Alzheimer

6.
11:AlzheimerDisease
PriorityMedicinesforEuropeandtheWorld "APublicHealthApproachtoInnovation"
BackgroundPaper
AlzheimerDisease OpportunitiestoAddressPharmaceuticalGaps
BySaloniTanna,Pharm.D;MPH 7October2004
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6.11:AlzheimerDisease
Table of Contents
1. Summary........................................................................................3 2. Introduction....................................................................................4 Cause............................................................................................................... 4 3. Size and Nature of Disease Burden..................................................4 Incidence and Prevalence................................................................................4 4. Control Strategy.............................................................................9 DiagnosisError: Reference source not found....................................................9 Research Directions in Diagnosis and Evaluation...........................................11 ManagementError: Reference source not found.............................................11 Pharmacological Therapy Review for AD........................................................12 Psychiatric Management of Non-Cognitive Symptoms...................................14 Affordability and Feasibility............................................................................15 5. Major Problem and Challenges for Disease Control: Why Does the Disease Burden Persist?....................................................................16 Risk Factors.................................................................................................... 16 Trends............................................................................................................ 18 6. Past/Current Research into Pharmaceutical Interventions of AD......18 Drugs for Disease Modification.......................................................................18 Drugs for Prevention and Disease Modification..............................................19 7. Current Pharmaceutical Product Pipeline for AD Treatment..........21 Research into Emerging Technologies...........................................................22 Europe and the Fifth Framework Program for Alzheimer disease...................22 8. Opportunities for Research into New Pharmaceutical Interventions. 24 Gaps Between Current Research and Potential Research Issues that Could Make a Difference.......................................................................................... 25 9. Barriers to Closing the Alzheimer Pharmaceutical Gap...................26 10. European Union Funding Opportunities for AD.............................27 11. Conclusion..................................................................................28 10 References...................................................................................30
Annexes
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1. Summary
Alzheimer disease is a neuro-degenerative disease of the brain that causes changes in brain function. AD usually affects people over the age of 65 years, with a progressive decline in memory, thinking, language and learning capacity. Age is the strongest predictor for the development and progression of AD and with the rapidly aging population of our society, AD clearly poses a major health problem. An estimated 5-10% of the population aged 65 years and over and 40% of the population greater than 85 years of age are likely to be affected by AD. The pathophysiology of AD is related to the injury and death of neurons, especially in the areas of the brain that are involved with memory and learning. Alzheimer disease is the most common dementia, accounting for 50%-75% of the total, with a greater proportion in the higher age ranges. There are nearly 18 million people with dementia in the world today. The number of people with dementia is expected to increase steadily over the next 25 years. By 2025, there will be about 34 million people with dementia in the world. There are currently no specific tests that may positively confirm the diagnosis of AD. AD may be diagnosed on physical and neurological exams, and checking for signs of intellectual impairment through standard tests of mental function. Definitive changes found in the brain of affected AD patients are microscopic and can be seen only when a sample of brain tissue is removed and examined, usually on autopsy. At present, there is no cure for AD, or any pharmacologic therapy that can delay its onset or affect the pathophysiology of the illness . The primary goals of treatment are to maximize the patients ability to function in daily life, maintain quality of life, slow the progression of symptoms, and treat depression or disruptive behaviors. The current pharmacologic therapy for AD only provides symptomatic relief for a short period of time, six to eighteen months.Error: Reference source not found, The only drugs approved in the US and several parts of Europe for treating AD are cholinesterase inhibitors and the NMDA antagonist, memantine. These drugs do not affect the pathology or progress of AD. Management of AD is complex and clinicians and caregivers are confronted with numerous challenges in managing the AD. Some of these include employing unique social and environmental interventions; knowledge and use of increasingly sophisticated medications, and providing individualized therapy to patients, working with care takers or varying systems providing care. Continuing efforts are still required. This includes developing medicines that would slow progression, halt, or prevent AD from occurring. Additionally, challenges for clinical services include early diagnosis, and intervening early with the most appropriate and effective medicine. Furthermore, validated therapeutic targets need to be identified, and better animal research models are needed which reflect the disease. Biotech and major industry also need to recognize the potential market opportunities for AD and despite the high risk, the rewards for effective medicines that could delay or halt the disease are huge. The high risks associated with research and development and the lack of makers for disease progression need to be overcome so that industry may confidently make further advances in this field and to implement phase II and larger phase III trials for novel therapeutic agents. 6.113
6.11:AlzheimerDisease 2. Introduction
Dementia is a generic term that describes the cognitive decline in brain function 1 . There are several causes of this condition, such as Alzheimer disease, AIDS, head injury etc. Some conditions that cause dementia can be reversed, and others cannot. The two most common forms of dementia in older people are Alzheimer disease and multi infarct dementia (sometimes called vascular dementia). These types of dementia are irreversible. 2 Alzheimer disease (AD) is the most common form of dementia; it accounts for 64 per cent of all dementias. 3 AD is characterized by a progressive decline in cognitive function. AD usually affects people over the age of 65 years, with a progressive decline in memory, thinking, language and learning capacity. AD should be differentiated from normal age-related decline in cognitive function, which are more gradual and associated with less disability.4 AD often starts with mild symptoms and ends with severe brain damage. People with dementia lose their abilities at different rates. On average, AD patients live from 8 to 10 years after they are diagnosed, though the disease can last for as many as 20 years.Error: Reference source not found, 5
Cause
The pathophysiology of AD is related to the injury and death of neurons, especially in the areas of the brain that are involved with memory and learning. Patients affected with AD, show two specific microscopic changes-senile plaques (abnormal deposits of a protein called amyloid) and neurofibrillary tangles (abnormal spiral filaments in neurons). Through some unknown mechanism, senile plaques and neurofibrillary tangles prompt the injury and death of neurons, and this subsequently produces the intellectual and behavioural symptomatic changes evident in AD. 6 Currently, theories about the development of AD have focused on how the death of neurons affects levels of essential brain chemicals called neurotransmitters. When injured neurons in the hippocampus and cortex die, there is a corresponding drop in neurotransmitter acetylcholine. Error: Reference source not found Other neurotransmitter systems are also affected later in the disease e.g. glutamate, serotonin.
3.
Size and Nature of Disease Burden
Incidence and Prevalence

Exact estimates of the prevalence of dementia depend on the definition and specific threshold used, but it is clear that the prevalence increases dramatically with age. The syndrome affects approximately 5%-8% of individuals over age 65, 15%-20% of individuals over age 75, and 25%-50% of individuals over age 85. Alzheimer disease is the most common dementia, accounting for 50%-75% of the total, with a greater proportion in the higher age ranges. Vascular dementia is probably next most common, but its prevalence is unknown. The remaining types of dementia account for a much smaller fraction of the total. 7 Figure 1 compares the absolute level of Alzheimer disease burden (measured by DALYs as "Alzheimer`s and other dementias" ) between the EU25, EU15, EU 10 and the world (including the EU25) for different age groups. Although the differences in absolute values are to be expected, females in all regions carry the higher burden of Alzheimer, in large part because of their longer life expectancy. 6.114
This gender divergence between males and females begins in terms of burden of disease begins between the ages of 60-69. Figure 1.
Alzheimer's Disease (DALYs)

2500000
2000000
World-F
1500000
World-M
1000000
500000
EU25-F EU15-F
EU25-M EU15-M
EU10-F EU10-M
0 0-4 5-14 15-29 30-44 45-59 60-69 70-79 80+
Source: World Health Organization Global Burden of Disease Database
Figure 2 plots the burden of disease for Alzheimer disease for the different EU and World regions as a fraction of all DALYs (both acute and chronic conditions) for different age groups. Alzheimer`s disease increases to nearly 20% of the total disease burden (both acute and chronic) among women in the EU15. Figure 2.
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ALzheimer's as Percent of All DALYS (by age group)
20.00% 18.00% 16.00% 14.00% 12.00% 10.00% 8.00% 6.00% 4.00% 2.00% 0.00% 15-29 30-44 45-59 60-69 70-79 80+ EU15-M EU15-F EU10-M EU10-F World-M World-F
Source: World Health Organization Global Burden of Disease Database
The mode of onset and subsequent course of dementia depend on the underlying etiology. Alzheimer disease has an insidious onset and slow decline in brain function, while vascular dementia is characterized by a more acute onset and stepwise decline. The effective management of dementia is a function of the underlying pathology and of the availability and timely administration of effective treatment Error: Reference source not found Dementia Worldwide 8: There are nearly 18 million people with dementia in the world today. The number of people with dementia is expected to increase steadily over the next 25 years (See also Figures 1 and 2 showing age distribution). By 2025 there will be about 34 million people with dementia in the world By 2025, 71% of people with dementia will live in developing countries. The overall incidence of dementia increases with age at 1% per year. This estimate is lower for men and people of African or Asian origin.Error: Reference source not found AD is more prominent in Europe and North America, and in developing countries dementia appears to be rare. These differences are difficult to explain and may be a result of poor diagnosis and survival bias due to high death rates at all ages.Error: Reference source not found AD prevalence among those older than 60 years is about 5% for men and 6% for women. With a growing aging population, these numbers are expected to increase rapidly over the next 20 years. Error: Reference source not found 6.116
Dementia in Europe 9 Work from the European Community Concerted Action on the Epidemiology and Prevention of Dementia group (EURODEM) allows countries participating in the study to estimate the number of people likely to be affected by dementia-provided that the accurate population statistics are made available. EURODEM is able to provide data on the prevalence of moderate to severe dementia and determine prevalence rates for men and women in 9 different age groups. The study includes people living with dementia in institutions, nursing homes, residential care as well as those living at home. The study was only based on diagnosed cases of dementia, and the report acknowledges the problems related to this, since many people fail to get diagnosed and are therefore excluded. Data for this study comes from the following European countries: Germany, Finland, France, Italy, The Netherlands, Norway, Portugal, Spain, Sweden, and UK.
Table 1. EURODEM Prevalence Rates for Men and Women in Nine Different Age Groups for Dementia (1980-1990 Findings)Error: Reference source not found
Age group 30-59 60-64 65-69 70-74 75-79 80-84 85-89 90-94 95-99 Male 0.16% 1.58% 2.17% 4.61% 5.04% 12.12% 18.45% 32.1% 31.58% Female 0.09% 0.47% 1.10% 3.86% 6.67% 13.50% 22.76% 32.25% 36.00%
Dementia in UK Error: Reference source not found Dementia affects over 750,000 people in the UK with Alzheimer disease being the most common form of dementia. (Table 3. shows the proportions of those with different forms of dementia). Over 18,000 people with dementia are under 65 years old. Dementia affects one person in 20 aged over 65 years and one person in five over 80 years of age. It is estimated that by 2010, there will be about 840,000 people with dementia in the UK, and this is expected to rise to over 1.5 million people with dementia by 2050.
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Table 2: Estimated Number of People with Dementia in the UK Using Population Figures for 2001Error: Reference source not found
England Scotland Northern Ireland Wales Total 652,600 63,700 17,100 41,800 775,200
Table 3: Proportions of Dementia in the UKError: Reference source not found

Alzheimer disease Vascular dementia Dementia with Lewy bodies Fronto-temporal dementia Pick's disease Other dementias 55% 20% 15% including 5% 5%
Dementia in Japan 10 By the end of Sept. 2003, there were 20,561 people over 100 years old in Japan, of which 84.6% were female. Prevalence of dementia increases with age with a prevalence of 1.5% in the group aged 65-69 and 27.3% in the group aged 85 and over. In Japan dementia of vascular type is more prevalent than Alzheimer type. Estimates of vascular versus Alzheimer dementia in Japan are probably distorted because of cultural factors, i.e. it is more acceptable to have a vascular disorder than a mental disorder. Dementia in CanadaError: Reference source not found There were an estimated 83,200 new cases of dementia in 2001. By 2011 new cases of dementia are expected to reach 111,600 per year. Alzheimer disease affects 1 in 20 Canadians over age 65. By 2031: over 3/4 million Canadians are expected to have Alzheimer disease and related dementias. Dementia in the US 11 An estimated 4.5 million Americans have Alzheimer disease, according to data from 2000 U.S. census. This data also shows that by 2050, the number of Americans with Alzheimer disease could range from 11.3 million to 16 million. National direct and indirect annual costs of caring for individuals with Alzheimer disease are at least $100 billion, according to estimates used by the Alzheimers Association and the National Institute on Aging. Alzheimer disease costs American business $61 billion a year, according to a report commissioned by the Alzheimers Association. Of this amount, $24.6 billion covers Alzheimer health care and $36.5 billion covers costs related to caregivers of individuals with AD, including lost work productivity, absenteeism and worker replacement. 6.118
More than 70 percent of people with AD live at home, where family and friends provide almost 75 percent of their care. The remainder is paid care costing an average of U.S $12,500 per year. Families pay most of this amount out of pocket. An estimated half of all nursing home residents have Alzheimer disease or a related dementia disorder. The average cost for nursing home care is estimated at $42,000 per year. The average lifetime cost taking care of a patient with AD of care is $174,000. Medicare costs for beneficiaries with Alzheimer disease are expected to increase 54.5 percent, from $31.9 billion in 2000 to $49.3 billion by 2010. Furthermore, Medicaid expenditures on residential dementia care will increase 80 percent, from $18.2 billion to $33 billion in 2010, according to a report commissioned by the Alzheimers Association. The Alzheimers Association has given more than $150 million towards research grants since 1982. The federal government estimates spending approximately $640 million for Alzheimer disease research in fiscal year 2003.
4.
Control Strategy
AD disease is a complex disease and its management is often challenging. Personality and behavioural changes, and the eventual inability to perform activities of daily living lead to dependence. As functional impairment deteriorates, health care utilization increases until patients are forced to become institutionalized for around the clock supervision. Patients can remain in severe stages of AD for several years. Error: Reference source not found, 12, Error: Reference source
not found
DiagnosisError: Reference source not found

There are currently no specific tests that may positively confirm the diagnosis of AD. AD may be diagnosed on physical and neurological exams, and checking for signs of intellectual impairment through standard tests of mental function. For a diagnosis of AD, the criteria adapted from the National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) include the following: dementia established by examination and objective testing; deficits in two or more cognitive areas; progressive worsening of memory and other cognitive functions; no disturbance in consciousness; and onset between ages 40 and 90. Absence of systemic disorders or other brain diseases, which could account for the deficits in memory and cognition, should also be ruled out. Diagnostics tests such as MRI and CT are also done to rule out medical causes of creased brain function. Definitive changes found in the brain of affected AD patients are microscopic and can be seen only when a sample of brain tissue is removed and examined, usually on autopsy.Error: Reference source not found ,Error: Reference source not
found
Alzheimer disease is characterized primarily by a gradual onset of progressive symptoms, including:13 memory loss changes in personality noticeable decline in cognitive abilities (including speech and understanding) 6.119
loss of executive function (decision-making) losses impairing activities of daily living (dressing, eating, toileting, etc.) Annex 6.11.1 identifies sources for the differential diagnosis of AD. The actual diagnostic work-up for AD is very involved and requires several steps this includes an initial evaluation including a medical history, a mental status evaluation, a clinical examination, and laboratory tests.Error: Reference source not found Alzheimer disease is the most common cause of dementia, however there are many disorders that can cause or simulate dementia. To appropriately diagnose for AD, other forms of dementia or diseases need to be ruled out. This includes the following:Error: Reference source not found Medication-induced dementia. Medication-induced dementia is the most frequent cause of reversible dementia. To rule out a medication-induced dementia, a thorough drug history and a review of all current medication (both prescription and over-the-counter) needs be undertaken. Metabolic/endocrine/nutritional/systemic disorders. Metabolic/endocrine/nutritional/ systemic disorders (e.g., hypothyroidism, B12 deficiency, and systemic infections) are additional causes of reversible dementias and can be diagnosed with routine laboratory tests. Tests recommended include blood count, sedimentation rate (if indicated), electrolytes (including calcium), liver and renal function tests, urinalysis, syphilis serology, B12 levels, thyroid function tests, and a toxicity screen (if medical history and the physical exam so indicate). Vascular dementia/hydrocephalus /tumors/hematoma. Vascular dementia (VaD) may result as a sequel to any form of cerebrovascular disease. VaD is responsible for approximately 20 percent of dementia cases and can Alzheimer disease. Normal pressure hydrocephalus, brain tumors, and subdural hematoma, the most common of the structural brain lesions, and stroke can also present with dementia. Confirmation or exclusion of their presence usually requires a CT or MRI scan. Depression. Depression is another common cause of dementia in the elderly population. The following symptoms cognitive impairment symptoms may be present: confusion, memory disturbance, and attention deficits, all of which can be mistaken for dementia. Depression may also coexist with dementia and exacerbate the problem, causing; excess disability. A good history and thorough mental-status is required as part of the treatment plan. The DSM-IV criterion for diagnosis of depression is often referred to confirm or rule out depression. The clinical criteria and diagnosis of dementias, including AD, has not changed since the 1990s. Given the advantages of early diagnosis and early intervention, there is an urgent need to revise the criteria for diagnosis so that the disease may be identified in the earlier stages. 14 The is much research in identifying the shift between EARLY cognitive changes associated with dementia and that associated with normal aging, an area known as mild cognitive impairment (MCI).Error: Reference source not found This remains a challenge for both clinicians and researchers since the Mini Mental State Examination (MMSE), Dementia Rating Scale and other evaluating tools are relatively insensitive to early cognitive symptoms.Error: Reference source not found 6.1110
A new blood test called APOE (apolipoprotein E) genotyping has been used to identify individuals who carry the APOP-4 gene. The presence of this gene increases a persons risk for AD and when the gene is present in a person with dementia, a diagnosis of AD is supported. This test is not recommended as a predictive test in individuals who do not have symptoms of cognitive impairment.Error: Reference source not found, Error: Reference source not found
Research Directions in Diagnosis and Evaluation

More research is needed for improved detection and evaluation of dementia, particularly in the prodromal stages and early stages of MCI. Another research area is improved detection of noncognitive symptoms, so as to facilitate quick and appropriate intervention. Development of useful and timely outcome measures, including neuropsychological testing and functional assessments are needed.Error: Reference source not found
ManagementError: Reference source not found

The primary goals of treatment are to maximize the patients ability to function in daily life, maintain quality of life, slow the progression of symptoms, and treat depression or disruptive behaviors. Treatment of AD takes on a systematic approach. First, if there are medical conditions that make Alzheimer symptoms worse that illness needs to be managed. There are several medications such as alcohol, sedatives and antihistamines, that can also aggravate AD, and these must be identified and removed, or switched to alternative medicinesError: Reference source not found. Medications may also be administered to treat depression, while antipsychotics medicines can be used to treat aggressive or violent behavior. Finally, caring for the caregiver is another vital part of any treatment strategy for AD. Experts within this field recognize that caregivers are at a high risk for depression and medical illness. As a result, recommendations and guidance to community resources and support is integrated into the overall management of the disease.Error: Reference source not found
Table 4: Therapeutics Options for Alzheimer disease
15, 16, 17, 18
Non Pharmacologic therapy Stimulation: Group activities, discussion groups, music therapy, multisensory stimulation Pharmacologic therapy Cholinesterase inhibitors (or cholinergics): Donepezil, rivastigmine, galantamine Glutamatergic agents: Memantine, D-cycloserine Selegiline Hormone replacement therapy (estrogen) Anti-inflammatory drugs (NSAIDs) Antioxidant therapies Vitamin E Nootropic Drugs Ginko Biloba Nicergoline Piracetam Therapy for psychiatric symptoms : behavioural disturbances, mood disorders, agitation with dementia (e.g. delirium, depression, psychosis, insomnia, sundowning, aggression or anger, osteoarthritic 6.1111
pain)
Pharmacological Therapy Review for AD

The current pharmacologic therapy for AD only provides symptomatic relief for a short period of time, six to eighteen months.Error: Reference source not found, At present there is no cure for AD, or any pharmacologic therapy that can delay its onset or affect the pathophysiology of the illness . 19 The only drugs approved in the US and several parts of Europe for short term alleviation of symptoms are cholinesterase inhibitors and memantine. These drugs do not affect the pathology of AD, but allows the brain to compensate for the loss of neurons that communicate via acetylcholine, a neurotransmitter.Error: Reference source not found, Error: Reference source not found This section reviews the clinical efficacy of approved and possible pharmacological therapies for AD. Cholinesterase inhibitors Cholinesterase inhibitors are a class of medicines that block cholinesterase-an enzyme that breaks down the neurotransmitter acetylcholine. AD is linked with low levels of acetylcholine, hence inhibiting or blocking the breakdown of acetylcholine through cholinesterase inhibitors may help to improve brain function, and possibly slow deterioration of cognitive function.Error: Reference source not found Treatment effects have been demonstrated with several different cholinesterase inhibitors, indicating that the class of agents is consistently better than placebo. However, the disease eventually continues to progress despite treatment and the average effect is often modest. However, global changes in cognition, behavior and functioning have been detected by both physicians and caregivers, indicating that even small measurable differences may be clinically significant. These drugs are similar yet have distinct pharmacology profiles such as onset of action, side effect profile, potential drug interactions, ease of administration (e.g. twice a day versus three times a day), and route of metabolism. However, the clinically relevance of these differences are unclear and the significance of these differences awaits head-to-head trials.Error: Reference source not found,Error: Reference source not found This class of drugs is indicated for mild to moderate AD. However, no published results are available for severe dementia, though open-label follow up from trials suggests that these drugs continue working as the cholinergic deficit increases.Error: Reference source not found Benefits reported for these medications tend to occur at higher doses. However, the higher the dose, the more likely the side effects.Error: Reference source not found Given the increase in AD prevalence, more studies are needed to determine the role of cholinergic medicines in patients with severe AD and to provide comparative data on therapeutic options for this subset of patients. 20 Cochrane reviews of the cholinesterase inhibitors suggest that treatment effects have been demonstrated with several agents, and that this class is generally more efficacious than placebo. See also Background Chapter 5. Positive changes in cognition, behavior and function were demonstrated, however, the disease continues to progress and the treatment effect is modest and short lived.Error: Reference source not found
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Reviewers conclusions for donepezil: In selected patients with mild or moderate Alzheimer disease treated for periods of 12, 24 and 52 weeks, donepezil produced modest improvements in cognitive function. No improvements were present on patient self-assessed quality of life and data on many important outcomes are not available. Furthermore, the 10mg dose showed only a marginal benefit to the 5mg dose. The practical importance of these changes to patients and caregivers is unclear .21 Reviewers conclusions for galantamine : Patients in these trials were similar to those seen in earlier anti dementia AD trials, and consisted predominantly of mildly to moderately impaired outpatients with AD. Evidence from studies show that there was an overall positive effect for trials of 3, 5 and 6 months in duration. Furthermore, there was evidence for efficacy of galantamine on global ratings, cognitive tests, assessments of ADLs (activities of daily living) and behaviour. Reviewers stated that the magnitude of cognitive effect was similar to other cholinesterase inhibitors including donepezil, rivastigmine, and tacrine. Also, galantamine's safety profile is similar to that of other cholinesterase inhibitors with regard to cholinergically mediated gastrointestinal symptoms. Longer-term use of galantamine has not been assessed in a RCTs (randomized controlled trials) and is desirable. 22 Reviewers conclusions for Rivastigmine : Studies show that rivastigmine is beneficial for people with mild to moderate AD. In comparisons with placebo, improvements were seen in cognitive function, ADL, and severity of dementia with daily doses of 6 to 12 mg. Further research is needed on dosage (frequency and quantity) in a search for ways to minimize adverse effects. Moreover, RCTs greater than 26 weeks are needed to determine the efficacy of rivastigmine. 23 The cholinesterase inhibitors (donepezil and rivastigime) may not be cost effective for the management of AD 24 but the study that reached this conclusion has been challenged by the industry which has asserted that it was under powered. Results of this study were asserted to " incompatible with many drug company-sponsored observational studies and advertisements claiming remarkable effects of cholinesterase inhibitors" .Error: Reference source not found In addition, previous claims that donepezil can stabilize cognitive deterioration and delay nursing home placement by two to three years have not been validated by this study. The study also showed that the long-term use of donepezil cost the UK National Health Service more than placebo.Error: Reference source not found The more general understanding is that these drugs do not work in the more severe states of the disease. Improvements in cognitive functions for the first two years were significantly better than placebo. This validates industry-sponsored studies. However, no benefits were seen in the long term endpoints of institutionalization, and the experts state that improvements in cognition does not reduce institutionalization as reported by pharmaceutical companies. Error: Reference source not found Glutamatergic agents One of the pathological hypotheses suggested to cause AD is neurotoxic mechanisms resulting is excessive amounts of amino acids being released. AD patients have a loss of glutametergic pyramidal neurons, while the receptors NMDA (N-methyl-D-aspartate) are preserved. An over stimulation of these receptors could lead to neuronal loss. Memantine, an NMDA blocker, is effective in treating severe AD. The drug has been approved in Germany since 1970s, but clinical trial data to support its use have been limited. Data from recent clinical trials investigating the safety and clinical efficacy of memantine show that it is 6.1113
effective for moderate to severe AD. The medication is still being studied and is approved in the US and several European countries. Error: Reference source not found Reviewers conclusions on Memantine: There is a short-term beneficial effect of memantine compared to placebo for patients with moderate to severe AD. The effect of memantine in patients with vascular dementia, Alzheimer disease and dementia of non-specified type at six weeks showed that there were beneficial effects on cognition, activities of daily living, and behaviour and in global impression of change. The drug is well tolerated and the incidence of adverse effects is low. However, most of the trials so far reported have been small and not long enough to detect clinically important benefits long term, therefore more studies that are extended in duration are needed to determine the efficacy of memantine.25
Psychiatric Management of Non-Cognitive Symptoms

Psychiatric and behavioural problems are present in up to 90% of patients with dementia.26 Non-cognitive symptoms of dementia tend to evolve over time, so regular monitoring allows adaptation of treatment strategies to current individual needs. For example, among the behavioural disturbances common in Alzheimer disease, depression is more common early in the illness, while delusions and hallucinations are more common in the middle and later stages. Behavioural issues to be addressed include major depression and other depressive syndromes, suicidal ideation or behaviour, hallucinations, delusions, agitation, aggressive behavior, disinhibition, anxiety, apathy, and sleep disturbances. 27 Early intervention is important since psychiatric symptoms can respond to treatment more readily than cognitive and functional deficits.Error: Reference source not found Table 5. shows the behavioural clusters manifested in AD and relevant classes of medications for intervention.Error: Reference source not found
Table 5: Behavioural Clusters Matched with Potentially Relevant Classes of MedicationsError: Reference source not found
Behaviour Agitation/aggression Anxiety Apathy Disturbed effect/mood Altered ideation/perception Vegetative features Agent Antipsychotics,anticonvulsants, antidepressants, anxiolytics Antidepressants, anxiolytics, anticonvulsants Antidepressants, stimulants Antidepressants, anticonvulsants Antispsychotics Antidepressants, anxiolytics, stimulants
There is sufficient evidence from randomized controlled trials to support the use of both traditional and atypical antipsychotics for the management of agitation and psychosis in dementia. Of the two classes atypical antipsychotics appear to be better tolerated compared to traditional antipsychotics.Error: Reference source not found, Error: Reference source not found 6.1114
There is evidence that SSRIs (selective serotonin reuptake inhibitors) antidepressants may be administered and are better tolerated than other antidepressants.
The American Academy of neurology practice guidelines conducted an in-depth review of pharmacological therapies for non-cognitive symptoms in dementia. The expert panel conclude that most studies in this area focus on mixed populations with dementia. Therefore, it is not entirely possible to assess the efficacy of specific medications for patients with specific form of dementias such as AD.Error: Reference source not found
Affordability and Feasibility

The financial costs of managing AD are enormous. The cost of illness is high in terms of both public and private resources. Caregivers who are required to provide care and patients affected by dementia also pay a high price in terms of their quality of life. Limited literature is available on the affordability, accessibility and cost of AD management. Further studies are required to assess the cost of disease management for AD. The following section provides some information on the cost of managing AD or dementia where available. UKError: Reference source not found Although dementia is a major area of expenditure in the UK, over three-quarters of health authorities surveyed (in 1997) were unable to identify the resources spent on dementia care. There have been relatively few studies in this area. Estimated annual cost of Alzheimer disease at between 5,400 and 5,800 million a year in the UK. Estimated costs associated with Alzheimer disease at different stages of the disease revealed that over a three-month period the total mean cost per patient with mild Alzheimer was 6,616, 10,250 for a person with moderate Alzheimer and 13,593 for a person with severe Alzheimer disease in the UK. The Alzheimers association of UK state that although all of these studies highlight the high costs of dementia they still under-estimate the true cost. For example, the costs of caring by partners and children of people with dementia are considerable. Also, what is often overlooked is the cost of not intervening early in the disease. The greatest proportion of direct costs of dementia care is also associated with institutional support. This is often provided at a crisis point, which is always expensive and often precipitated by lack of effective support. US In a report by Delagarza on the pharmacological management of Alzheimer disease, the authors state that in the US AD accounts for $100 billion per year in medical and custodial expenses, with the average cost per patient at US $27,000 annually. This includes medical and nursing care.Error: Reference source not found Canada The annual cost of caring for patients with dementia has been estimated to range from $941 per patient with mild disease to $36,794 per patient with severe disease, with an average net cost of about 4 billion dollars.Error: Reference source not found
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6.11:AlzheimerDisease 5. Major Problem and Challenges for Disease Control: Why Does the Disease Burden Persist?
A cure for AD is still not available and clinicians and caregivers are challenged with caring for an increasing aging population affected by dementia. Increased life expectancy has seen a rise in chronic medical disease and associated illnesses, including dementia. For example, there will be an estimated 400% increase in population of North Americans aged 85 and older by 2050, 40% of whom will develop dementia. Error: Reference source not found Clinicians providing care for patients with dementia are confronted with numerous challenges in managing AD. Some of which include employing unique social and environmental interventions; knowledge and use of increasingly sophisticated medications, and providing individualized therapy to patients, working with care givers or varying systems providing care. The burden for the general practitioner is not necessarily an increase in sophisticated medicines - it is really the lack of specific medicines for AD that is the problem - the physician has a limited range of therapeutic options, e.g. frequently used neuroleptics have mixed pharmacologies that can cause memory impairment, etc. Management of AD is also complex since it requires differentiating and managing various changing neuropsychiatric and behavioural problems. A balance also has to be reached between aggressive intervention and palliative care continued treatment versus withdrawal of medicines, and patient benefit versus caregiver burden. Managing AD is complex and presents a major public health concern for the today and the future.Error: Reference source not found,Error: Reference source not found
Risk Factors
The following are some of the risk factors that are thought to have some relationship on the development of AD. Many of these risk factors are still being studied.
Table 6. Some Risk Factors Associated with Alzheimer diseaseError: Reference source not found, Error: Reference source not found, Error:
Reference source not found, 28
Risk factor Age Positive family history
High life expectancy. Normal aging process increases the risk of AD. Studies indicate that AD may be inheritable. Relatives with AD (i.e. parent or sibling) are at a risk for developing AD. Recent research has identified the presenilin 1 gene on chromosome 14 and the presenilin 2 gene on chromosome 1. Both genes appear to be strong indicators for Alzheimer Disease at an early age of onset (before the age of 65). Error: Reference source not found Preliminary research has also found markers on chromosomes 9, 10 and 12 that might be linked to late-onset Alzheimer Disease (over the age of 65). Several research studies are underway collecting blood samples from people with Alzheimer Disease and their family members. These samples enable scientists to analyze DNA material within families with the intent of identifying genes that may be responsible for causing Alzheimer Disease.Error: Reference source not found
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Risk factor Down Syndrome Head injury
Education
Aluminum
Estrogen
Social, productive and Physical activity
Comorbid diseases Other risk factors being studied
Almost all individuals with Down syndrome over the age of 40 have changes to brain cells characteristic of Alzheimer Disease. In these individuals, dementia usually develops in 50's or 60's of age. Some studies have shown that people who have had a head injury with loss of consciousness have an increased chance of developing Alzheimer disease. Research into the development of AD as a result of head injuries is ongoing.Error: Reference source not found The increased risk is probably due to the upregulation of APP seen after brain trauma. Several studies have shown that people who have less than six years of formal education appear to have a higher risk of developing AD. Low education may reflect early experiences that were not beneficial to brain development. Higher education is thought to delay the onset of symptoms of Alzheimer Disease probably due to greater brain reserve or educational activities that may stimulate brain activity. Education as a protective factor requires more study to determine whether it is education that makes a difference or other factors related to it (e.g., income level).Error: Reference source not found,Error: Reference source not found The correlation between AD and aluminum is still under debate in the scientific community. Some studies have indicated that exposure to aluminum in drinking water may increase the chances of individuals developing Alzheimer Disease.Error: Reference source not found Research has been conducted on estrogen and its impact on various diseases, including AD. Current research indicates that combined estrogen therapy (estrogen plus progestin) in women over the age of 65 doubled their risk of developing Alzheimer Disease and Vascular Dementia, over a five-year period. Research continues to investigate the effects of estrogen-only therapy on cognition. Previous research has shown that women with Alzheimer Disease who were treated with estrogen showed no sign of improvement. Error: Reference source not found,Error: Reference source not found Recent data from the CSHA-2 (Canada Study for Health and Aging) show that regular physical activity was associated with reduced risk of AD. This information supports previous clinical trials showing exercise to benefit cognitive function. Identifying the protective effect of regular physical activity is an important finding since it may represent a relatively safe and available strategy to help prevent AD, as well as many other chronic conditions. The CSHA-2 recommends that further research still needs to be conducted in this area.Error: Reference source not found Hypertension, high cholesterol, diabetes mellitus and low estrogen may affect the development of AD. Co-morbid diseases that may affect the development of AD are being researched.Error: Reference source not found,Error: Reference source not found,Error: Reference source not found Other factors being investigated by researchers in relation to Alzheimer Disease include: Existing diseases or conditions that a person may have (such as heart disease, high cholesterol or high homocysteine levels in the blood) Toxins in the environment (such as fertilizers or pesticides) Antioxidants (such as vitamin E) Lifestyle choices (such as wine and coffee consumption, and diet)
6.1117
Trends
Age is the strongest predictor for the development and progression of AD. According to ADEAR (Alzheimer disease Education and Referral Center), a service of the NIA (National Institute of Ageing), the number of people with AD doubles every 5 years after the age of 65 .Error: Reference source not found AD is a terminal disease, with deterioration in physical and mental health over time. Cause of death is usually pneumonia and infections as a result of the weakened immune system. 29 With the rapidly aging population of our society, AD clearly poses a major health problem. There are approximately 8-10 million people affected with AD within countries with strong pharmaceutical markets. (UK, USA, Spain, France, Germany, Italy and Japan) and these numbers will most likely continue to rise as the baby boomer generation approach 65 years of age. Pharmaceutical sales of cholinesterase inhibitors, the only major approved class at present for AD, are estimated to be at approximately 1 billion dollars, with about 60% of diagnosed AD patients receiving medications. This market will most likely grow with a three to five fold increase with the inclusion of patients diagnosed with MCI (mild cognitive impairment), a precursor to AD. Much will depend on whether MCI is recognized as a reimbursable disease.
6. Past/Current Research into Pharmaceutical Interventions of AD

At present, all treatments for AD offer only modest symptomatic relief for periods between six to eighteen months. Cholinergic therapies are the mainstay of AD management today. Unfortunately, there are no drugs that can halt or reverse AD progression. This section provides some information on some of the areas of ongoing research for AD. The past 5 years has seen a growth in the number of drugs being developed for AD. Future compounds under research are aimed at delaying, preventing progression of the illness and drugs that may alleviate the underlying pathology.Error: Reference source not found, Error: Reference source not found
Drugs for Disease Modification

Secretase inhibitors. One of the features of AD pathophysiology is the accumulation of senile plaques at the end of degenerating brain neurons. amyloid, a major constituent of these plaques, is toxic to neurons in vitro and is considered to be responsible for the neuronal cell loss in AD. and secretases are the two enzymes critically responsible for forming amyloid. This discovery has prompted new therapies directed at blocking these enzymes, thus preventing or slowing the progression of the disease. At present most of the research is limited to animal testing.30 Metal chelation. As mentioned above, brain damage in Alzheimer disease is caused by amyloid, but metal ions, such as zinc and copper, both of which accumulate in the brain with old age, are also neurotoxic. Research has shown that these metals cause amyloid aggregation, and the mixture of the two (i.e. amyloid and metal ions) results in the production of hydrogen peroxide, which in turn causes oxidative damage. Clioquinol, an antibiotic, which acts as a chelating agent, facilitates the removal of metal ions, and has the potential to slow progression of AD. Phase II trial results have been promising and large treatment trials are expected.Error: Reference source not found
6.1118
Vaccine. Efforts to develop a vaccine so that an immune mediated response targets the disease are still being investigated. The phase II trial of an active vaccination approach in AD was stopped in 2001 since it resulted in meningoencephalitis (inflammation of the brain and surrounding areas). Despite this set back, research still continues in the area of safe vaccine development, which may be able to combat AD.Error: Reference source not found The use of passive immunization is less likely to cause the inflammation seen with the active vaccination approach. High cholesterol, an increased risk factor for AD, has also been implicated in the pathology of AD and is thought to promote amyloid production. New focus on 8 th international conference on AD reports that an autopsy study in the US found that a 10% increase in blood cholesterol level doubles the risk of amyloid deposits in the brain. Clinical trials in the US to compare the progression of AD in those taking statins versus placebo are to be launched.Error: Reference source not found
Statins.
Neurotransmitter targets. Cholinesterase inhibitors, are currently the only widely approved class for the treatment of AD. This therapeutic class inhibits the enzyme acetylcholinesterase, which breaks down acetylcholine in the synaptic cleft and therefore they increase acetylcholine levels in the brain. These drugs, do not attack the underlying disease pathology, instead they compensate for the loss of neurons that communicate via this enzyme. Cholinesterase inhibitors appear to slow down cognitive decline, however the improvements are very modest. Memantine, which works to inhibit the action of neurotransmitter glutamate, has been launched in the US and some European countries. It has been approved for moderate to severe patients Experts within the field suggest that the two classes may be used in combination or combined with other therapies under development.Error: Reference source not found, 31
Drugs for Prevention and Disease Modification

AD is an insidious disease; sometime years go by before symptoms become noticeable. Disease prevention, therefore may be beneficial, and may decrease the prevalence of AD. Studies assessing prevention are underway. NSAIDS: One such prevention study is evaluating the use of NSAIDS (non steroidal anti-inflammatory drugs) on AD. Preliminary results are promising, however AD researchers are reluctant to recommend NSAIDS given the toxicities (gastrointestinal ulcers, renal toxicity, hypertension) associated with taking these medicines. Researched are waiting for results from large RCTs in order to weigh the risks versus benefits of NSAID therapy before making any recommendations.Error: Reference source not found Antioxidants. Pathological data indicates that oxidative stress and the accumulation of free radicals results in neuronal damage in AD. There are several studies evaluating the effects of antioxidative compounds on AD. Vitamin E and selegeline appear to delay progression. Research continues on the use of antioxidative vitamins and large US studies are underway to clarify the role of vitamin E in AD prevention.Error: Reference source not found , Error: Reference source not found A number of studies have evaluated selegeline for the treatment of AD. Most of these studies show some improvement in cognition, however there is very little evidence to support global improvements in cognition, functional ability and behavior. In a metanalysis of 15 selegiline trials, authors concluded that there 6.1119
was insufficient evidence to recommend its use for AD.Error: Reference source not found A chochrane review of selegeline for AD concluded that there may be some benefit in cognition and its use may be promising. However, at present there is insufficient evidence to recommend its use in practice.Error: Reference source not found Hormones. The attention and potential uses of hormone replacement therapy to treat AD is derived from epidemiological, clinical, and neuropathological observations and are still ongoing. Women are at a higher risk of developing AD than men since women are estrogen deficient post menopause whereas men benefit from estrogen as testosterone undergoes aromatization to estradiol. Estrogen is considered to have numerous beneficial properties some of which were thought to be antioxidant and anti-inflammatory properties, interactions with neurotransmitters such as acetylcholine and its ability to alter apolipoprotein which could lower the risk of developing AD. Unfortunately, no studies to date have demonstrated a positive impact on improving the biological course of AD. Studies are still ongoing and need to assess the type of HRT administered, timing of HRT in AD, effect of HRT with cholinergics. Currently, there is insufficient evidence for HRT in AD management.Error: Reference source not found ,Error: Reference
source not found
Other Agents. Various other pharmacological agents to treat AD are being studied. Gingko Biloba, a plant extract that contains numerous pharmacological properties, some of which are thought to be antioxidative, anti-inflammatory or neurotransmitter modulators. Current research suggests that the use of Gingko Biloba provides smaller effects that that of cholinergics. Also, it is currently unknown which of the active components of this alternative compound contributes to cognitive enhancing effects. Furthermore, the compound is a nonregulated supplement in several countries and standardized preparations are not available.Error: Reference source not found
Table 7: Current and Some Potential Treatments for ADError: Reference source not found
Symptomatic
Probable-in use Acetylcholinesteras e inhibitors Donepezil Rivastigmine Galantamine Muscarinic agonists Inverse Benzodiazepine agonists Transmitter releasing factors/channel blockers
Disease modification
Vitamin E Acetylcholinesterase inhibitors (?) Memantine (?) Ginkgo biloba (?) Antioxidants Estrogen NSAIDS Nootropics e.g. piracetam NGF stimulators Amyloid modifying drugs and vaccines (but secretases are amyloid modifying drugs) Kinase inhibitors Tau-modifying agents Amyloid-modifying agents Gene product manipulation Secretase blockers
Cure
None
Possible-in clinical trial
Nonevaccination approaches are in trial as are the gamma secretase inhibitors
Possible-in clinical developme nt
Nicotinic agonists 5HT6 antagonists PDEIV inhibitors
Gene product manipulation
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6.11:AlzheimerDisease 7. Current Pharmaceutical Product Pipeline for AD Treatment

Currently there are numerous medicines under investigation in the pharmaceutical pipeline. Both the European Agency for the Evaluation of Medicinal Products (EMEA) and the US Food and Drug Administration (FDA) were reviewed to determine the current pipeline. Table 3 indicated the new medications under development for AD.
Table 8:. New Medicines in Development for Alzheimer disease32,

Drug name
271046 (5HT6 antagonist) 737552 (s-8510)
34
33
Indication
Alzheimer disease Alzheimer disease Alzheimer disease Alzheimer disease Alzheimer disease, mild cognitive impairment Alzheimer disease Alzheimer disease Alzheimer disease Alzheimer disease Alzheimer disease, mild cognitive impairment, vascular dementia Alzheimer disease Alzheimer disease Alzheimer disease, neuropathic pain Alzheimer disease Alzheimer disease, Parkinson disease Alzheimer disease Alzheimer disease, Parkinsons disease Alzheimer disease, antimitotic neuropathies (AIM), multiple sclerosis
Company
GlaxoSmithKline GlaxoSmithKline Bristol-Myers Squibb Neurochem Cortex Pharmaceuticals Praecis Pharmaceutical Serono Centaur Pharmaceutcals Bristol-Myers Squibb Memory Pharmaceuticals Mitsubishi Pharma Mzriad Genetics Forest Laboratories Ceregene Boehringer-Ingelheim Pharmaceuticals Axonyx Sanofi-Synthelabo Sanofi-Synthelabo
Developme nt Status
Phase 1 Phase II Phase III Phase III Phase II Phase I Phase I Phase II Phase II Phase I
Abilify (aripipazole) Alzhemed Ampalex (CX 516) Apan-1, APAN Breaker peptide CPI-1189 DP 543 MEM 1003
MKC 2313 MPC 7869 Namenda Nerve growth factor (gene therapy) NS 2330 Phenserine tartate SR 57667 SR 57746
Phase II Phase II Phase III Phase I Phase II Phase II/III Phase II Phase II
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Research into Emerging Technologies
Proteomics involves the identification of unknown proteins following their separation. The application of proteomics to Alzheimer disease (AD), is a very new and emerging technology. Differences in protein expression and posttranslational modification (mostly oxidative modification) of proteins from AD brain and peripheral tissue, as well as in brain from rodent models of AD, have yielded insights into potential molecular mechanisms of neurodegeneration in AD. Further work in this area hopefully will bring new insights about the pathology, biochemistry, and physiology of AD are beginning to. 35
Europe and the Fifth Framework Program for Alzheimer disease
Alzheimer disease is an important topic of the key action on "The aging population and disabilities" of the European Union's Fifth Framework Programme. The European commission recognizes the impact of AD on individuals and society and the urgent need for treatments that can prevent, arrest and reverse degeneration and death of neurons. The multidisciplinary projects launched with EU support set a prerequisite in the understanding of the fundamental molecular and cellular mechanisms of AD and the development of diagnostic tools that may identify patients at an early pre-symptomatic stage. Furthermore a consortium of 21 of the most experienced AD laboratories from Europe and beyond are to carry our research projects integrating data from studies with tissue cultures and genetically modified animals into a clinical investigations of demented patients. A broad array of bio-technological methods is also to be used. Results of these studies will lead to diagnostic screening strategies combing genetic, pathophysiological and biomarker information. Annex 6.11.2 is the records of the current fifth framework research projects related to AD. 36 Six EU-funded projects were launched in 2000 with a total EU support of 2 million over 3 years. The ultimate aim of the projects is to diagnose, prevent, delay the onset or treat Alzheimer disease.37 Five of the 6 projects seek to understand the mechanisms involved in neurodegeneration and complement each other by studying various aspects of these mechanisms. All aim at identifying and testing potential therapeutic strategies, for instance anti-inflammatory drugs. Two pharmaceutical industries are already involved as partners in two projects and others will be involved in others when new potential therapeutic targets are identified. One project focuses on the needed improvement of cost-effective early diagnosis of dementia and on the differential diagnosis among the various types of dementia. Differentiating Alzheimer disease from other dementias is indeed important, since some of the latter can be treated. This project will essentially try and define widely available diagnostic procedures, by comparison to positron 6.1122
emission tomography (PET), a little available and expensive non-invasive metabolic imaging technique. 5827
6.1123
8. Opportunities for Research into New Pharmaceutical Interventions

A great deal more is known about AD and dementia than previously, but new found knowledge and new drugs currently being studies also pose new questions. The following sections are some opportunities of research for AD. Cholinergic therapies only bring about a temporary relief in AD symptoms, and it is not possible to predict who will respond. It is also unclear whether patients who do not respond to one anticholinesterase inhibitor will respond to another. Systematic clinical research is needed to answer these clinical questions. Furthermore, ways of measuring, determining response, and assessing when medications need to be stopped remain unclear and need to be addressed.38 There may also be a need for more comparative clinical trials of these agents to determine which agent offers the greatest benefit and causes least resistance. The effective and appropriate administration of cholinergic and other medicines requires good baseline assessment with validated scales for objective measurement. Further work is required and practice guidelines are needed to assist clinicians in effectively diagnosing patients suspected with AD. There is also a need for better scales for the non-cognitive symptoms.Error: Reference source not found,Error: Reference source not found Cholinesterase inhibitors are licensed for use in mild to moderate AD and at present, there is insufficient data on their safety and efficacy in severe AD. Further studies are required to assess this.Error: Reference source not found,Error: Reference source not found More comparative trials evaluating multiple cholinergic medicines, as well as combination therapy with different classes for drugs, also remains unanswered and well-designed RCTs, with clear indications for appropriate doses for various stages of AD are needed.Error: Reference source not found Additional well-designed studies, adequately powered, are needed to assess the beneficial properties of anti-inflammatory compounds such as ginkgo biloba, ibuprofen, and cerebrolysin.Error: Reference source not found Studies are also needed to compare and assess different formulations and doses of vitamin E in altering the course of AD.Error: Reference source not found Research recommendations for management of non-cognitive behavioural disturbances: There is a need for more randomized clinical trials on the pharmacological treatment of anxiety, disinhibition, compulsive behaviors, wandering, agitation, and sleep disturbances associated with AD. Studies are required to assess which behavioural disturbance are best treated with pharmacological and non-pharmacological therapies. Furthermore, comparative studies are needed comparing anxiolytic, tri-cyclic antidepressants, SSRIs and novel antipsychotic medicines in AD.Error: Reference source not found AD is a complex disease overlaid with neuro-psychotic and behavioural symptoms, and management rarely responds to medicines alone. Important factors other than cognitive functions and activities of daily living need to be studied. Behavioural modification and education combined with drug therapies as well as caregivers interventions require systematic clinical research. This will include time to institutionalization, quality of life issues as well as economic evaluations.Error: Reference source not found,Error: Reference source
not found
6.1124
Gaps Between Current Research and Potential Research Issues that Could Make a Difference
A review of currently available treatments suggests a number of areas for further study. Some of these recommendations are within the realm of improved evaluation and assessment.39 Improved detection and evaluation of dementia, especially in the prodromal and early stages, when treatment that slows progression would be more likely to be beneficial. This implies the development of a reliable diagnostic tool. There is a clear need for increase biomarkers for measuring disease progression the lack of these means that trials of disease modifying therapies will not move ahead as rapidly as possible. The use of surrogate endpoints e.g. imaging also needs more investigation. (see below). Development of consensus on clinically meaningful outcome measures and hard endpoints, such as institutionalization and mortality.Error: Reference source not found Within the field of pharmacologic therapy, there is a critical need for medicines with greater ability to improve cognition or at least halt the progression of dementia. Areas that are already being actively studied in patients with AD include cholinergic agonists, vitamin E, NSAIDs and antioxidants.Error: Reference source not found Despite the progression in the areas mentioned above, research and development needs to further identify and test new cognition-enhancing medicines based on the pathophysiology and information learned about the disease from neuroscience and molecular genetics. For example, pharmacologic agents that prevent or slow amyloid deposition or remove precipitated amyloid which might serve to prevent or reverse AD.Error: Reference source not found Other research directions that can greatly affect management of AD, is the optimal pharmacologic treatment of noncognitive symptoms, including psychosis, agitation, depressions and sleep disturbances. Many current recommendations are based on small-uncontrolled studies or agents no longer in common use and/or at doses well above those used in current practice. There is, therefore, a critical need for randomized controlled studies and guidelines on up-to-date treatments for non-cognitive symptoms present in AD.Error: Reference source not found Clinical questions that need to be further evaluated and studied include what to treat? There is a problem surrounding the terminology, and diagnosis associated with dementia and AD. Confusion remains about when to initiate treatment; how to treat -i.e. what agents to start, how to switch drugs in the case of decreased efficacy, intolerance, adverse effects or drug interactions and how long to treat AD.Error: Reference source not found In addition to symptomatic or palliative options, increased knowledge of the anatomical, cellular and molecular basis of AD, together with the identification of new drug targets, which may prevent, slow or delay its onset are needed. These possibilities may be expedited by the further progress in research and development of improved animal; introduction of more efficient and effective clinical trials, and the use of non-invasive imaging to monitor the progression of the disease. It has been estimated that delaying the onset of AD by approximately 5 years would reduce the numbers dramatically by about 50% by 2050.40 6.1125
Combination therapies are likely to offer maximum benefit in longer term disease modification. See Background Chapter 7.1
9.
Barriers to Closing the Alzheimer Pharmaceutical Gap

Lack of validated targets. AD requires a clinical diagnosis, and at present, there are no reliable tests to confirm a diagnosis. Definitive diagnosis can only be made postmortem from brain tissue. Despite years of research, there is still an unclear understanding on the pathogenesis of AD. Further research is still needed at the basic neuroscientific level. Companies are already investing large amounts of money in AD, but the high risk and cost coupled with long clinical trials in disease modification, mean that at most a company could only take one or two approaches forward in disease modification trials at present. The problem is the high risk and the lack of markers to increase confidence in moving from Phase II to large Phase III trials. Lack of animal models. There are no good animal models that reflect the disease state. Those models that do exist model only aspects of pathology e.g. amyloid over expression. Equally as important is the issue of access to animal models. Current animal models are not readily accessibly for research and drug screening at the preclinical level because of intellectual property and licensing issues. Many of these models belong to academia (not industry) and institutes and the costs of the models are prohibitive to academic scientists and small biotech companies. Barriers in the design and implementation of clinical trials . Long trials are needed to determine the efficacy and safety of AD medicines. In an effort to control AD at the early stages, clinical studies are evaluating the effectiveness of therapies at mild cognitive impairment (MCI) stages, which is considered the prodromal stage to AD. Guidelines for MCI studies have not been established. Another area that requires further work is the design and outcomes measures for AD prevention. Scientific evidence has determined that neuropathology processes resulting in AD occurs several years prior to the onset of AD symptoms. However, conducting long-term clinical studies to monitor a patients progression or decline in function is costly and requires a lot of effort. Lack of surrogate markers. The lack of surrogate markers for therapeutic endpoints remains a major barrier in the clinical development of efficacious AD drugs. The availability of such surrogates would benefit and hasten AD drug development. Any reliable predictor of clinical outcome will step up the development of effective AD medicines. Much work in this area is already ongoing, however continued efforts are still required. Commonly accepted markers in cerebrospinal fluid (CSF) or blood such as alpha -amyloid and tau are still not adequately validated and may not be sensitive for longitudinal progression and treatment effects on AD. Additionally, neuroimaging markers, as determined by MRI are reasonably validated and sensitive for use in long-term trials but are not suitable for shortterm duration, proof of-concept trials. There is also a need to develop an infrastructure to speed up validation studies, such as large-scale biologic sample collection from ongoing aging populations. The availability and development of specific imaging technology such as Positron Emission Tomography (PET) to determine whether changes in 6.1126
the brain or its function can be identified before the person develops symptoms of the disease is also needed. Error: Reference source not found Barriers in academia41. Academic drug discovery and development programs are usually under funded and lack infrastructure, in terms of staff and equipment especially at the preclinical level. Furthermore, the lack of communication, interaction and collaboration between necessary research groups can limit drug discovery and research. Today, science and medicine requires an interdisciplinary approach to solving medical conditions. Barriers in biotechnology 42 AD drug discovery and development is considered high risk and attracting capital for early high-risk projects is very difficult, especially when the return on investment is questionable or long-term. The cost of conducting clinical trials is also another major barrier to small companies: risks are high and the probabilities of scientific success low. Therefore, external funding is important. EUROPA, the European commission group to improve innovation proposes that a small business innovation research programme (SBIR) mechanism-like that employed in public funding in the US, be introduced into the FP6-through integrated projects. This will speed up the creation of new companies and provide capital for smallto-medium sized enterprises. In the US SBIR mechanisms amounts to US 1.3 billion dollars.43 Regulatory barriers. Another barrier that affects both the pharmaceutical and biotech industry is the lack of international harmonization of clinical trials and regulatory requirements. Designing trials that meet individual requirements is costly and timely. A further barrier to drug development is the definition of therapeutic effectiveness of AD medicines. The FDA requires that medicines show superiority to placebo on a performance-based test and a measure of global clinical function. Outcome measures are still unspecific and need to be established by the medical community. Other outcome efficacy measures that affect AD function are needed to guide drug development, and registration.
10. European Union Funding Opportunities for AD

New and emerging science and technologies (NEST) is a new activity within the 6th Framework Program (2002-2006), supporting scientific research with the potential to open new fields for European science and technology. It will also help to consolidate European efforts in emerging fields of research. NEST activities will also assist in planning future activities in the European Research Area. They will help to sustain projects that will need larger-scale support in future European research programs. The overall budget for NEST within FP6 is 215 million. 44 The following activities set by the FP6 will further enable research and development into AD. Scientists internet networks - SINAPSE Error: Reference source not found The European Commission is setting up a network called SINAPSE (Scientific Information for Policy Support in Europe), which will put science at the service of policy development. The network began its work in 2003, and has a number of different functions: To develop an electronic library of scientific opinions and advice which will give public authorities seeking expert advice on scientific issues, 6.1127
the opportunity to check whether any work has been done on the subject; enable the Commission to conduct informal scientific consultations, give the scientific community and other stakeholders the chance to initiate discussions on potentially contentious scientific issues and to provide a secure network for discussions between scientists.
Giving advice on research Error: Reference source not found The European Research Advisory Board is a high-level independent advisory committee, made up of 45 top experts from EU countries, which provides advice on the design and implementation of EU research policy. It focuses on realizing the European Research Area, and on using policy instruments such as the Community Research and Development Framework Programme.
11. Conclusion
AD is the most common cause of dementia in people aged > 65 and affects more than 18 people worldwide. This number will increase considerably in the future and will present enormous financial burdens to health care systems. Thus, there is an urgent need for effective medicines. Currently only symptomatic treatment is available. While there is research and development already in this area, much work still is required. This includes: basic research in the pathophysiology of the disease and its risk factors; noninvasive and clinically effective diagnostics tools; wider scale outcome efficacy measures for the disease function and progress and developing medicines that slow progression, halt, or prevent AD from occurring. Additionally, challenges for clinical services include early diagnosis, and intervening early with the most appropriate and effective medicine. Error: Reference source not found There are several barriers to closing the obvious pharmaceutical "gaps" with regard to AD. Specific recommendations include the following: The EU and EU-based philanthropic organizations need to recognize and help overcome the various scientific and systemic barriers to improving pharmaceutical R&D for Alzheimer disease and provide funding for making animal models more accessible and affordable. Also new grant agreements should be implemented that compensate investigators and institutions while making the models more widely available. There is a need for improved AD assessment tools, with increased sensitivity and efficiency for patient evaluation for AD primary prevention. More specifically, curtailing time requirements for clinical staff, data monitoring and data entry could decrease costs for trials. An important research goal should also be the development and evaluation of new instruments in relevant domains that are sensitive, reliable, and valid for detecting changes in normal aging and early AD. Furthermore, it would be helpful if these can be self-administered and not require significant professional involvement. New uses of technology, such as computerized assessments and telephonic methods are some options and may be desirable in this field. There needs to be more collaboration and a multidisciplinary approach in the areas of research and development for AD. Neurobiologists, clinicians, medical chemicals need to work together. Funding resources and guidelines that can assist scientists in preclinical drug development is required.
6.1128
New funding models should be explored which can support core research facilities and non-tenured staff in academic institutions, such as the creation of endowments for facilities and pharmaceutical and biotech consortia.
6.1129
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6.

Size and Nature of Disease Burden

Incidence and Prevalence

Alzheimer's Disease (DALYs)

0 0-4 5-14 15-29 30-44 45-59 60-69 70-79 80+

Source: World Health Organization Global Burden of Disease Database

ALzheimer's as Percent of All DALYS (by age group)

Source: World Health Organization Global Burden of Disease Database

Table 3: Proportions of Dementia in the UKError: Reference source not found

DiagnosisError: Reference source not found

Research Directions in Diagnosis and Evaluation

ManagementError: Reference source not found

Table 4: Therapeutics Options for Alzheimer disease

15, 16, 17, 18

Pharmacological Therapy Review for AD

Psychiatric Management of Non-Cognitive Symptoms

Affordability and Feasibility

Risk factor Age Positive family history

Risk factor Down Syndrome Head injury

Social, productive and Physical activity

Comorbid diseases Other risk factors being studied

6. Past/Current Research into Pharmaceutical Interventions of AD

Drugs for Disease Modification

Drugs for Prevention and Disease Modification

Possible-in clinical trial

Nonevaccination approaches are in trial as are the gamma secretase inhibitors

Possible-in clinical developme nt

Nicotinic agonists 5HT6 antagonists PDEIV inhibitors

Gene product manipulation

6.11:AlzheimerDisease 7. Current Pharmaceutical Product Pipeline for AD Treatment

Table 8:. New Medicines in Development for Alzheimer disease32,

Europe and the Fifth Framework Program for Alzheimer disease

8. Opportunities for Research into New Pharmaceutical Interventions

Barriers to Closing the Alzheimer Pharmaceutical Gap

10. European Union Funding Opportunities for AD

Ritchie K, Lovestone S. The Dementias. Lancet 2002; 360 (30): 1759-66.

http://www.alzheimer.ca/english/disease/stats-people.htm . Alzheimers organization of Canada. Last accessed March 08, 2004.

http://www.alzheimers.org.uk/News_and_Campaigns/Policy_Watch/demography.htm. Alzheimers Society UK. Last accessed March 10, 2004.

http://www.alzheimer.or.jp. Alzheimers organization of Japan. Last accessed March 08, 2004.

http://www.alz.org/Health/Diagnose/overview.asp. Alzheimers Association. Diagnosis. Last Accessed July 27, 2004.

http://www.alzheimer-europe.org/?lm1=D8105B21BD2C. Alzheimer Europe. Last accessed March 09, 2004.

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