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Alzheimer's Disease

On November 5th, 1994, the former 40th president of the United States, Ronald Reagan, issued the following statement in a handwritten letter addressed to the American public:

“My fellow Americans,

I have recently been told that I am one of the millions of Americans who will be afflicted with Alzheimer's disease. Upon learning this news, Nancy and I had to decide whether as private citizens we would keep this a private matter or whether we would make this news known in a public way. In the past, Nancy suffered from breast cancer and I had cancer surgeries. We found through our open disclosures we were able to raise public awareness. We were happy that as a result many more people underwent testing. They were treated in early stages and were able to return to normal, healthy lives. So now we feel it is important to share it with you. In opening our hearts, we hope this might promote greater awareness of this condition. Perhaps it will encourage a clear understanding of the individuals and families who are affected by it. At the moment, I feel just fine. I intend to live the remainder of the years God gives me on this earth doing the things I have always done. I will continue to share life's journey with my beloved Nancy and my family. I plan to enjoy the great outdoors and stay in touch with my friends and supporters. Unfortunately, as Alzheimer's disease progresses, the family often bears a heavy burden. I only wish there was some way I could spare Nancy from this painful experience. When the time comes, I am confident that with your help she will face it with faith and courage. In closing, let me thank you, the American people, for giving me the great honor of allowing me to serve as your president. When the Lord calls me home, whenever that may be, I will leave the greatest love for this country of ours and eternal optimism for its future. I now begin the journey that will lead me into the sunset of my life. I know that for America there will always be a bright dawn ahead.

Thank you, my friends.

Sincerely,
Ronald Reagan”

Former U.S. President Reagan died of Alzheimer’s on June 5th, 2004, at the age of 93, approximately ten years after having been diagnosed with the disease.

During his presidency, prior to his knowledge that he would be stricken with this disease himself, Ronald Reagan made no less than 8 formal statements on Alzheimer’s, referring to it as an “indiscriminate killer of mind and life” and a “devastating” illness that “deprives its victims of the opportunity to enjoy life.” He correctly acknowledged the disease as ranking “among the most severe of afflictions, because it strips people of their memory and judgment and robs them of the essence of their personalities.” Without yet knowing that he, himself, would be subject to such symptoms, President Reagan correctly declared that, “Slowly, victims of the disease enter profound dementia.”

Indeed, Ronald Reagan’s acknowledgment that he was entering “the sunset of my life” is applicable today for the approximately 5.1 million Americans who share the same fate from the same disease. It has been estimated that someone in the United States is diagnosed with Alzheimer’s disease every 72 seconds, and direct medical expenses incurred by Alzheimer’s patients in the U.S. alone are measured in the billions of dollars. Of all the various types of dementia, Alzheimer’s is the most common, accounting for as much as 70% of all cases. (From www.alz.org).

In addition to U.S. President Ronald Reagan, many other prominent individuals have suffered with Alzheimer’s disease, including the former Prime Minister of Britain, Harold Wilson, the choreographer George Balanchine, the composer Aaron Copeland, and the actress Rita Hayworth.

Rita Hayworth’s daughter, the Princess Yasmin Aga Khan, has established the “Rita Hayworth Gala” in honor of her mother. Since its founding in 1985, this annual event has raised more than $47 million to support Alzheimer’s research. Additionally, Princess Yasmin has also established a worldwide network for the coordination of Alzheimer’s disease research. More information is available at www.wic.org/bio/pkhan.htm.

Characteristics:

Alzheimer’s disease is characterized by very specific neurological abnormalities, which ultimately result in very specific types of behavioral abnormalities.

Neurologically, there are 3 main identifying features of Alzheimer’s disease:

1/ beta-amyloid plaques, which form outside and around neurons,
2/ neurofibrillary tangles, which form inside dead neurons, and
3/ overall dramatic shrinkage of neural tissue.

The “plaques” and “tangles” in particular have come to be regarded as the hallmarks of Alzheimer’s, although it is not yet known whether these features are a cause of the disease or merely a byproduct of it. The gross atrophy of the brain that is seen in advanced stages of Alzheimer’s is a result of the widespread death of neuronal cells. In severe cases the brain may be reduced by as much as a third of its normal size.

Behaviorally, the symptoms of Alzheimer’s disease are often mistaken in the early stages for a normal part of the aging process. However, Alzheimer’s does not represent normal aging.

The website of the National Institute of Neurological Disorders and Stroke (NINDS), a branch of the National Institutes of Health (NIH), offers the following definition:

“Alzheimer's disease is a progressive, neurodegenerative disease characterized in the brain by abnormal clumps (amyloid plaques) and tangled bundles of fibers (neurofibrillary tangles) composed of misplaced proteins.” (From www.ninds.nih.gov).

From the same website, NINDS researchers add,

“There is no cure for Alzheimer’s disease and no way to slow the progression of the disease.”

Similarly, the precise causes of Alzheimer’s are not known with certainty, although various genetic as well as environmental factors seem to be involved.

Background and History:

Alzheimer’s disease bears the name of its discoverer, the German physician Alois Alzheimer, who first noted the symptoms of this disease in a 51-year-old patient named “Auguste”. Dr. Alzheimer first saw Auguste in 1901, at which time her symptoms did not seem to fall into any known classification of diseases. Increasingly plagued by mental confusion, disorientation, memory loss, a paranoiac suspicion of others and difficulty with verbal expression, Auguste died bedridden and mute after 4 years of decline. When Dr. Alzheimer performed an autopsy on her, he noted a dramatic shrinkage of her brain along with 2 types of neurological deposits that he had never before seen. In 1906 he presented his findings at a medical meeting in Tubingen, Germany, at which he stated that, “All in all, we are faced obviously with a peculiar disease process.”

These 2 types of unprecedented neurological deposits which Dr. Alzheimer was the first to document are today known as the “plaques” and “tangles” that are characteristic of this disease.

Over a century later, although much progress has been made in unraveling the mystery of Alzheimer’s, medical science continues to be puzzled by its precise causes.

Approximately 37 million people worldwide suffer from various forms of dementia, with Alzheimer’s disease constituting the majority of cases. It has been estimated that 18 million people throughout the world are afflicted with Alzheimer’s, and that figure is expected to double by the year 2025. Although Alzheimer’s is often associated with industrialized societies, currently over half of all people who suffer with this disease are reportedly living in developing nations.

Age is considered to be the greatest “risk factor” for Alzheimer’s, as the number of people diagnosed with the disease doubles for every 5 years beyond the age 65. While only approximately 5% of men and 6% of women have developed Alzheimer's by the age of 65, approximately half of all people over the age of 85 are believed to have the disease, according to the National Institute of Aging (NIA), a division of the National Institutes of Health (NIH). Of the 5.1 million Americans officially diagnosed with Alzheimer’s as of 2007, approximately 4.9 million of these people are over the age of 65, although an additional 200,000 Americans have been diagnosed with the early-onset form of Alzheimer’s, which occurs prior to the age of 65. The early-onset form of the disease is relatively rare, however, and it is the “late-onset” form of Alzheimer’s which constitutes the vast majority of cases. (From www.nia.nih.gov).

According to the U.S. Centers for Disease Control and Prevention (CDC), Alzheimer’s was officially reported as the “underlying cause of death” for 65,829 Americans in 2004, ranking as the 7th leading cause of death in the U.S., and the 5th leading cause of death for all people age 65 or older in the United States. As populations age, and as the percentage of populations over the age of 80 continues to increase, especially in developed countries, it is estimated that by the year 2050 there will be 20 million people with Alzheimer’s disease in the United States alone. (From www.cdc.gov).

The World Health Organization (WHO) has estimated that in the year 2000, the direct national economic cost of Alzheimer’s disease in the U.S. alone was approximately $536 billion, while the total cost, combining direct medical expenses with all other indirect expenses, was approximately $1.75 trillion. (From www.who.int). Clearly, Alzheimer’s is one of the most devastating of all diseases, not only upon individual lives but also upon national economies.

The Neuroscience of Memory and Cognition:

Although the precise causes of Alzheimer’s disease are yet to be discovered, researchers are continually learning more about the neurological processes themselves which characterize Alzheimer’s disease.

A basic understanding of the physiology of the brain will thus enhance one’s understanding of the symptomology of Alzheimer’s, and of the progression thereof.

The average adult brain contains approximately 100 billion neurons that are interconnected with each other throughout an extensive “neural network” by approximately 100 trillion synapses, or connecting points, across which electrochemical signals are transmitted. From neuronal cell to neuronal cell, these signals flow in constant activity, the dynamic patterns of which create our thoughts, skills, memories and indeed the very personalities and identities that are associated with our lives. The cellular basis of even the simplest of memories consists of these neural patterns: specific networks of electrically firing synapses which create specific processes of cognition, and across which neurotransmitters such as acetylcholine are conveyed. Neurotransmitters play an important role in such processes, especially acetylcholine, which acts not only as a neurotransmitter but also as a neuromodulator, being a key component of synaptic “plasticity” and of the rewiring and reenforcement of newly developed neuronal connections that are constantly being established in learning and cognitive development.

Every thought, memory and skill, whether physical or mental in nature, such as an intellectual aptitude, the ability to play a musical instrument, or even an athletic talent, is encoded at the cellular level in the particular patterns that are formed by the interconnecting neuronal and synaptic networks of the brain. Such networks are as much electrochemical in nature as they are physical, since they consist not merely of neurons but also of neurotransmitters and electrical signals firing across synapses. These neural networks are by necessity highly “plastic” and dynamic in nature, since their constant ability to change and to establish new connections is what allows for the normal cognitive processes of learning new tasks or of remembering new information. Newly formed “networks”, or patterns of synaptic firing activity, may be strengthened and reenforced by experience, but even in healthy individuals such networks will eventually deteriorate, as will the particular corresponding skill, thought or memory associated with each network, if not exercised.

When this cellular basis of our cognitive processes is strengthened, so are the corresponding cognitive processes. Likewise, when the cellular basis of our cognitive processes deteriorates, so do the corresponding cognitive processes. If there is an increase in the number and strength of synaptic connections throughout the brain’s neural networks, the corresponding cognition will become more robust; conversely, if there is a decrease in the number and strength of synaptic connections throughout the brain’s neural networks, the corresponding cognition, such as the associated thoughts, skills and memories, will also decline.

In the first stages of Alzheimer’s disease, it is the electrochemical signals ordinarily transmitted between synapses which begin to decline, after which the number of synaptic connections themselves begins to decline, after which the neurons begin to die. In the advanced stages of Alzheimer’s disease, the dramatic atrophy of the brain that is visible is a result of this widespread death of neuronal cells. The characteristic “debris”, such as the plaques and tangles, that are scattered throughout the remaining tissue, are also recognizable. Thus the presence of Alzheimer’s disease is verifiable by postmortem inspection of neural tissue via an autopsy, and in fact this is the only definitive way in which to determine the presence of Alzheimer’s disease.

When neurons begin to die, and the interconnected networks of synapses are broken, the results are outwardly noticeable, depending on the particular areas of the brain that are affected. If the deteriorating neurons are located in the cerebral cortex, for example, skills such as language, reasoning and judgment will be seen to decline in the person. Similarly, if the deteriorating neurons are located within the hippocampus, memory recall will be seen to fail. In the advanced stages of Alzheimer’s disease it is not uncommon for all areas of the brain to have been ravaged by extensive neuronal death.

Researchers are working to determine the causes of beta-amyloid production, as well as the mechanisms by which the tau protein twists into “tangles”. Of particular scientific interest are the brain’s built-in natural processes for discarding such misplaced proteins, and researchers are hoping to discover possible ways of stimulating these natural “cleansing” mechanisms of the brain. Scientists are also studying various metabolic byproducts that contain highly reactive oxygen, and the processes by which such byproducts are formed, since the neural tissue of Alzheimer’s patients typically exhibits signs of severe oxidative stress.

An interactive “tour” of the brain, showing the functions that correspond to particular neurophysiological regions, may be viewed at the website of the Alzheimer’s Association:

www.alz.org/alzheimers_disease_4719.asp

Similarly, a “Whole Brain Atlas” developed by Harvard Medical School may be viewed at their website:

www.med.harvard.edu/AANLIB

And an “interactive brain map” developed by the BBC (British Broadcasting Corporation) may be viewed on their website:

www.bbc.co.uk/science/humanbody/body/interactives/organs/brainmap

Causes:

The precise causes of Alzheimer’s disease are believed to involve a complex interaction of genetic and environmental factors, as no one particular etiology has been identified that would explain all cases.

It is not known, for example, what triggers production of the beta-amyloid protein fragments in some individuals and not in others, but whatever the cause or causes may be, once this protein is produced, a cascading series of events is set into motion which ultimately results in neuronal death. Electrochemical signals that would normally be transmitted across synapses are jammed by these microscopic plaques, neuronal circuitry is thereby disrupted and disabled along with its corresponding cognitive functions, and neuronal tissue degenerates. Nor are the precise mechanisms known by which the tau protein forms into twisted “tangles” within the dying neurons, but once this process has begun, neuronal death is assured.

As already mentioned, inflammation and oxidative stress have been found in the brain tissue of Alzheimer’s patients, and the possible causes of such physiological abnormalities remain topics of intense research activity. Because of the common association of cellular stress with diet and environmental factors, even in healthy individuals, there is a growing belief that diet and the environment may constitute certain risk factors for Alzheimer’s disease. There is also increasingly strong evidence to indicate that some of the same risk factors associated with heart disease and stroke may also increase the risk of Alzheimer’s disease, such as high blood pressure, high cholesterol, and physical inactivity.

The vitamin folate (the anion form of folic acid) is known to offer protection against a variety of neurological and cardiovascular disorders, so this and other nutrients are being studied for their possible beneficial effects in preventing Alzheimer’s in people who have not yet developed the disease.

Additionally, there is increasing data to suggest that social activity and stimulation, including both mental and physical exercise, may also serve as protective factors against Alzheimer’s in people who have not yet developed the disease.

Although some genes have already been identified with Alzheimer’s disease, it is believed that several other genes, not yet discovered, may also be involved, and scientists suspect that together these genes may interact with non-genetic factors, such as environmental agents or conditions, to trigger the actual manifestation of the disease.

In fact, as with any disease, the field of genetics offers a wealth of information and insight into the molecular processes at work, and Alzheimer’s disease is no exception. Investigations into the genetic characteristics of this disease therefore constitute a major focus of research throughout the world.

Genetics:

Three genes have been discovered that are involved in causing the early onset (or “familial”), form of Alzheimer’s, namely, the APP (amyloid precursor protein) gene, the PS1 (presenilin 1) gene, and the PS2 (presenilin 2) gene. A mutation in any one of these genes will be inherited in an autosomal dominant manner, meaning that only one copy of the mutated gene is sufficient for developing the disease. Six mutations have been found in the APP gene, the most common one having been discovered in 16 families of Japanese and European descent, while the other 5 mutations have so far been found only in one family. More than 40 different mutations have been discovered in PS1, and people who inherit a copy of any one of the possible mutated forms of this gene typically develop Alzheimer’s disease between the ages of 29 and 62. Mutations in PS2 are extremely rare. The normal roles of the non-mutated forms of the PS1 and PS2 genes in healthy individuals are not yet known. The early-onset forms of Alzheimer’s disease are relatively rare, however, and all known mutations in these 3 genes only account for approximately 5% of all cases.

The much more common age-related, late-onset (or “sporadic”) form of Alzheimer’s disease has been most clearly associated with three mutations in a single gene that is now known to cause excessive accumulation of the beta-amyloid protein. The apoE (apolipoprotein E) gene normally plays an active role in healthy individuals in a number of physiological and metabolic processes that include cholesterol transport, immune regulation and nerve regeneration, among other functions, but in its mutated forms the apoE gene has been well studied for its link to late-onset Alzheimer’s disease. These mutations account for only approximately 15% of all late-onset cases, however, and scientists therefore suspect that other genes, yet to be discovered, may ultimately be implicated in the development of this most common form of the disease.

Three isoforms of the apoE gene, namely, apoE2, apoE3, and apoE4, have been shown to play distinctly different roles in the development of the late-onset form of Alzheimer’s disease. Specifically, apoE4 has been associated with a higher incidence, and an earlier age of onset, while the apoE2 protein has been shown to have the opposite association, and is believed to exhibit a protective effect against the development of the disease.

Everybody inherits 2 forms of the apoE gene, one from each parent, but people who inherit only one copy of the apoE4 mutation, from only one parent, exhibit a three-fold risk of developing Alzheimer’s later in life, while those people who inherit two copies of the apoE4 mutation, one from each parent, exhibit a tenfold risk of developing Alzheimer’s disease. Although the apoE4 mutation has been found to occur in 10 to 25% of the general population, and in 40% of people with late-onset Alzheimer’s disease, some people who inherit this mutated gene will never develop Alzheimer’s at all. Nevertheless, apoE4 has also been found to be associated with altered brain activity and impaired neuronal development in adults, and this particular mutation remains an area of widespread research interest. The reader is referred to the section entitled “Future Research Directions” for a more detailed elucidation of these genetic isoforms.

Symptoms:

Alzheimer’s disease manifests itself by a progressive decline in cognitive abilities such as memory, comprehension, language expression, learning capacity, calculation, abstraction, judgment, spatial orientation and the recognition of familiar people or places.

Although the specific symptoms that are most pronounced may differ with each individual, a basic pattern is common to all, as are the stages of progression of the disease. The disease usually begins slowly, and can take anywhere from 5 to 20 years to reach the advanced stages.

The initial stages are typically characterized by a difficulty remembering new information, which is followed in later stages by confusion and disrupted thinking which occur with increased regularity. Physical disorientation usually begins in the earlier stages of the disease, although impaired judgment, an inability to concentrate and difficulty with verbal expression may not become noticeably problematic until the intermediate stages.

As the neural circuitry of the brain is increasingly disrupted and neurons deteriorate more extensively, people with advanced Alzheimer’s may ultimately be unable to recognize even close family members, they may completely lose the ability to communicate, and they often become bedridden.

According to the Alzheimer’s Association, individuals with Alzheimer’s “may also experience changes in personality and behavior, such as anxiety, suspiciousness or agitation, as well as delusions or hallucinations.” (From www.alz.org).

Although infection is the most common cause of death among Alzheimer’s patients, the disease itself is ultimately fatal.

Diagnosis:

Since a specific diagnostic test for Alzheimer’s disease does not exist, doctors must rely upon general physiological as well as neuropsychological tests, medical history, and brain scans to arrive at a “probable” diagnosis, or what is often called a “diagnosis by exclusion”.

The highest rate of accuracy in diagnosing Alzheimer’s disease may be found at various medical centers that specialize in Alzheimer’s diagnosis, where physicians attain a 90% accuracy rate in diagnosing the disease.

In its early stages Alzheimer’s is similar to a medically unrelated disorder known as “mild cognitive impairment” (MCI), which also differs somewhat from normal age-related memory changes, but which may develop into Alzheimer’s disease over time. Physicians should be consulted in order to distinguish between Alzheimer’s disease, MCI, and symptoms of ordinary aging which are unrelated to any disease.

Medical specialists, such as neurologists or psychiatrists, who are trained in evaluating memory disorders, may offer comprehensive evaluations that measure one’s capacity for problem solving, language, counting, abstraction, memory and attention. Blood, urine and spinal fluid may also be evaluated in an effort to rule out other diseases. Still, even with the most thorough of evaluations, some degree of error and uncertainty always exists.

It is not uncommon for such routine tests to reveal the causes of Alzheimer-like symptoms that are not in fact related to Alzheimer’s disease. At least in the initial stages, Alzheimer-like symptoms may be caused by a variety of other disorders such as thyroid problems, adverse drug reactions, depression, brain tumors, and various blood vessel or other neurovascular disorders. In such cases, the causes of the symptoms may be easily treatable.

Since the hippocampus and the frontal lobes of the cerebral cortex are most noticeably atrophied by Alzheimer’s disease, as these regions typically reveal a selective loss of cholinergic neurons throughout their pathways, it is possible that cerebral blood flow studies may be able to detect such abnormalities, depending on the stage of the disease. In the latter stages, the ventricular dilation and overall reduced volume of the brain may also be detectable via certain imaging techniques. In some cases it is also possible that electroencephalography (EEG) may show a slowing of the beta waves in the advanced stages of the disease, the beta waves of the brain being defined as those frequencies that are normally above 12 Hertz.

The accuracy and applicability of various imaging technologies in detecting the neuroanatomical changes that are caused by Alzheimer’s disease is a topic of research unto itself, since such changes in physiology are not always visible on brain scans. A reliable method of imaging would be a very useful, and much needed, diagnostic tool, but it is not yet clear whether magnetic resonance imaging (MRI) and positron emission tomography (PET) scans will be refined to the level of detail and precision that are required for an accurate Alzheimer’s diagnosis. The National Institute of Aging (NIA), a division of the National Institutes of Health (NIH), is therefore engaged in a large scale study to investigate the next steps that would be required in developing these technologies further.

Treatment:

Since there is no recognized cure for Alzheimer’s disease, conventional medical treatment has typically consisted primarily of drug therapy which is prescribed with the hope of managing symptoms, although such medication does not alter the progression of the disease itself.

For people in the early and middle stages of the disease, donepezil (Aricept), rivastigmine (Exelon) and galantamine (Razadyne, previously known as Reminyl prior to 2005) are typically prescribed. A fourth medication, tacrine (Cognex), was commonly prescribed in the past but is no longer marketed since it has been associated with liver toxicity.

While the other medications have not been linked to liver toxicity, they are, like all drugs, metabolized in the liver, and therefore may possibly interfere with the metabolism of other drugs, possibly increasing the risk of side effects from other medications that are taken simultaneously.

Donepezil was expected to be marketed in Europe as well as in the U.S., but in early 2007 the manufacturer withdrew the application from the European Agency for the Evaluation of Medicinal Products (EMEA).

Galantamine is extracted from the bulb of some types of daffodils, and is not recommended for people with liver, kidney or heart problems, stomach or duodenal ulcers, epilepsy, respiratory disease, bladder disease or galactose intolerance.

All 4 of these medications fall into a class of drugs known as cholinesterase inhibitors, which work by inhibiting the breakdown of acetylcholine in the brain. More specifically, these drugs block acetylcholinesterase, which is the enzyme responsible for the destruction of the neurotransmitter acetylcholine. By inhibiting this enzyme, these drugs cause an increase in the concentration of acetylcholine in the brain, which leads to some noticeable improvement in mental concentration for some Alzheimer’s patients. These drugs do not, however, stop the formation of plaques or tangles in the brain, nor are they capable of regenerating dead neurons, nor do the manufacturers make any such claims. The benefits of these drugs are strictly seen as offering a temporary means of delaying the inevitable severity of symptoms.

As with any medication, patients should discuss possible contraindications with their physician, as well as possible side effects which, for cholinesterase inhibitors, may include abdominal pain, chest pain, muscle pain, headaches, clumsiness, unsteadiness, dizziness, confusion, digestive problems, pulmonary problems, respiratory problems, liver problems, kidney problems, genitourinary problems, infections, depression, anxiety, insomnia, indigestion, vomiting, loss of appetite, loss of weight, fatigue, sleeplessness, and inflamed nasal passages.

A fifth drug, memantine (Namendal) has been approved for moderate stages of Alzheimer’s disease in the U.S., and when combined with donepezil both drugs were found to be more effective than either drug prescribed separately. Memantine falls into a different class of drugs than the other medications, and rather than inhibiting cholinesterase, memantine’s method of action involves blocking the activation of NMDA-R (the N-methyl-D-aspartate receptor), which is an amino acid receptor and membrane calcium channel that acts as a mediator in cellular excitotoxicity, overstimulation of which triggers cell death. The properties of NMDA-R are important for neuronal plasticity, and dysfunction in NMDA-R is believed to be involved in a number of neurological disorders.

Since inflammation seems to be a factor in Alzheimer’s disease, it was thought that nonsteroidal anti-inflammatory drugs (NSAIDs) might be able to help slow the progression of the disease by alleviating the inflammation. Results from clinical trials, however, have not demonstrated a benefit from such medications. One clinical trial testing both refecoxib (Vioxx) and naproxen (Aleve) showed strong evidence that neither drug delays the progression of Alzheimer’s disease, and another clinical trial which tested the NSAIDs celecoxib (Celebrex) and naproxen was suspended for adverse side effects that included a potential cardiovascular risk. The exact role of inflammation in Alzheimer’s disease has yet to be determined, although researchers are hopeful to discover an anti-inflammatory drug that might delay the progression of the disease.

Because oxidative stress is often found in the neurological tissue of Alzheimer’s patients, antioxidants are believed to offer a potential protective measure against the development of Alzheimer’s disease. Vitamin E (tocopherol) was shown in a clinical trial to slow the progression of Alzheimer’s by approximately seven months once the disease has already been diagnosed, and it is believed that vitamin E in combination with vitamin C (ascorbic acid) and the trace mineral selenium may help to prevent Alzheimer’s in people who have not yet developed the disease.

Additional studies are ongoing to assess the potential protective effects of ginko biloba and estrogen, although women who use hormone replacement therapy that includes progestin as well as estrogen were found to be at a greater risk of developing various types of dementia, of which Alzheimer’s disease is just one.

Future Research Directions:

Since processes of memory, in all of their myriad varieties, constitute the main, central concern in Alzheimer’s disease, most research has evolved in directions that will help improve our knowledge and understanding of the neurophysiological mechanisms that are associated with memory. Alzheimer’s research therefore branches out from 2 general disciplines, namely, genetics and neurology.

In genetics, researchers are investigating the particular genes that are active during normal, healthy neurological function, and the mutated genes that are associated with the type of neurological decline that is common among Alzheimer’s patients. Scientists hope that more genetic similarities might be discovered among people who suffer with Alzheimer’s, and that these discoveries will lead to a better understanding of the mechanisms by which such genes are expressed. It is also hoped that those mutated genes already identified in certain forms of Alzheimer’s disease may be better understood in their non-mutated forms, such as the PS1 and PS2 genes, the normal roles of which, in healthy individuals, are not yet fully understood.

In the field of neurology, scientists are pursuing a variety of novel approaches for delving into the intricacies of the brain. Newly formed neurons are studied for the ways in which they get “recruited” into memory storage, modified viruses are being used to map the neuronal circuitry of the brain, and the technology of protein imaging is being further developed and refined. There are also many applications in neurology for the exciting new field of bio-nanotechnology, in which scientist are using self-assembling nanostructures to repair neural tissue. As one of the most interdisciplinary of fields, neurology also engages the talent and resources of chemists, immunologists, molecular biologists, mathematicians, software engineers and specialists from other fields who are collaborating in ongoing research into Alzheimer’s disease. Some examples of their findings are included herein.

Researchers at the University of Illinois at Urbana-Champagne have determined that a protein which is known primarily for its ability to kill cells also plays an important role in memory function. The caspase-3 enzyme, which is fundamental to apoptosis (programmed cell death) has also been found to trigger a synaptic process that is involved in memory storage, and when activated, the caspase-3 enzyme sets in motion a series of synaptic events that constitute the formation of memory. Although caspase-3 is best known for its role in the biochemical cascade that eventually leads to apoptotic cell death, the results of this research indicate that the behavior of the enzyme is different under different conditions. By understanding the specific signals that activate this and other enzymes to behave in different ways at different times, researchers are hoping to be able to control some of the mechanisms of neural regulation that malfunction in neurodegenerative diseases such as Alzheimer’s. The research was reported in the journal Neuron.

Researchers at UCLA and the University of Toronto have collaborated in a study of memory formation in an animal model, from which they discovered that the protein CREB is responsible for controlling whether or not any particular neuron will be recruited in the formation of a new memory. CREB (cAMP response element-binding) proteins are transcription factors which either increase or decrease the transcription of genes, and which are also used by the brain in its designation of cells for the encoding of memories. The study was led by Dr. Alcino Silva, the principal investigator in this research, a professor of neurobiology and psychiatry at the David Geffen School of Medicine at UCLA and a member of the UCLA Brain Research Institute. As Dr. Silva explains, “Making a memory is not a conscious act. Learning triggers a cascade of chemicals in the brain that influence which memories are kept and which are lost. Earlier studies have linked the CREB protein to keeping memories stable. We suspected it also played a key role in channeling memories to brain cells that are ready to store them.” The amygdala was of particular interest in this study, since it is a region of the brain that is critical to emotional memory. The scientists therefore tracked a genetic marker that reveals recent neuron activity throughout the amygdala, and they found that cells which contain low levels of CREB are unlikely to store a memory, whereas cells which contain high levels of CREB have a higher likelihood of storing a memory. Specific regions of the brain in which memories are stored could therefore possibly be determined by a controlled manipulation of CREB levels. Dr. Silva adds, “Our memories define who we are, so learning how the brain stores memory is fundamental to understanding what it is to be human. A memory is not a static snapshot. Memories serve a purpose. They are about acquiring information that helps us deal with similar situations in the future. What we recall helps us learn from our past experiences and better shape our lives.” The findings, which were reported in the April 20th, 2007 edition of Science, have potential application in preserving the memories of people suffering from Alzheimer’s disease and other brain disorders.

In a related study, other scientists in Toronto have further elucidated the process by which newly generated neurons are selected during the formation and recall of memories. Rather than focusing on the amygdala, however, this study focused on the hippocampus, which, like the amygdala, is part of the limbic system and therefore is also involved in emotional memory and spatial navigation. Furthermore, the hippocampus is one of the first regions of the brain to deteriorate in Alzheimer’s patients. This particular study examined the expression of proteins that are activated in the mouse hippocampus when new synapses are formed. The scientists discovered that by the 4th week these newly developed neurons are more likely than are older cells to be activated when the mice perform a spatial learning task. Once successfully incorporated into memory-related neural circuits, the neuronal cells were then preferentially reactivated whenever the animals were tested for their ability to recall previously learned spatial locations. Preferential activation was found to decline by the 8th week, however, by which time the new cells were no more likely to be recruited than were the older cells. Since new neurons are constantly being formed for learning processes, even in the adult brain, such results have widespread applications to a variety of neurological disorders. The results were published in the journal Nature Neuroscience.

At Carnegie Mellon University in Pittsburgh, Pennsylvania a team of researchers has created a “computational approach” for providing a rapid way to identify the genes that are involved in learning processes. The scientists have identified the genes that are activated during learning and which alter the neuronal activity of the brain, disruptions in the normal gene expression of which may result in seizures or epilepsy. “The work could ultimately lead to the development of drugs to treat neurological disorders,” according to Alison Barth, assistant professor of biological sciences and a member of the university’s Center for the Neural Basis of Cognition. She further adds, “We also expect this work to provide a valuable platform for any investigator to understand how neurons change at the molecular level during learning and the formation of memory.” The results were published in the March 13th, 2007 issue of the journal Neuroscience.

Scientists at Purdue University have developed an inhibiting chemical that blocks the first step in a chain reaction that ultimately results in the formation of beta-amyloid plaques in the brain. The chemical consists of an enzyme known as memapsin 2, or beta-secretase, which inhibits the amyloid precursor protein that leads to the formation of plaques in the brain by specifically targeting memapsin 2, thereby blocking the reaction, and possibly preventing the disease. Researchers hope that this novel chemical may lead to a drug treatment specifically designed for Alzheimer’s disease. The findings were published in the Journal of Medicinal Chemistry in May of 2007.

At the University of Pennsylvania School of Medicine, researchers have reported in the journal Neuroscience that they have developed a method for imaging proteins as they move along the cell body of axons, which are the long extensions of the neurons. The “slow component-b” group of transport proteins are of particular interest, as both synuclein and tau are included in this group, each of which is involved in Alzheimer’s disease. There are 2 basic groups of transport proteins, namely, the “slow components” and the “fast components”, with a 200- to 300-fold difference between their velocities. While properties of the fast components have been elucidated in detail, the slow components are relatively unstudied and remain of particular interest for possibly revealing defects in axonal transport that occur in neurodegenerative diseases.

Researchers at the Salk Institute for Biological Studies in La Jolla, California have reported that they have successfully modified the rabies virus, such that this virus can be used as a “tool” which crosses a targeted synapse only once, and which thereby is capable of mapping out a “wiring diagram” of all the neuronal connections of the brain. The researchers are hoping that such a “map” will yield a more detailed understanding of the neurophysiological pathways of memory.

Other scientists at the Vision Center Laboratory of the Salk Institute have reported that the neurons of the visual cortex do not behave as static nerve cells, as previously thought, but instead alternate rapidly between different methods of collecting information from moving objects. Previously it was believed that two types of motion-sensitive neurons exist in the visual cortex, namely, those that integrate features belonging to a single moving object, and those that distinguish between features belonging to multiple objects. The Salk researchers have discovered neurons that are capable of performing both functions, although not simultaneously. These neurons exhibit the ability to switch between one type of function to the other type in a few milliseconds, depending on the nature of the stimulation received from the visual field. This newly discovered ability of neurons to alternate between functions, and to “choose” the type of tasks that they perform, according to the nature of environmental stimuli, may also hold profound implications for the treatment of neurodegenerative diseases such as Alzheimer’s.

Dr. Samuel Stupp, director of the Institute of BioNanotechnology in Medicine at Northwestern University, is involved in applications of nanotechnology to biology. Known as “bio-nanotechnology”, this new discipline has already shown promising results in animal models in which methods are employed for activating the body’s ability to heal itself. The principle involves injecting a nanomaterial that consists of molecules with self-assembling properties, such that these molecules do not actually form into the nanostructures until they are injected into the target tissue. Dr. Stupp specializes in “self-assembly”, which is itself a subdiscipline of growing popularity within nanotechnolgy. The process stimulates the body to regenerate its own damaged tissue and cells, and may have applications not only for the treatment of Alzheimer’s disease but also of Parkinson’s and other neurological disorders. Researchers in Mexico and Canada are also collaborating with Dr. Stupp on the use of bioactive nanostructures in combination with proteins to regenerate cardiac tissue and heart function. The research was presented at the Project on Emerging Nanotechnologies and was described in the new report, “NanoFrontiers: Visions for the Future of Nanotechnology.”

As previously mentioned, there are 3 isoforms of the apolipoprotein E gene, namely, apoE2, apoE3, and apoE4, which have been shown to play distinctly different roles in the development of Alzheimer’s disease. Namely, apoE4 has been associated with a higher incidence, and an earlier age of onset, for the “late-onset” or “familial” form of Alzheimer’s disease, while the apoE2 protein has been shown to have the opposite association, and a protective effect against Alzheimer’s disease. Drs. Aleshkov, Abraham and Zannis at the Boston University Medical Center have investigated the various roles of these apoE isoforms in modulating the formation of neurofibrillary tangles and amyloid deposits in the brains of Alzheimer’s patients, and indeed they have confirmed such findings which had already been established through population studies.

Further corroborating such research, scientists at the National Institute of Mental Health (NIMH), a division within the National Institutes of Health (NIH), have independently confirmed from magnetic resonance imaging (MRI) and other brain scanning techniques that the cortex of the brain is thinner in youth who have inherited the apoE4 mutation. In particular, it is the entorhinal cortex, a structure in the lower middle part of the brain’s outer mantle, which was found to be thinner, earlier in life, in people with the apoE4 gene, thereby rendering such individuals more susceptible to the degenerative features that are characteristic of Alzheimer’s disease later in life. As the main input to the hippocampus, the entorhinal cortex provides an important pathway in the brain’s memory structures, and it serves as an integral component of the limbic system. In people who develop Alzheimer’s disease, the entorhinal cortex is usually the first structure to shrink in volume and to develop the neurofibrillary tangles that are characteristic of the disease. In adults who have the apoE4 mutated gene, but who have not yet developed Alzheimer’s disease, it was already known that the entorhinal cortex is smaller and less active, although the variation does not seem to affect intellectual ability, nor does the thinning progress over time, but rather it appears to be stable. Long-term brain imaging, conducted over decades, would be necessary to determine whether this anatomical anomaly is in fact a biological marker for Alzheimer’s or not. Conversely, people who were known to have inherited the apoE2 isoform were found to have the thickest entorhinal cortex, and are believed to be less likely to develop Alzheimer’s disease later in life. The apoE2 isoform is estimated to occur in 5 to 10% of the population. The apoE3 isoform, which is the most common, has a prevalence in 65 to 85% of the population, and people with two copies of this gene exhibit average cortices of intermediate thickness. The apoE4 isoform is estimated to occur in 10 to 25% of the general population, but in 40% of all patients with late-onset Alzheimer’s disease. The apoE4 mutated gene was also found to be a reliable indicator of the thinning of two other regions of the brain, namely, the medial temporal and posterior orbitofrontal areas, both of which are known to be affected in the initial stages of Alzheimer’s disease and which, like the entorhinal cortex, are involved in learning and memory. Scientists are investigating whether these regions of the brain, which are so noticeably affected in Alzheimer’s disease, exhibit any irregularities in brain activity during learning and memory in children who carry these genes. This research was presented in the June 2007 issue of Lancet Neurology.

At the University of California at Irvine, researchers have discovered that omega-3 fatty acids may help slow or possibly prevent the neuronal degeneration that is typically found in Alzheimer’s patients. Known also as docosahexanoic acid, or DHA, this particular fatty acid is already recognized for its numerous beneficial effects and for its important role in a multitude of physiological processes, but this is the first study indicating that it may also offer a preventative measure against the development of Alzheimer’s disease. The study was led by Frank LaFerla, professor of neurobiology and behavior at UC-Irvine, who has stated, “We are greatly excited by these results, which show us that simple changes in diet can positively alter the way the brain works and lead to protection from Alzheimer’s disease pathology.” The study involved mice which had been genetically modified and bred to develop the plaques and tangles associated with Alzheimer’s disease, from which a control group of mice were fed a diet which mimicked that of the typical American, while another group of mice were fed a diet rich in DHA. It is not merely the absolute amounts but the ratio of fatty acids in one’s diet that is important, and an ideal ratio of omega-6 fatty acids to omega-3 fatty acids is considered to be between 3:1 and 5:1. The average American diet consists of a ratio that ranges between 10:1 and 30:1, although the diet that was fed to the mice was conservatively “American”, containing a ratio of 10:1. The results were nevertheless dramatic, as even in these amounts DHA was found to slow the progression of tau, which is the protein that causes the development of neurofibrillary tangles, and DHA was also found to reduce levels of beta-amyloid, which is the protein that forms the characteristic plaques of Alzheimer’s disease.

Previous studies have already shown that DHA may have therapeutic value for Alzheimer's patients, but this is the first study to indicate that DHA may possibly delay the onset of the disease. DHA was also found to lower levels of presenilin, a protein which is part of the gamma-secretase protease complex that mediates proteolysis of the beta-amyloid precursor protein to generate beta-amyloid. Without presenilin, therefore, the beta-amyloid plaques that are characteristic of Alzheimer’s disease cannot form in the brain. Omega-3 fatty acids are most commonly found in cold water fish, although supplements are also widely available. Omega-6 fatty acids are found in grains, some legumes and nuts and their oils, and the beef of grain-fed livestock. But diet is not the only preventative measure that may be taken against Alzheimer’s disease, as the investigators also found a preventative connection that results from mental activity and stimulation. Dr. LaFerla and his colleagues demonstrated that short but repeated learning sessions were able to slow the neurophysiological progression of Alzheimer’s disease in mice, suggesting that humans might also be able to delay the course of the disease by keeping their intellects as active as possible. Conversely, stress hormones such as adrenaline, noradrenaline (norepinephrine), and especially the glucocorticoid hormones cortisol and cortisone, when produced in excessive amounts for prolonged periods of time, were found to expedite the formation of plaques and tangles, having a rapidly exacerbating effect on the progression of Alzheimer’s disease. Although low levels of noradrenaline have been associated with Alzheimer’s disease by postmortem toxicology analyses, these low levels may be due to a loss of norepinephrine transporter sites located on the terminals of noradrenergic neurons in the locus coeruleus (Tejani-Butt, Yang, and Zaffar). While a certain amount of stress is healthy, desirable, and unavoidable, the deliberate management of such stress, and the avoidance of severe or prolonged stress, should be serious considerations for the Alzheimer’s patient. Dr. Kim Green, one of the investigators and a lead author of the study, summarized the data on DHA as follows: “Combined with mental stimulation, exercise, other dietary intakes, and avoiding stress and smoking, we believe that people can significantly improve their odds against this disease.” The findings were published in the Journal of Neuroscience.

The National Institute of Aging (NIA), a division of the National Institutes of Health (NIH), has sponsored a study to assess the genetic risk factors in Alzheimer’s by studying families in which two or more living siblings have been diagnosed with Alzheimer’s disease. People who may be interested in participating in this study may contact the National Cell Repository for Alzheimer’s Disease (NCRAD) through their website at http://ncrad.iu.edu.

Stem cells:

As a chronic, progressive, neurodegenerative disorder, Alzheimer’s disease is a prime candidate for adult stem cell treatment. Indeed, research has shown a variety of promising approaches to the treatment of this disease with adult stem cells.

As already described, Alzheimer’s is characterized by the destruction of neuronal circuitry which is the result of a buildup of beta-amyloid plaques in combination with the tangles that form from the tau protein. An effective treatment for Alzheimer’s disease, therefore, would be one which would prevent and reverse the formation of such plaques and tangles, while also regenerating lost neuronal connections. Thus far, the only therapy that offers the possibility of accomplishing these objectives is stem cell therapy.

At the University of Central Florida, researchers have demonstrated positive results in an animal model in which stem cells were transplanted from a patient’s blood and bone marrow as a treatment for Alzheimer’s disease. When enhanced with bromodeoxyuridine, which becomes integrated into the DNA of cells, the adult stem cells derived from human bone marrow were stimulated to differentiate into specific types of neural cells. With autologous transplantation (in which the donor and the recipient are the same person), the risk of immunological rejection does not exist.

Researchers are also studying the mechanisms by which dormant stem cells already present in the brain may be activated to regenerate local tissue. Potential “switches” within these stem cells have been identified, and a variety of means are being studied for the activation of such stem cells via the appropriate signals. Since endogenous stem cell activation is a noninvasive procedure which utilizes chemicals that specifically target the brain’s own stem cells, this method holds particular promise.

Adult stem cells already have a well-established history in regenerating the various types of specialized neural tissue, and such regeneration has been repeatedly documented for numerous neuropathologies. In the adult human brain, neural stem cells have been found in the subventricular zone and the subgranular zone of the hippocampal dentate gyrus, as well as throughout the adult human nervous system. Researchers have developed effective ways of stimulating the stem cells that already naturally exist in these regions, and transplantation, either with autologous or with carefully matched adult stem cells, has also yielded very positive results.

Research with neuroprotective factors, also known as trophic factors, has shown that the delivery of nerve growth factor (NGF) to specific areas of the brain already affected by Alzheimer’s disease may prevent further degeneration of such neural tissue. Research has also shown that stem cells may be genetically modified in the laboratory such that they may be used not only for their own regenerative properties but also as delivery vehicles for the NGF and for other agents, including genes.

Adult stem cells offer the same pluripotency of embryonic stem cells, but without the danger of forming teratomas (tumors), which remains a serious risk from embryonic stem cells. It is neither necessary nor desirable to use embryonic stem cells in the treatment of Alzheimer’s or other diseases, since a growing number of studies are showing increasing success with adult stem cells. In fact, the only stem cell studies that have ever shown success in the treatment of any human disease have involved adult stem cells, since no study has ever been conducted in which a disease was successfully treated with human embryonic stem cells, although this fact is not generally reported by the media. Ethics and politics aside, adult stem cells are highly preferable to embryonic stem cells purely for scientific reasons. (Please see the section entitled “Stem Cell Primer” for an explanation of the different properties of the different types of stem cells).

Adult stem cell therapy offers a safe and effective treatment for a disease which was previously considered to be irreversible. Not only for Alzheimer’s disease but also for other neurological disorders, adult stem cell therapy provides a healthy and efficacious alternative to drug-related therapies.

More information on Alzheimer’s disease is available from the following organizations:

Alzheimer’s Disease Education and Referral Center (ADEAR) -

National Institute of Mental Health (NIMH) - www.nimh.nih.gov

Alzheimer’s Association - www.alz.org

Alzheimer’s Foundation of America - www.alzfdn.org

Family Caregiver Alliance/National Center on Caregiving - www.caregiver.org

Association for Frontotemporal Dementias (AFTD) - www.FTD-Picks.org

C-Mac Informational Service/Caregiver News [For Alzheimer’s-Type Dementia Caregivers] - www.caregivernews.org

National Family Caregivers Association - www.the familycaregiver.org

Well Spouse Association - www.wellspouse.org

National Respite Network and Resource Center - www.archrespite.org

American Health Assistance Foundation - www.ahaf.org

National Hospice and Palliative Care Organization/Natl. Hospice Foundation - www.nhpco.org

Alzheimer’s Drug Discovery Foundation (formerly the Institute for the Study of Aging) - www.alzdiscovery.org

John Douglas French Alzheimer’s Foundation - www.jdfaf.org


 

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