Current Issues Involving Alzheimer’s Drug Research & Development.
Alzheimer’s disease (AD), the most common dementia, affects one in ten over 65 and half over 85. AD, a degenerative neurological condition, is characterized by the deposition of debris (amyloid plaques and neurofibrillary tangles) from neuron (brain cell) death plus another characteristic – demyelination or loss of insulation on electrical signaling ‘wires’ connecting the brain’s neurons.
AD is considered a neurodegenerative disease that is limited to the central nervous system. It is considered to be one of the most frequent causes of severe cognitive dysfunction in adults. It clinically manifests as a form of dementia leading to the loss of mental capacities, such as memory loss, ability to concentrate, and abstract and problem solving capabilities, leaving the individual disorientated and confused as the disease progresses. It is physically characterized by neuron degradation causing atrophy in the frontal and temporal lobes of the brain. The neuron degradation is most likely caused by the formation of senile plaques with amyloid deposits, neurofibrillary tangles (NFTs), and granulovacuolar degeneration. NFTs are most commonly known as a primary marker of Alzheimer’s disease.
The actual causes of AD continue to be the subject of aggressive research. Strong evidence exists that the disease has a genetic component based on incidence of familial dementias. This can be attributed to an inherited gene mutation and to the presence of genetic markers (e.g., ApoE4) – risk factors that make particular individuals more susceptible to developing AD. But genetics is not necessarily destiny. Newly understood factors can change the activation of gene expression such that it is not able to act as originally set. Environmental factors, such as how – and how much – the brain is ‘exercised’, how much of which kind of stress the brain is exposed to, as well as a variety of lifestyle factors from diet to drugs, and from memory skills training to sleep, for example, impact greatly on memory fitness in late life. Memory fitness can impact the path that age-related memory loss takes in any individual regardless of their genetic inheritance.
Therefore, developing – and maintaining – good memory fitness habits and consciously targeting personal optimal levels is an important ‘environmental’ (non-cognitive) consideration and should never be underestimated as a way to reduce the risk of dementia onset.
However, AD can also be attributed to various changes in an individual’s brain resulting in reduced production of the neurotransmitter acetylcholine that transmits electrical communication signals between neurons in and out of the central nervous system. Acetylcholine in the central nervous system is believed to be involved in learning and memory. Loss of acetylcholine results in reduced memory function. For lack of a better strategy, most of the currently available AD drugs boost the production of acetylcholine. This helps increase functionality of available neurons, producing symptomatic relief – depending on the level of degeneration — but is not a cure.
Boosting acetylcholine is the strategy on which currently approved drug therapies for AD were developed. The pharmaceutical industry characterizes currently marketed AD drugs as ‘treating the symptoms, not the cause’. The following descriptions are from material published by pharmaceutical manufacturers and are based on what is given to physicians treating patients with AD:
“Orally administered acetylcholinesterase inhibitors, such as rivastigmine (Exelon, Novartis) – indicated for the treatment of mild-to-moderate AD. Results of clinical trials of rivastigmine showed the drug provides cognitive and non-cognitive benefits, such as improved quality of life, increased independence and improvements in the ability to perform everyday tasks, and donepezil (Aricept, Eisai) – indicated for the treatment of moderate-to-severe AD, are both available worldwide. Also approved for the treatment of moderate-to-severe AD is memantine (Namenda, Forest Laboratories), which was the first NMDA receptor antagonist to be approved for this indication. The glutamate NMDA receptor, controls synaptic plasticity and memory function. The drug is considered to be only modestly effective.”
Modern drug development is very costly (industry estimates suggest amounts per successful drug can be as high as $800 million to $1 billion), time consuming (human clinical trials typically take 5 years or longer) and carry a high risk of failure. The last 10 – 15 years has seen significant increases in drug research around central nervous system diseases, including AD. While initially promising, many developmental molecules and compounds fail to prove effectiveness in late-stage human clinical testing for any number of reasons, such as incorrect dose for optimal effect. Once a human clinical trial is designed, it is virtually impossible to modify dosage. Early success with animals does not always translate to humans. The human brain is vastly complex and incompletely understood and even the most promising drugs can fail as indicated by manufactures’ literature:
“A late-stage development failure was the discontinuation of Eli Lilly’s semagacestat, a gamma-secretase inhibitor of the final step in amyloid-beta protein synthesis. Phase III trials were halted after results suggested worsening of cognitive decline and development of skin cancer indicating little potential for this class of drugs. This includes ELND005 (Elan) which appears to break down neurotoxic fibrils to allow clearance of beta-amyloid (Aß) peptides, responsible for amyloid plaques. Low-dose ELND005 failed to outperform placebo in primary cognitive and functional endpoints. Another early-stage AD drug was dimebolin (Dimebon, Medivation). Phase III failed to meet its primary endpoints of cognition, memory and global function in patients with mild-to-moderate AD.”
Although a cure for AD is unlikely soon, some success has been noted for drugs such as memantine, rivastigmine and donepezil, and other drugs in development, such as immune globulin, have considerable potential. However, the failure of promising compounds in late-stage development, such as semagacestat and ELND005, suggests a new approach is needed for the treatment of this irreversible and progressive disease.
Current research has also been focusing on gene mutations as they relate to the familial forms of Alzheimer’s disease (FAD), both early and late onset. Scientists have thus linked three gene defects with early-onset FAD which include amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2), and a defect in the apolipoprotien E (APOE4) gene in the late-onset form. These defective genes allow the accumulation of neurotoxic proteins in the neural cells, known as amyloid β-proteins. Amyloids are insoluble fibrous protein that can accumulate abnormally in various body organs leading to disease by causing dysfunction.
There have been many different therapeutic focuses, however, the only currently approved are for treating the symptoms of AD. Current therapy methods cannot cure or stop the progression of the disease. Newly published research suggests defective ‘lysosomal proteolysis’ (poor removal of waste material inside the neuron cell walls) as the basis for the pathogenic protein accumulation and suggests new therapeutic targets. Lysosomes are small organelles found in cells that contain catabolic enzymes that digest and break down proteins. A defect in the lysosomes ability to break down proteins would allow for its accumulation within the cell and in a large enough quantity eventually the dysfunction and death of the cell. This is most notably seen in Lysosomal Storage Diseases (LSD). This research indicates that cognitive decline can possibly be prevented by improving the functioning of the lysosomal enzymes so that waste proteins can be broken down and removed faster. Ideally the new therapy would eliminate the toxic amyloid β-proteins from the brain cells before damage is done.
Other alternatives
Other alternatives to the amyloid-plaque hypothesis are gaining in popularity as results suggesting that the immune system was playing a major role in the disease are taken seriously by a new crop of investigators looking at Alzheimer’s pathogenesis with fresh eyes and finding that neuronal stress and the consequent overexpression of proinflammatory proteins are the likely instigators of neuropathological changes, including both plaque and tangle formation. The idea that amyloid plaques are more likely to be a response to the disease, rather than its initiator, is gaining acceptance.
Until recently, prominent immunologists believed that the immune system and the central nervous system (CNS) were completely independent of each other. But observations of the developing rat brain suggests that there is a connection as displayed silver-stained sections from the brains of Alzheimer’s patients showing immune-like cells scattered among the plaques, offered a possibility for the role of inflammation in AD. In fact some research showed enlarged, activated microglia and astrocytes lying among the neurons and amyloid plaques.
Researchers believed that microglia were a type of brain cell, but it would later be shown that microglia came from the same stock—hematopoietic stem cells—as peripheral immune cells, and were essentially the immune cells of the brain.
It was known that they resembled macrophages, the peripheral immune cells that engulf pathogens and secrete the cytokine interleukin-1 (IL-1), activating multiple immune functions of T helper cells. It was also known that the overexpression of IL-1 in arthritis led to progressive joint deterioration. But did microglia in the brain also overexpress IL-1 in Alzheimer’s patients and lead to neuronal deterioration.
What if damaged or stressed neurons were activating microglia to release excessive amounts of IL-1, which in turn activated astrocytes (analogous to macrophage IL-1 activation of T helper cells) and caused them to release S100, a soluble astrocyte inflammatory cytokine that might also aid in neuronal repair?
Tissue levels and cellular expression of IL-1 and S100 in brains of patients who had succumbed to Alzheimer’s disease was measured against brains of disease-free individuals. Indeed, activated glia as well as measure profuse overexpression of IL-1 and S100, thus demonstrating that the inflammatory cytokines IL-1 and S100 were associated with AD.
Research in developmental disabilities showed that people with Down syndrome exhibited the clinical and pathological features of Alzheimer’s by early middle age. Down syndrome brain slices were stained for IL-1 and S100 in identified many microglia and astrocytes activated and overexpressing IL-1 and S100 in Down fetuses and newborns, years before plaques were present—supporting the idea that cytokine release was a result of neuronal stress, providing the first evidence of a meaningful immune response in the human brain. The fact that the response was related to a neurological disease convinced some that overexpressed cytokines might act as driving forces in AD. Later, researchers showed that neuronal stress is associated with increased release of a secreted fragment of βAPP, called sAPP, which induces microglial activation and the release of IL-1.
By carefully mapping the density of plaques, a pattern showing that early plaques, those that are dispersed rather than dense, are surrounded by a multitude of microglia and astrocytes expressing IL-1 and S100, while later stage dense plaques had fewer activated glia, suggesting that neuroinflammation plays an important role early in the disease, and could, in fact, be a driving factor.
Additional reports from other labs showed that microglia produce IL-1 for activation of astrocytes and that S100 is essential for neuronal development and repair, few journal editors shared the view that IL-1 and S100 act as drivers of Alzheimer’s disease progression. Many studies have added credence to the idea that neuronal stress and excess inflammatory cytokine production is a driving force in neurodegeneration and genesis of amyloid plaques.
Reserachers at the Scripps Research Institute reported that high levels of IL-1 might reduce learning and neurotransmission. Examination of the possibility that IL-1 might contribute to the memory deficits in Alzheimer’s via decreasing the levels of the neurotransmitter acetylcholine, a decrease often seen in Alzheimer’s patients. We found that IL-1 elevated the levels of acetylcholinesterase, an enzyme that degrades acetylcholine. This acetylcholine-metabolizing enzyme is, in fact, the principal target of Alzheimer drugs.
To more clearly define how IL-1 inflammatory pathways were triggered by neuronal damage, reearchers studied initiators such as aging, head trauma, epilepsy, and HIV/AIDS. Indeed, aging and each of these other conditions put those affected at an increased risk for the development of Alzheimer’s, and all are characterized by increased IL-1 production that is associated with further neuronal damage.
Neuroscientists began thinking about IL-1 and inflammation as part of a cytokine feedback cycle, with the initiating insult coming from a variety of sources: genetic predisposition (e.g., inheritance of APOE ε4 allele or alleles), repeated injury (head trauma or epilepsy), or infection (HIV), and the wear and tear of time. Although inflammatory mechanisms probably help to clear damaged cells in limited situations, in the long term, chronic microglial activation and elevation of IL-1 becomes cyclical, leading to more neuronal damage and death and, as a consequence, more microglial activation. And this is followed by the production of βAPP, more microglial activation, further production of hyperphosphorylated tau and βAPP, favoring formation of neurofibrillary tangles, beta amyloid plaques, and Lewy bodies.
A Johns Hopkins report showed that among genetically predisposed identical twin pairs who did not show same-age Alzheimer’s onset, use of nonsteroidal anti-inflammatory drugs (NSAIDs) by one of the twins was associated with a several-year delay in the onset of Alzheimer’s. A Dutch study comparing a large group of AD patients who were taking NSAIDs for other ailments to those who were not showed a reduced risk or delayed onset of Alzheimer’s disease—as calculated by the overall risk for the disease per year of life—of almost one-half.
A Department of Veterans Affairs report on 50,000 AD patients and 200,000 control patients, researchers showed that those who took ibuprofen for as long as five years had a reduced AD risk of almost one-half. A more direct approach in a clinical trial (ADAPT) of NSAIDs, observed that continued use for two more years revealed a protective effect of one of the drugs, naproxen, when started before the onset of symptoms and taken for more than two years.
Much progress has been made regarding the understanding that meaningful immune responses has a central place in the central nervous system, including pathogenesis. In 2004, based on the increasing level of interest in the role of inflammation in neural diseases, the Journal of Neuroinflammation, providing a source of high-quality, peer-reviewed articles was launched in 2004. It encourages creative research in the promising field of neuroinflammation in finding a cure for ADs.
Prevention and early detection.
Despite significant progress in AD research, there is no cure. Therefore, current treatments focus on maintenance of mental function, management of behavioral symptoms and delaying the progression of the disease. Of course, ‘prevention’ is the best ‘cure’ and even though it may be difficult – if not impossible – to prevent dementia, it is possible to reduce the risk – and delay the onset – of dementia until late life, with appropriate attention to personal memory fitness. Estimates for delaying dementia onset by one year could save $ billions annually and increase the quality of life of an ever aging at-risk population.
Prevention will be promoted by health care reform (whatever the final version) because of its potential to reduce long-term nursing home costs. The longer a person can live independently, the less time required for costly assisted living. This approach involves awareness of cognitive health literacy and active maintenance of optimal memory fitness.
The Alzheimer’s Prevention Initiative is an intensive, coordinated effort spearheaded by the National Institute on Aging (NIA) to accelerate basic research and help translate basic research findings into the development of novel compounds that delay or slow the progress of Alzheimer’s or to prevent it entirely. Potentially promising strategies are being identified, based on new information about the initial stages and events in the brain that lead to Alzheimer’s, as well as data from studies of genetic and environmental risk factors. To follow up on these leads, NIA has implemented a five-year research initiative to speed the development of vaccine and other novel approaches for preventing AD. Another research initiative will examine changes in immune function with age, including the response to different vaccination protocols. Along with the prevention initiative, other studies will continue to look at the many similarities in the biological mechanisms underlying neurodegenerative diseases such as Alzheimer’s, Parkinson’s disease, and other dementias, and will help to characterize age-related change in the normal, healthy brain.
Along with prevention, one strategy for treating a disease effectively is early detection. This implies that the best time to treat AD is prior to clinical symptoms such as unusual memory loss. The Alzheimer’s Prevention Initiative, proposes to accelerate the development of early detection biomarkers for AD and to develop methods for screening individuals at high risk of AD. Clinical trials of those at high risk would reduce the cost and better show the effectiveness of treatments without ‘low risk data’ that dilutes positive results.
As lifespans extend, demand for therapies to treat late-onset diseases such as AD will increase. However, approved drug treatments – that are long-term solutions and can change the underlying disease process – will rely on an early diagnosis.
About the Alzheimer’s Drug Discovery Foundation (ADDF)
The ADDF is the only public charity whose sole mission is to accelerate the discovery and development of drugs to prevent, treat and cure Alzheimer’s Disease, related dementias and cognitive aging. Since 1998, the ADDF has granted more than $45 million to fund over 325 Alzheimer’s drug discovery programs in academic centers and biotechnology companies in 17 countries.
The latest studies reported by the National Institutes of Health have found:
Researchers at Boston University School of Medicine found that people taking statins reduced their risk of developing Alzheimer’s by 29 percent. The study, the largest to date on this subject, tracked more than 2,300 participants and included African-Americans. Alzheimer’s incidence was reduced equally in both whites and African-Americans.
A team at St. George’s Hospital Medical School in London found that using statins to reduce cholesterol levels dramatically lowered the production of beta amyloid in laboratory experiments. Beta amyloid is a protein that abnormally accumulates in the brain in Alzheimer’s disease. The group has also shown that raising cholesterol levels increases beta amyloid production. A Tokyo-based research group found similar results, and identified a specific pathway through which statins may exert their effect on beta amyloid.
Scientists at Georgetown University found that high cholesterol levels increase the rate at which beta amyloid breaks off from its “parent” protein and accumulates into the plaques found in Alzheimer’s disease. They also showed that high cholesterol increases the production of another protein, called APOE, which contributes to nerve cell toxicity when overproduced.
A large, prospective clinical trial is currently underway to try to determine conclusively if statins can prevent or delay the onset of Alzheimer’s disease.
In the meantime, currently available drugs are not useful as long-term treatments because they do not deal with the underlying causes… only the symptoms, and therefore may only be effective for a few months to a few years.
Researchers Trace Alzheimer’s Process Seeking Breakthrough For Effective Treatment
Neurological researchers at Rush University Medical Center report a breakthrough in treatment that may lead to halting the progression of Alzheimer’s disease. The treatment focuses on a new therapeutic target neutral sphingomyelinase, a hydrolase enzyme involved in sphingolipid metabolism that can potentially lead to a new way to stop the progressive disease. Study results appear in the Journal of Neuroscience.
Researchers speculate that stopping the activation of the neutral sphingomylinase enzyme may stop Alzheimer’s disease (AD) progression and memory loss. Alzheimer’s, an irreversible, progressive disease, is the most common cause of dementia affecting as many as 5.3 million Americans over 60.
Multiple, neurotoxic, disease-causing pathways converge on the neutral sphingomyelinase that can cause neuronal loss in the brain of an AD patient.
Two abnormal structures – plaques and tangles – are prime suspects in damaging and killing brain nerve cells. While neurons (grey Matter) die, other glial (white matter) brain cells (e.g., astroglia and microglia) do not. Rather, these glial cells which form the first line of immune defense, become activated. Glial cell activation plays a key role in the destruction of neurons. Until now, the molecular mechanisms by which activated glial cells can kill neurons have been poorly understood.
Development of a clinical medication that would target the neutral sphingomyelinase enzyme, might allow doctors to halt memory loss in Alzheimer’s patients. These results are promising, according to researchers, who will be turning their efforts to clinical interventions. A breakthrough in stopping AD could provide hope for an aging population in the US that could otherwise see 14 million cases of AD by 2050.
WHAT THE ALZHEIMER’S ASSOCIATION IS DOING TO FIND A CURE
In 2011, the oldest Baby Boomers turn 65 —the age when Alzheimer’s disease starts to rise. Thus begins an 18 year process when every 7 seconds another American turns 65— 12,342 people daily ending in 2029 when half of those remaining will be impacted by Alzheimer’s disease. To bring a sense of urgency to the real risks facing the 78 million Boomers – and to our economy, the Alzheimer’s Association released a groundbreaking study called Generation Alzheimer’s: The Defining Disease of the Baby Boomers. The good news is that death rates for many major diseases – HIV, stroke, heart disease, prostate cancer, and breast cancer – are declining. Unfortunately, that can’t be said about Alzheimer’s.
The reason, argues this well documented report, is that massive research investments in the National Institutes of Health (NIH) are paying off in lives saved. Each year, NIH invests over $6 billion on cancer, $4 billion on heart and cardiovascular disease and $3billion on HIV/AIDS research — but only $480 million on Alzheimer’s and other dementia research as Alzheimer’s disease deaths soar.
The report makes a convincing case for increased investment in Alzheimer’s research now. For example, a person with Alzheimer’s disease (AD) costs Medicare three times more – and Medicaid nine times more – than someone without Alzheimer’s. Also, for every $100 invested in AD research, Medicare spends over $25,000 for AD care. Another point is that research for drug and other prevention interventions, like educating the public about ways to maintain memory fitness, that delay AD onset by just five years would cut Medicare AD spending by 45 percent.
Overall, America spends $172 billion for AD care annually. With the aging of the Boomers, costs will reach over $1 trillion in 2050. Curing Alzheimer’s is crucial to saving Medicare and Medicaid, not to mention millions of lives and the quality of life of their families.
Alzheimer’s is the only disease in the top 10 causes of death in America without a way to prevent it, cure it or slow its progression. This is why the Alzheimer’s Association – the leading voluntary health organization in Alzheimer care, support and research – argues so vigorously for “significantly increasing AD research budgets at NIH now”….to levels comparable to cancer, cardiovascular and heart disease.
WHAT YOU CAN DO TO HELP FIND A CURE
Generation Alzheimer’s is designed to help insure the public understands what can be done to conquer this devastating disease. In addition to improving your cognitive health literacy and taking steps to optimize your memory fitness – by incorporating the latest scientific methods from neuroscience incluing neuroplasticity and epigenetics – to reduce your own risks of age-related memory loss, you can support aggressive Alzheimer’s disease research for a cure.
MemoryZine suggests that you read the Alzheimer’s Association groundbreaking study Generation Alzheimer’s and let your congressional representatives (easily identified by zip code) know how you feel about NIH research budgets for this vital issue today.
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