite a lot of periodontal disease, and at that time in Sweden there was a lot of poverty."
The study, titled "Potentially Modifiable Risk Factors From Dementia: Evidence From Identical Twins," also found that mental activities at age 40, such as reading or attending cultural events, did not seem to lower the risk of developing Alzheimer's.
So crossword puzzles do not help. Then I guess writing a blog isn't going to help either. Heavy sigh.
Previous reports have suggested a link between education and lowered risk of Alzheimer's. But when education is controlled for by using twins with different levels of education then the education effect becomes very low. One possible explanation might be that level of education is a proxy for level of intelligence. Higher intelligence people might be more likely to avoid behaviors (like eating junk food or not practicing good dental hygeine) than lower intelligence people. Or perhaps having smarter brains allows a person to deteriorate for longer from a higher level of initial cognitive function before the effects of Alzheimer's become apparent.
Participants who had more education than their twins were at slightly lower risk of developing dementia, but the influence of education on Alzheimer's risk was statistically negligible."Once one controls for genes, the level of education is not a huge risk factor," said Gatz, who questioned popular attitudes linking Alzheimer's or dementia to mental inactivity.
Drinking soda leads to tooth decay. So if you don't want your kids to get Alzheimer's Disease in their old age then do not let them drink soda.
The human body has its own defense against brain aging: the innate immune system, which helps to clean the brain of amyloid-beta waste products. However, UCLA researchers discovered that some patients with Alzheimer's disease have an immune defect making it difficult to clean away these wastes. This may lead to over-saturation of the brain with amyloid beta, which form amyloid plaques, the definitive hallmark of Alzheimer's disease.
Published in the June 10 issue of the Journal of Alzheimer's Disease, the findings could lead to a new approach in diagnosing and treating Alzheimer's disease by helping to diagnose and correct this immune defect. This is the first time that researchers have discovered that the innate -- or more primitive -- part of the immune system may play a role in the development of Alzheimer's disease.
Using blood samples, investigators found that in healthy people, cells belonging to the innate immune system called macrophages, cleared amyloid-beta in a test tube test developed at UCLA. However, the macrophages of some Alzheimer's patients could not adequately perform this cleaning job.
"Macrophages are the janitors of the innate immune system, gobbling up waste products in the brain and throughout the body," said Dr. Milan Fiala, first author and UCLA researcher.
Fiala notes that there may be a problem either with the macrophages not effectively binding to amyloid beta or a problem in the absorption or uptake, which is called "phagocytosis." He adds that this immune defect may also be present in other diseases where a build-up of waste and plaques occur, such as in cardiovascular disease and Gaucher's disease.
"If further study shows that this defective macrophage function is present in most Alzheimer's disease patients, new hormonal or immune-boosting approaches may offer new approaches to treating the disease," adds Fiala.
Researchers add that this new approach differs from the amyloid-beta immunization method, which utilizes another part of the immune system called the adaptive immune system. According to Fiala, the immunization approach has resulted in amyloid-beta clearance in the lab in an animal model, but in a human clinical trial led to brain inflammation in a subset of patients.
In future studies, investigators plan to regulate the innate immune system by natural substances such as hormones, and natural products such as curcumin (from the curry powder). Currently in their lab, Fiala and Dr. George Bernard who is a professor in the UCLA Department of Oral Biology and Medicine,are testing the effectiveness of a naturally occurring hormone, called insulin-like growth factor I, in conjunction with a research team from the MP Biomedicals LLC Company.
This is a valuable piece of work. Perhaps immune system aging causes the innate immune system to fail to clear beta amyloid plaques. If so, restoring its proper function might turn out to be difficult because immune system rejuvenation might be necessary. Or perhaps a genetic difference causes the lower ability to remove the plaques. If so, perhaps a gene therapy could give the macrophages a capability that they lack.
Among the 7 Strategies for Engineered Negligible Senescence (SENS) to halting and rejuvenate bodies is the removal of accumulated extracellular junk. The amyloid plaque accumulations which likely cause Alzheimers are a form of extracellular junk and treatments to remove those plaques will likely be among the earliest rejuvenation treatments used in clinical practice. Because the amyloid plaques are associated with a major neurological disorder the development of means to remove them gets much more attention than some of the other SENS approaches. For example, little effort is going into the development of treatments to remove intracellular junk from lysosomes or to develop gene therapies to repair mitochondrial mutations.
Researchers at the University of Illinois at Chicago have had preliminary success with a method of immunization intended to dissolve the plaques in brain tissue that are associated with Alzheimer's disease.
When injected directly into the brain of mice, antibodies against a plaque protein retarded growth of the plaques by up to two months. No adverse side effects were found.
"By injecting the antibodies directly into the brain, we were able to circumvent the problems others have encountered in developing a vaccine for this terrible disease," said Neelima Chauhan, research assistant professor in the UIC College of Medicine.
Results of the study appear in the current issue of the Journal of Neuroscience Research.
Two methods of immunization have been tried in Alzheimer's disease. In the first, called active immunization, researchers inject the antigen itself -- pieces of the sticky beta amyloid protein that constitutes the plaques -- into patients to spur the production of antibodies that should neutralize the protein and prevent it from accumulating in brain cells.
But after success in animals, clinical trials of active immunization failed when 6 to 8 percent of the patients in the study developed meningocephalitis, an inflammation of the tissue surrounding the brain.
Passive immunization did not even succeed in animal studies. In this method, researchers inject ready-made antibodies, rather than the antigen, into the animal. But high concentrations of the antibodies are required to be effective, and the large doses were found to cause hemorrhaging and inflammation.
Aware of such problems, Chauhan tried a modified passive immunization method in laboratory mice that are used as a model for the disease. In a single injection, she delivered the antibody directly into the third ventricle, a narrow cavity located between the two hemispheres of the brain, and then examined the animals' brain tissue at one, four and eight weeks.
Since the antibody did not have to circulate throughout the mouse's body where it might be absorbed, Chauhan was able to use a smaller dose than in other passive immunization studies.
Note the plaques came back more slowly in young mice. The ability to clear the plaques by itself would not fully restore brains to a more youthful condition in which plaques would not form in the first place. We still need many other rejuvenation therapies for the brain.
At one and four weeks, the density of amyloid protein was 67 percent less than in control animals. But by eight weeks, with no further antibody injections, the protein had again accumulated. The younger the animals were, the slower the plaques regrew.
No side effects, such as hemorrhaging or inflammation, were evident.
"The results suggest that periodic administration of antibodies directly into the brain might offer a safer method for treating Alzheimer's," Chauhan said. "The vaccine reduces the accumulation of amyloid proteins for at least four weeks, providing a window during which other treatments could be used to prevent the formation of new plaques."
Alzheimer's is an age-associated degenerative neurological disease and the leading cause of dementia in older people. An estimated 10 percent of Americans over the age of 65 and half of those over age 85 have Alzheimer's.
Imagine the cost of Alzheimer's ballooning up to $300 billion per year or more in the United States in a few decades. Makes the cost of research to cure it seem very cheap by comparison. Keep in mind that the money spent finding a way to prevent Alzheimer's is a fixed cost. Once the cure is found the research on that topic doesn't have to continue. Whereas if we do not get a cure for decades to come them the high yearly cost of treatment keeps rising and it goes on continually. Biomedical research spending can produce cures that basically pay from the day the cure is found until humans no longer exist in this universe (I'm assuming that we won't be able to transfer our knowledge to humans who may exist in parallel universes but that assumption may some day prove to be incorrect).
Currently, more than 4 million Americans suffer from the disease and the number is projected to balloon to 10 to 15 million over the next several decades. Alzheimer's is now the third most expensive disease to treat in the United States, costing close to $100 billion annually.
You can read the abstract of the paper here: Effect of age on the duration and extent of amyloid plaque reduction and microglial activation after injection of anti-A[Beta] antibody into the third ventricle of TgCRND8 mice.
While the Elan Pharmaceuticals experimental vaccine AN-1792 against Alzheimer's amyloid plaques caused brain inflammmation in a small subset of people treated I still think a better vaccine may be able to eventually work well against amyloid plaques. In fact, a new oral vaccine has just been tested in mice and shows promise.
Alzheimer's disease is characterized by progressive loss of cognitive function due to amyloid-beta (Aß) deposits in the central nervous system. If these deposits could be stopped or slowed, Alzheimer's disease might become more manageable. In the current issue of the Journal of Alzheimer's Disease, a novel paper from researchers from the National Institute for Longevity Sciences, NCGG, Japan and Center for Neurological Diseases, Brigham & Women's Hospital, Harvard Institute of Medicine shows that a new oral vaccine treatment is effective in reducing Alzheimer's disease pathology.
Immunization results from the production of antibodies which attack the harmful agent, using the body's own defenses to remove the threat. In an earlier immunization study, 6 percent of the subjects developed acute meningoencephalitis, most likely caused by autoimmune T-cell activation. This caused the trial to be stopped. By developing vaccines that can minimize this T-cell activation while retaining the production of Aß-antibodies, a safer treatment might result.
The researchers attached Aß DNA to an adeno-associated virus vector and administered this vaccine to mice orally. Not only were the Aß levels decreased, but the T-cell immune response was significantly reduced. A single dose of this vaccine enhanced the production of Aß-antibodies for more than 6 months. Immunohistochemistry of the mouse brain tissue showed that the extra-cellular amyloid deposits were clearly decreased compared to the non-treated mouse.
Hideo Hara, M.D, writes "This new oral vaccine does not induce strong T cell immune reactions, and hence it could reduce the side effect of such meningoencephalitis…This new therapy seems to be effective for prevention and treatment of Alzheimer's disease."
The article is "Development of a safe oral Aß vaccine using recombinant adeno-associated virus vector for Alzheimer's disease" by Hideo Hara, Alon Monsonego, Katsutoshi Yuasa, Kayo Adachi, Xiao Xiao, Shin'ichi Takeda, Keikichi Takahashi, Howard L. Weiner and Takeshi Tabira. It appears in the Journal of Alzheimer's Disease, Vol.6, Number 5, published by IOS Press
You can view the abstract here.
Antibodies injected into a small number of Alzheimer's Disease (AD) patients appear to have stopped the progression of Alzheimer's by attacking the plaques assocated with the disease.
Immunoglobulins which are already being used to treat multiple sclerosis may also be able to help patients with Alzheimer's. This, at least, is the finding of a pilot study on five patients at the University of Bonn. The results are set out in the forthcoming edition of the Journal of Neurology, Neurosurgery and Psychiatry (vol. 75, pp. 1472-1474), which also devotes its editorial to this discovery.
Immunoglobulins contain, among other things, anti-bodies against a protein which is the 'main suspect' thought to trigger off Alzheimer's. After six months of immuno-globulin doses the concentration of this protein in the patients' cerebrospinal fluid was reduced by one third. The patients' cognitive abilities improved slightly.
Even if the treatment is effective it is not surprising there was not a bigger improvement in cognitive function. AD kills neurons. A halt of the disease progression is still going to leave current AD patients with a lot of brain damage. Even if replacement neurons can eventually be grown a large portion of who an AD sufferer was originally is irretrievably lost.
However, the medical team involved emphasise that their findings are still very tentative. They are now planning a large-scale double-blind clinical trial with about sixty patients so as to further confirm the positive effect of the immunoglobulins.
The cerebral cortex of Alzheimer's patients regularly contains large protein aggregates, what are known as Alzheimer's glands. They predominantly consist of beta-amyloid peptide, a small protein. This peptide collects in the brain of Alzheimer's patients and forms protein deposits which can damage and even destroy the sensitive nerve cells.
A promising approach in combating the disease seems to be the treatment with anti-bodies which are specifically effective against beta-amyloid. Thus, in animal experiments the injection of beta-amyloid anti-bodies led to a reduction in the protein deposits and an improvement in the behavioural deficits in these animals. Another study recently showed that immunising was not only able to reduce amyloid plaques, it also prevented the formation of the abnormal tau protein.
Recently the team led by the Bonn lecturer Dr. Richard Dodel was able to show that every person's blood contains anti-bodies against beta-amyloid, but that the concentration in Alzheimer's patients is markedly lower. Their findings have been confirmed by two US teams. 'There are already anti-body blood preparations which are used for particular diseases of the nervous system such as multiple sclerosis, which are known as immunoglobulins,' Dr. Dodel explains. 'We have now investigated whether these preparations contain anti-bodies against beta-amyloid and if these can be used to fight Alzheimer's.' His team did in fact find anti-bodies in one type of immunoglobulin medication which are very effective specifically against beta-amyloid. In a pilot study carried out on five Alzheimer's patients the team then studied the effect of the immunoglobulins on the progress of the disease. This involved giving the patients an immunoglobulin injection intravenously every four weeks throughout the six-month study. Before beginning and on completing the therapy the researchers determined the beta-amyloid content in the blood and the CSF fluid – the latter being the liquid which is present in the brain and spinal cord. 'On average the beta-amyloid concentration in the fluid decreased in the course of the study by over 30 per cent, while the concentration in the blood rose 2.3 times,' Dr. Dodel says. 'The immunoglobulins therefore seem to have the effect of flushing out the beta-amyloid from the brain' – how exactly this occurs is as yet unclear.
At the same time the team carried out various tests which enabled them to check the cerebral performance of dementia patients. After six months four of the five patients did slightly better than before in what is known as the ADAS-cog test (Alzheimer's Disease Assessment Scale, cognitive subscale). In the MMSE (Mini-Mental State Examination) test three patients improved. 'What is even more remarkable is that none of our test persons deteriorated,' Dr. Dodel explains. 'Without treatment Alzheimer's patients on average score seven to eleven points worse in the ADAS-cog test one year later, and even patients on medication score four to six points worse. In our study they improved on average by 3.7 points.'
These researchers still need to follow up with a larger and double-blind study that they are planning. But if ths treatment could work it would save the minds of tens of millions of people (4.5 million Americans currently suffer from AD) while saving the families of those sufferers enormous amounts of work, money, and a tremendous stress and burden.
This result is not surprising. In a previous study with a vaccine called AN-1792 many of the patients experienced a slowing or stopping of Alzheimer's Disease progression. Unfortunately, 17 out of the 300 patients in that study developed an encephalitis probably caused by an auto-immune response. But if I was an Alzheimer's Disease patient who was just diagnosed (i.e. if I still could reason well enough to make choices) I'd jump at those odds and take the risk of the encephalitis. However, governments do not let us take risks even when we are in the process of losing our minds to a fatal disease.
Another Alzheimer's vaccine appears to work in rhesus monkeys. Also, drugs are under development to block beta amyloid plaque formation.
With the baby-boom generation aging and life expectancy continuing to increase, Alzheimer's disease has become a ticking time bomb. The fastest-growing segment of the population is 85 and older. In Mr. Dillon's age group, 65 to 74, 3 percent have Alzheimer's; in the 85-and-over group, it is a staggering 47 percent, according to the National Institutes of Health.
Absent an effective treatment the number of AD cases is expected to triple by the middle of the 21st century. However, AD is a much more approachable problem as compared to cancer. The proteins that form into plaques that appear to play a vital role in AD development are turning out to be removable via immune system approaches. So I expect that within 20 or 30 years we will have effective treatments to stop AD progress. However, once we can stop the disease that will still leave millions with the brain damaged they suffered before a cure was developed. Also, while effective treatments are probably going to happen in the next couple of decades this is not reason for complacency. We ought to be trying even harder to achieve a cure. Money spent on AD research will pay itself back many times over.
If you want to reduce your risk of AD then my advice is to get lots of omega 3 fatty acids to slow disease progess and plenty of folic acid and vitamin B12 to keep down blood homocysteine which is an AD risk factor. If you are curious to review the literature on AD risk factors check out this list of summaries of AD risk factor studies. Even if some of the controllable factors listed there do not help reduce the risk of AD a diet aimed at those factors will certainly lower the risk of heart disease and stroke. Exercise helps lower Alzheimer's Disease risk too.
UCLA neuroscientists have shown for the first time that a diet high in the omega-3 fatty acid DHA helps protect the brain against the memory loss and cell damage caused by Alzheimer's disease. The new research suggests that a DHA-rich diet may lower one's risk of Alzheimer's disease and help slow progression of the disorder in its later stages. The journal Neuron reported the findings on Sept. 2.
"This is the first proof that our diets affect how our brain cells communicate with each other under the duress of Alzheimer's disease," said Greg Cole, senior author and a professor of neurology at the David Geffen School of Medicine at UCLA. "We saw that a diet rich in DHA, or docosahexaenoic acid, dramatically reduces the impact of the Alzheimer's gene.
"Consuming more DHA is something the average person can easily control," added Cole, associate director of the UCLA Alzheimer's Disease Research Center. "Anyone can buy DHA in its purified form, fish-oil capsules, high-fat fish or DHA-supplemented eggs."
Cole and his colleagues focused on Alzheimer's damage to synapses — the chemical connections between brain cells that enable memory and learning.
By using mice bred with genetic mutations that cause the brain lesions linked to advanced Alzheimer's disease, the UCLA researchers created a mouse model to test environmental risk factors for the disorder. When the mice developed the lesions, but showed minimal memory loss or synaptic brain damage, however, the scientists took a closer look at the animals' diet.
"We discovered that the mice lived on a nutritious diet of soy and fish — two ingredients chock-full of omega-3 fatty acids," said Sally Frautschy, co-author and an associate professor of neurology at the school.
"Because earlier studies suggest that omega-3 fatty acids may prevent Alzheimer's disease, we realized that the mice's diet could be countering the very thing we were trying to accomplish — showing the progression of the Alzheimer's-related brain damage," she said.
The UCLA team swapped safflower oil for the soy and fish to create an unhealthful diet depleted of omega-3 fatty acids. They divided the animals into two sets of older mice, which already showed brain lesions but displayed no major loss of brain-cell activity. The researchers placed both groups on the new diet, but fed the second group DHA supplements from algae.
After five months, the researchers compared each set of mice to a control group that consumed the same diet but did not carry the Alzheimer's genes. The results surprised them.
"We found high amounts of synaptic damage in the brains of the Alzheimer's-diseased mice that ate the DHA-depleted diet," Frautschy said. "These changes closely resembled those we see in the brains of people with Alzheimer's disease."
Although the mice on the DHA-supplemented diet also carried the Alzheimer's genes, they still performed much better in memory testing than the mice in the first group.
"After adjusting for all possible variables, DHA was the only factor remaining that protected the mice against the synaptic damage and memory loss that should have resulted from their Alzheimer's genes," Cole said. "We concluded that the DHA-enriched diet was holding their genetic disease at bay."
The present results provide, for the first time, evidence that the combination of genetic (mutant human APP) and environmental risk factors (dietary essential fatty acids) for AD can act synergistically to quantitatively reduce synaptic proteins, specifically, dendritic scaffold proteins, that are critical for cognition as evidenced by memory deficits observed in the Morris water maze paradigm," wrote the researchers.
"The results show a dramatic impact of diet on the expression of the AD-related postsynaptic marker phenotype and provide new insight into how essential fatty acid intake may modulate the expression of neurodegenerative diseases, including AD," they wrote.
The researchers also wrote that their findings "suggest that patients bearing a genetic risk of AD may be more vulnerable to a lack of essential fatty acids," which tend to be reduced in the brain both in normal aging and AD. They concluded that their findings "support the idea that increased DHA intake should be considered as a potential neuroprotective strategy for AD."
Omega 3 fatty acids are not the only nutrients that have been found to slow Alzheimer's Disease progression in mice genetically engineered to develop the disease. Dr. James Joseph, associate professor of nutrition and chief of the Neuroscience Laboratory at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts Univesity has found that blueberries help maintain normal cognitive function in mice genetically engineered to develop Alzheimer's.
Joseph continues to research the benefits of blueberries, which, among other things, have been found to improve memory. Collaborating with researchers at the University of Florida, Joseph is working worked with double-transgenic mice that have been genetically programmed to have Alzheimer's disease. When fed a diet of blueberries for 11 months, the mice's Y-maze performance was normal, and he recorded in them a higher level of expression of enzymes associated with signal transduction than in the control group.
"Either directly or working as an antioxidant, the diet appears to have an effect on synaptic plasticityÑthe signal transduction or communication between neurons," says Joseph.
The challenge, then, is to find a way to make a blueberry fish dish. I personally find that pineapple works mixed in as a flavoring with salmon. Haven't tried blueberries and salmon yet.
Peter P. Zandi, Ph.D., of The Johns Hopkins University Bloomberg School of Public Health, Baltimore, and colleagues examined the relationship between antioxidant supplement use and risk of AD.
The researchers assessed the prevalence of dementia and AD in 4,740 elderly (65 years or older) residents of Cache County, Utah in 1995 to 1997 and collected information about supplement use. These residents were followed-up in 1998 to 2000 for new cases of dementia or AD. The researchers identified 200 cases of AD (prevalent cases) between 1995 and 1997, and 104 new cases (incident cases) of AD during follow-up.
The researchers categorized participants as vitamin E users if they reported taking an individual supplement of vitamin E or a multivitamin containing more than 400 IU (international units) of vitamin E. Vitamin C users reported taking vitamin C supplements or multivitamins containing at least 500 micrograms of ascorbic acid. Individuals were classified as multivitamin users if they reported taking multivitamins containing lower doses of vitamin E or C.
The researchers found the greatest reduction in both prevalence and incidence of AD in participants who used individual vitamin E and C supplements in combination, with or without an additional multivitamin. "Use of vitamin E and C (ascorbic acid) supplements in combination reduced AD prevalence [by about 78 percent] and incidence [by about 64 percent]," the authors write.
The researchers also found "no appreciable association with the use of vitamin C alone, vitamin E alone, or vitamin C and multivitamins in combination," and prevalence of AD.
"The current… recommended daily allowance for vitamin E is 22 IU (15 micrograms), and for vitamin C (ascorbic acid), 75 to 90 micrograms," the researchers write. "Multivitamin preparations typically contain these approximate quantities of both vitamins E and C (more vitamin C in some instances), while individual supplements typically contain doses up to 1,000 IU of vitamin E and 500 to 1,000 micrograms or more of vitamin C (ascorbic acid). Our findings suggest that vitamins E and C may offer protection against AD when taken together in the higher doses available from individual supplements."
Antioxidant vitamin supplements, particularly vitamins E and C, may protect the aging brain against damage associated with the pathological changes of Alzheimer's disease, according to a study conducted by the Johns Hopkins Bloomberg School of Public Health and other institutions. The researchers believe antioxidant vitamin supplements may be an ideal prevention strategy for our aging population as they are relatively nontoxic and are thought to have wide-ranging health benefits. The study, "Reduced Risk of Alzheimer's Disease in Users of Antioxidant Vitamin Supplements" is published in the January 2004, issue of the journal Archives of Neurology.
Peter P. Zandi, PhD, lead author of the study and an assistant professor in the School's Department of Mental Health, said, "These results are extremely exciting. Our study suggests that the regular use of vitamin E in nutritional supplement doses, especially in combination with vitamin C, may reduce the risk of developing Alzheimer's disease."
The researchers examined data from the Cache County Study, which is a large, population-based investigation of the prevalence and incidence of Alzheimer's disease and other dementias. Residents who were 65 or older were assessed from 1996-1997 and again from 1998-2000. Study participants were asked at their first contact about vitamin usage. The researchers then compared the subsequent risk of developing Alzheimer's disease over the study interval among supplement users versus nonusers to come to their conclusions.
Researchers believe the most effective doses were vitamin E in liquid capsules of 400 to 1,000 International Units and vitamin C in pill form of 500 to 1,500 milligrams.
If you want to take Vitamin E to reduce your risk of Alzheimer's Disease then be aware that it is best to take E with oil and perhaps a food grain for maximum absorption. (same article here)
The pill of 400 I.U. vitamin E taken with just a glass of milk, in theory should have provided more than 13 times the RDA of this nutrient. But, in fact, it raised the level of new vitamin E in the blood by only 3 percent. By comparison, the cereal fortified with 30 I.U. vitamin E raised the blood plasma level of new vitamin E five times higher than that, and the cereal fortified with 400 I.U. raised the new blood plasma level 30 times higher.
The effect of a pill of 400 I.U. taken with a serving of plain wheat cereal was inconsistent; some participants had a significant increase in blood plasma levels of vitamin E, others almost none. "This study clearly showed that applying vitamin E onto a grain cereal provided a huge and consistent increase in its bioavailability," said Scott Leonard, an LPI research assistant who conducted the study. "Even 30 I.U., the RDA for this vitamin, produced a large increase in new blood plasma levels."
Vitamin E with pasta and a pasta sauce with oil would probably be a great way to maximize absorption.
"This model embraces the human brain as a high-speed Internet rather than a computer. The quality of the Internet's connections is the key to its speed, fidelity and overall capability," said Dr. George Bartzokis, the author and visiting professor of neurology at UCLA's David Geffen School of Medicine. He also is director of the UCLA Memory Disorders and Alzheimer's Disease Clinic and Clinical Core director of the UCLA Alzheimer's Disease Research Center.
As the brain continues to develop in adulthood and as myelin is produced in greater and greater quantities, cholesterol levels in the brain grow and eventually promote the production of a toxic protein that attacks the brain. The protein attacks myelin, disrupts message transfer through the axons and eventually leads to the brain/mind-destroying plaques and tangles visible years later in the cortex of Alzheimer's patients.
Bartzokis' analysis of magnetic resonance images and post-mortem tissue data suggests that genetic factors coupled with the brain's own developmental process of increasing cholesterol and iron levels in middle age help degrade the myelin. The papers describe how complex connections that take the longest to develop and allow humans to think at their highest level are among the first to deteriorate as the brain's myelin breaks down in reverse order of development.
"The body was designed to myelinate through the natural lifespan. Medical advances, however, have expanded the lifespan well beyond the brain's natural capacity to operate in a healthy, efficient manner," Bartzokis said. "The process of adult brain development and becoming 'wiser' has this downside that evolution could not anticipate."
This new model of brain development and degeneration suggests that the best time to address the inevitability of myelin breakdown is when it begins, in middle age. By the time the effects of Alzheimer's disease become apparent in a patient's 60s, 70s or 80s, it may be too late to reverse the course of the disease.
Preventive therapies worth investigating include cholesterol- and iron-lowering medications, anti-inflammatory medications, diet and exercise programs and possibly hormone replacement therapy designed to prevent menopause rather than simply ease the symptoms. In addition, education or other activities designed to keep the mind active may stimulate the production of myelin. Finally, there may be ways to address genetic and environmental factors that accelerate the degeneration process.
The brain is probably going to turn out to be the most difficult organ in the body to develop therapies for to stop and reverse aging. For many organs the solution will simply be to grow replacements. But your brain is your identity. Swapping out the brain defeats the whole purpose of trying to delay aging and death.
Repairing the brain in place will be helped by the eventual ability to deliver replacement stem cells into the hippocampus to replaced aged reservoirs of stem cells. But we also need gene therapies that can be delivered to neurons throughout the brain to do repairs on individual cells. The development of those therapies may take 10, 20, or even 30 or more years.
In the mean time it would be helpful to have better ways to slow down brain aging. Lowering blood LDL cholesterol and raising blood HDL cholesterol would both likely slow brain aging. While there are drugs for lowering overall cholesterol so far we have no good way to raise HDL cholesterol aside from exercise and healthier living (aside: having a dog that wants to be run every day has done more to make me exercise than anything else I've tried). Also, the development of pharmaceuticals that would reduce the stress on the brain (both emotional and due to free radicals and other compounds in the blood) is another potential avenue of attack.
The ability to prevent brain deterioriation would have enormous beneficial economic consequences. Brain work makes up an increasing fraction of the economy as so many manual tasks are automated. A delay in the decay of the mental abilities of middle aged and elderly people would boost their productivity and allow them to work for more years. Western countries faced with aging populations ought to spend more money on research aimed at slowing and reversing brain aging. The cost of the research will be paid back many times over through increased productivity, longer work lives, and avoidance of costs for care of mentally incapacitated elderly.