There are two main approaches to the treatment of Alzheimer's disease. The first approach is to prevent the neurodegenerative changes that ultimately cause irreversible damage to the brain. As the excessive formation of beta- amyloid protein appears to play a primary role in the neurodegenerative process, attempts have been made to block the synthesis of this protein. Secondary changes that may be initiated by beta-amyloid include local inflammatory factors, in particular cytokines 1 and 6. There is evidence that nonsteroidal anti-inflammatory drugs such as indomethacin may have a role to play in preventing such inflammatory changes. The second approach is to slow the decline of the neuronal degeneration and to treat the symptoms of the disease. As many of the core symptoms appear to be associated with a degeneration of the cortical cholinergic system, centrally acting anticholinesterases such as tacrine and donepazil have been shown to be helpful in a minority of patients. An alternative approach to treating the cause of brain damage in Alzheimer's disease is to administer neurotrophic factors which could stimulate neuronal growth and development. So far, these approaches are only experimental. Other approaches involve drugs used to reduce free radical formation.
One of the most feared aspects of ageing is the deterioration of memory and cognitive function that characterises dementia and whose frequency increases with advancing years. It has been estimated that, in industrialised countries, 10 per cent of the population over 65 years suffer from mild to moderate dementia, while 4±5 per cent suffer from severe dementia; severe dementia occurs in less than 5 per cent of those 65±70 years, but increases to 20 per cent in those of over 80 years (Terry and Katzman, 1983). As the majority of elderly patients with dementia require additional health care either in the home, or increasingly in specialised nursing homes or hospitals, the cost to the health services is enormous and likely to increase. In the United States, for example, it has been estimated that nearly $600 billion per annumis spent on the care of such patients. As approximately 60 per cent of those patients with dementia has been ascribed to Alzheimer's disease (approximately 20 per cent of the remaining causes being due to dementias associated with Parkinson's disease, multi-infarct dementia and related disorders), both the patients and society would clearly benefit if drugs could be developed which would either slow down the progress of the disease or, eventually, prevent it. Perhaps it is not surprising to find that the sale of drugs in the USA to treat the symptoms of Alzheimer's disease will probably reach $3 billion per annum by the year 2000.
There appears to be two major types of Alzheimer's disease which are differentiated by their age of onset rather than by their neuro- pathological differences (McKhann et al., 1984). Familial Alzheimer's disease usually occurs before the age of 50 years and is inherited within families; several genetic mutations have been discovered that directly relate to the cause of the disease (Raskind et al., 1995). The main type of Alzheimer's disease that occurs in patients over 65 years of age is the sporadic form in which genetic variation may account for the differences in susceptibility to the disease. In both the familial and sporadic forms of Alzheimer's disease, life expectancy is considerably reduced, making the disease one of the leading causes of premature death in the elderly (Molsa et al., 1986).
There are three main stages that patients with Alzheimer's disease pass through before death (Hasegawa and Aoba, 1994). Stage one, termed the amnesia stage, corresponds to the early clinical symptoms of the disease that include short-term memory deficits, dyscalculia, apraxia and lack of emotional spontaneity. Many of the patients are unable to understand for example, the meaning of true love. In stage two, the confu- sional state, the patient exhibits dysphasia, agnosia, disorientation in time and place, severe mental confusion and personality changes such as aggres- siveness and wandering. The final stage, stage 3, termed the dementia stage, involves the total withdrawal of the patient from normal life. The patient is generally bedridden, incontinent and unable to care for himself or (more usually) herself. The patient then usually dies from a viral or bacterial infection. In addition to these symptoms of dementia, the patient often suffers from depres- sion (5±15 per cent of cases) and delusions or hallucinations in 20±40 per cent of cases. Violent behaviour towards the caregiver often accompanies the delusions (Lawlor, 1994). From the pharma- cological viewpoint, it is usually possible to control the ancillary symptoms (for example, depression with the use of SSRI antidepressants such as sertraline, hallucinations and delusions with neuroleptics such as thioridazine or sulpiride) and those symptoms that are associated with dementia such as a disturbed sleep pattern with sedative antidepressants or neuroleptics.
Since there is no cure for Alzheimer's disease, all current treatment strategies are aimed at alleviating the symptoms or decreasing the rate of neuronal degeneration. In addition, current research is also aimed at preventing the onset of the neuro- pathological processes, such as the deposition of beta-amyloid protein, that appears to be causally related to the disease (Gandy and Greengard, 1994). However, while such research has shown promise in slowing the accumulation of beta-amyloid in transgenic mouse models of Alzheimer' s disease, there is no evidence as yet that such an approach is effective in patients.
Initial attempts at the symptomatic treatment of Alzheimer's disease were based on the hypothesis that age-related cognitive dysfunction was due to impaired cerebral blood flow. Vasodilators and anticoagulants were therefore used to improve cerebral blood flow, but with no evidence of clinical benefit. Retrospectively this is not surprising as in the patient with Alzheimer's disease it is probable that the cerebral vessels that are not impaired by the deposition of amyloid plaques are already optimally dilated. Cerebral vasodilators are more likely to dilate peripheral blood vessels and therefore are unlikely to have any benefit in improving the cerebral circulation. The following vasodilators have been used: isoxsuprine HCl, inositol nicotin- ate, co-dergocrine mesylate, naftidrofuryl oxalate. Other approaches that have been used in the past, but with little evidence of clinical benefit, include stimulants such as methylphenidate. While such drugs may have marginal benefit in alleviating fatigue and motor retardation, there is little evidence of any real improvement in the patient's condition.
More recently nootropic agents, also known as cognitive enhancers, have been widely used in some European countries in an attempt to enhance attention, learning and memory (Giurgea, 1980; Schindler, 1994). The potential value of such agents is based mainly on their ecacy in animal models used to screen for putative therapeutic agents. Piracetam is the most extensively studied nootropic agent. More recently other pyrrolidine derivatives such as aniracetam, oxiracetam and paramiracetam have been developed. Despite proven ecacy of such drugs in enhancing the performance of various learning and memory tasks in rodents, including tasks involving amnesia caused by lesions of the central cholinergic system, there is no evidence from properly conducted clinical trials that more than a subset of patients with Alzheimer's disease (of the order of 10 per cent) positively respond to such drugs. Thus, despite the fascinating experimental studies that demonstrate interesting changes in the brain biochemistry and behaviour in animals, the clinical studies have been disappointing.
At best, the drugs so far developed for the treatment of Alzheimer's disease produce a relief of some of the symptoms in a minority of the patients, but only for a relatively short time period. A more worthwhile therapeutic approach would be to prevent the neurodegenerative process by correcting the deficits in neurotrophic factors that promote neuronal survival, growth and differen- tiation (Selkoe, 1991; Kosik and Coleman, 1992). In recent years, attention has been directed towards the nerve growth factor (NGF). This approach has been encouraged by the finding that the intracere- broventricular (icv) administration of purified mouse beta NGF to an Alzheimer patient for a period of three months resulted in an increased cerebral blood flow and nicotinic receptor binding, a reduction in abnormal cortical EEG and a transient improvement in some aspects of cognitive performance (Seiger, 1993). Experimental studies have shown that NGF selectively enhances the growth and development of the basal forebrain cholinergic neurons that innervate the cortex and the hippocampus (Tuszynski and Gage, 1994). NGF does not apparently extend a trophic action on central noradrenergic neurons thereby limiting the application of the therapeutic potential of this neurotrophin (Maness et al., 1994). At present the studies on the use of NGF in the treatment of Alzheimer's disease have been limited by the lack of availability of human recombinant beta-NGF.
However, in future, therapy with NGF or other neurotrophins that cannot cross the blood±brain barrier, and must therefore be given by intracere- broventricular administration, could be accom- plished by the cerebral implantation of NGF secreting cells. It is not without interest that hormone replacement therapy in elderly females has been shown to protect individuals from the onset of Alzheimer's disease. There is evidence that the oestrogen component of hormone replacement therapy increased neurotrophin activity, particu- larly in the basal forebrain region. Gangliosides have also been shown to have neurotrophic proper- ties in experimental studies, but their use in patients is so far inconclusive (Ledeen, 1984).
Mention has already been made of the possible involvement of the immune system in the aetiology of Alzheimer's disease. It is well established that microglia (which have macrophage activity in the brain) are prominent at the lesion sites in the Alzheimer patient's brain (Wilmot et al., 1995). The presence of microglia may be the result of local infiltration and proliferation. Microglia-derived cytotoxic products and other secretory factors may therefore contribute to the progression of the disease. In addition, the cytokines inter-leukins 1 and 6 (IL-1, IL-6) are elevated in the brains of Alzheimer patients indicating that there is an active inflammatory response; acute phase proteins (alpha1-antichymotrypsin and alpha2- macroglobulin) are raised and are also associated with the immune response (Strauss et al., 1992; Abraham et al., 1988). It would appear that cytokines may contribute to the pathology of Alzheimer's disease by regulating amyloid precur- sor protein gene expression (the main abnormal component of the plaques) and/or proteolytic processing. Support for the hypothesis that an abnormal inflammatory process is involved in the aetiology of Alzheimer's disease comes from the evidence that anti-inflammatory drugs may have a protective effect against the disease (McGeer and Rogers, 1992; Han et al., 1990). A retrospective analysis of the incidence of Alzheimer's disease in patients with rheumatoid arthritis showed that the prevalence of the disease in arthritis clinics was about 0.4 per cent, whereas the incidence in the general population of 64 or more years was estimated at 2.4±10.3 per cent. Conversely, in a post mortem study on a group of patients with Alzheimer's disease, only 0.7 per cent had a history of rheumatoid arthritis. Thus potent nonsteroidal anti-inflammatory drugs (NSAIDs) such as indo- methacin may protect against Alzheimer's disease by reducing the local inflammatory processes that results from the increase in the prostaglandin and leukotriene pathways activated by the cytokines (Rogers et al., 1993).
Finally, accumulated evidence suggests that free- radicals induce amyloid aggregation and deposition (characteristic features of the plaques) and nerve membrane damage may make an important con- tribution to the pathophysiology of Alzheimer's disease. Thus drugs reducing free-radical formation within the brain, and protecting neurons from the toxic effects of free-radicals, could provide a useful therapeutic approach to slowing the degenerative process (Hall, 1992). Besides vitamin E supple- ments, the free radical scavengers idebenone and tirilizad mesylate have already undergone limited therapeutic trials and iron chelating agent desfer- rioxamine has been claimed to have therapeutic benefit (Crapper-McLachan et al., 1991; Nappi et al., 1992; Senin et al., 1992).
In conclusion, it would appear that there are several different approaches which are being made to prevent or reduce the neurodegenerative process which characterises Alzheimer's disease. If it is assumed that the main causative factor in the development of Alzheimer's disease is the excessive formation of the beta-amyloid protein, which may be associated with cellular damage and cytokine mediated inflammation, those drugs which block the formation of beta-amyloid and/ or reduce the localised inflammatory processes could be of therapeutic value. So far only NSAIDs have been shown to offer some potential protection in this regard. Other fundamental approaches, which are currently in the early stages of clinical development, include the administration of specific growth factors (such as NGF) that may assist in the survival and growth of damaged neurons. How- ever, these preventative approaches are still largely experimental and drug treatment currently rests with the use of drugs that treat the symptoms of the disease by increasing cholinergic transmission. Such approaches, while of limited clinical benefit to a minority of patients, do appear to delay the onset of the major symptoms of the disease if administered early in its development. Perhaps we must wait until the developments in the field of gene substitution therapy can be usefully applied before a really effective treatment of this devastat- ing disease can be obtained.
One of the most feared aspects of ageing is the deterioration of memory and cognitive function that characterises dementia and whose frequency increases with advancing years. It has been estimated that, in industrialised countries, 10 per cent of the population over 65 years suffer from mild to moderate dementia, while 4±5 per cent suffer from severe dementia; severe dementia occurs in less than 5 per cent of those 65±70 years, but increases to 20 per cent in those of over 80 years (Terry and Katzman, 1983). As the majority of elderly patients with dementia require additional health care either in the home, or increasingly in specialised nursing homes or hospitals, the cost to the health services is enormous and likely to increase. In the United States, for example, it has been estimated that nearly $600 billion per annumis spent on the care of such patients. As approximately 60 per cent of those patients with dementia has been ascribed to Alzheimer's disease (approximately 20 per cent of the remaining causes being due to dementias associated with Parkinson's disease, multi-infarct dementia and related disorders), both the patients and society would clearly benefit if drugs could be developed which would either slow down the progress of the disease or, eventually, prevent it. Perhaps it is not surprising to find that the sale of drugs in the USA to treat the symptoms of Alzheimer's disease will probably reach $3 billion per annum by the year 2000.
There appears to be two major types of Alzheimer's disease which are differentiated by their age of onset rather than by their neuro- pathological differences (McKhann et al., 1984). Familial Alzheimer's disease usually occurs before the age of 50 years and is inherited within families; several genetic mutations have been discovered that directly relate to the cause of the disease (Raskind et al., 1995). The main type of Alzheimer's disease that occurs in patients over 65 years of age is the sporadic form in which genetic variation may account for the differences in susceptibility to the disease. In both the familial and sporadic forms of Alzheimer's disease, life expectancy is considerably reduced, making the disease one of the leading causes of premature death in the elderly (Molsa et al., 1986).
There are three main stages that patients with Alzheimer's disease pass through before death (Hasegawa and Aoba, 1994). Stage one, termed the amnesia stage, corresponds to the early clinical symptoms of the disease that include short-term memory deficits, dyscalculia, apraxia and lack of emotional spontaneity. Many of the patients are unable to understand for example, the meaning of true love. In stage two, the confu- sional state, the patient exhibits dysphasia, agnosia, disorientation in time and place, severe mental confusion and personality changes such as aggres- siveness and wandering. The final stage, stage 3, termed the dementia stage, involves the total withdrawal of the patient from normal life. The patient is generally bedridden, incontinent and unable to care for himself or (more usually) herself. The patient then usually dies from a viral or bacterial infection. In addition to these symptoms of dementia, the patient often suffers from depres- sion (5±15 per cent of cases) and delusions or hallucinations in 20±40 per cent of cases. Violent behaviour towards the caregiver often accompanies the delusions (Lawlor, 1994). From the pharma- cological viewpoint, it is usually possible to control the ancillary symptoms (for example, depression with the use of SSRI antidepressants such as sertraline, hallucinations and delusions with neuroleptics such as thioridazine or sulpiride) and those symptoms that are associated with dementia such as a disturbed sleep pattern with sedative antidepressants or neuroleptics.
Since there is no cure for Alzheimer's disease, all current treatment strategies are aimed at alleviating the symptoms or decreasing the rate of neuronal degeneration. In addition, current research is also aimed at preventing the onset of the neuro- pathological processes, such as the deposition of beta-amyloid protein, that appears to be causally related to the disease (Gandy and Greengard, 1994). However, while such research has shown promise in slowing the accumulation of beta-amyloid in transgenic mouse models of Alzheimer' s disease, there is no evidence as yet that such an approach is effective in patients.
Initial attempts at the symptomatic treatment of Alzheimer's disease were based on the hypothesis that age-related cognitive dysfunction was due to impaired cerebral blood flow. Vasodilators and anticoagulants were therefore used to improve cerebral blood flow, but with no evidence of clinical benefit. Retrospectively this is not surprising as in the patient with Alzheimer's disease it is probable that the cerebral vessels that are not impaired by the deposition of amyloid plaques are already optimally dilated. Cerebral vasodilators are more likely to dilate peripheral blood vessels and therefore are unlikely to have any benefit in improving the cerebral circulation. The following vasodilators have been used: isoxsuprine HCl, inositol nicotin- ate, co-dergocrine mesylate, naftidrofuryl oxalate. Other approaches that have been used in the past, but with little evidence of clinical benefit, include stimulants such as methylphenidate. While such drugs may have marginal benefit in alleviating fatigue and motor retardation, there is little evidence of any real improvement in the patient's condition.
More recently nootropic agents, also known as cognitive enhancers, have been widely used in some European countries in an attempt to enhance attention, learning and memory (Giurgea, 1980; Schindler, 1994). The potential value of such agents is based mainly on their ecacy in animal models used to screen for putative therapeutic agents. Piracetam is the most extensively studied nootropic agent. More recently other pyrrolidine derivatives such as aniracetam, oxiracetam and paramiracetam have been developed. Despite proven ecacy of such drugs in enhancing the performance of various learning and memory tasks in rodents, including tasks involving amnesia caused by lesions of the central cholinergic system, there is no evidence from properly conducted clinical trials that more than a subset of patients with Alzheimer's disease (of the order of 10 per cent) positively respond to such drugs. Thus, despite the fascinating experimental studies that demonstrate interesting changes in the brain biochemistry and behaviour in animals, the clinical studies have been disappointing.
At best, the drugs so far developed for the treatment of Alzheimer's disease produce a relief of some of the symptoms in a minority of the patients, but only for a relatively short time period. A more worthwhile therapeutic approach would be to prevent the neurodegenerative process by correcting the deficits in neurotrophic factors that promote neuronal survival, growth and differen- tiation (Selkoe, 1991; Kosik and Coleman, 1992). In recent years, attention has been directed towards the nerve growth factor (NGF). This approach has been encouraged by the finding that the intracere- broventricular (icv) administration of purified mouse beta NGF to an Alzheimer patient for a period of three months resulted in an increased cerebral blood flow and nicotinic receptor binding, a reduction in abnormal cortical EEG and a transient improvement in some aspects of cognitive performance (Seiger, 1993). Experimental studies have shown that NGF selectively enhances the growth and development of the basal forebrain cholinergic neurons that innervate the cortex and the hippocampus (Tuszynski and Gage, 1994). NGF does not apparently extend a trophic action on central noradrenergic neurons thereby limiting the application of the therapeutic potential of this neurotrophin (Maness et al., 1994). At present the studies on the use of NGF in the treatment of Alzheimer's disease have been limited by the lack of availability of human recombinant beta-NGF.
However, in future, therapy with NGF or other neurotrophins that cannot cross the blood±brain barrier, and must therefore be given by intracere- broventricular administration, could be accom- plished by the cerebral implantation of NGF secreting cells. It is not without interest that hormone replacement therapy in elderly females has been shown to protect individuals from the onset of Alzheimer's disease. There is evidence that the oestrogen component of hormone replacement therapy increased neurotrophin activity, particu- larly in the basal forebrain region. Gangliosides have also been shown to have neurotrophic proper- ties in experimental studies, but their use in patients is so far inconclusive (Ledeen, 1984).
Mention has already been made of the possible involvement of the immune system in the aetiology of Alzheimer's disease. It is well established that microglia (which have macrophage activity in the brain) are prominent at the lesion sites in the Alzheimer patient's brain (Wilmot et al., 1995). The presence of microglia may be the result of local infiltration and proliferation. Microglia-derived cytotoxic products and other secretory factors may therefore contribute to the progression of the disease. In addition, the cytokines inter-leukins 1 and 6 (IL-1, IL-6) are elevated in the brains of Alzheimer patients indicating that there is an active inflammatory response; acute phase proteins (alpha1-antichymotrypsin and alpha2- macroglobulin) are raised and are also associated with the immune response (Strauss et al., 1992; Abraham et al., 1988). It would appear that cytokines may contribute to the pathology of Alzheimer's disease by regulating amyloid precur- sor protein gene expression (the main abnormal component of the plaques) and/or proteolytic processing. Support for the hypothesis that an abnormal inflammatory process is involved in the aetiology of Alzheimer's disease comes from the evidence that anti-inflammatory drugs may have a protective effect against the disease (McGeer and Rogers, 1992; Han et al., 1990). A retrospective analysis of the incidence of Alzheimer's disease in patients with rheumatoid arthritis showed that the prevalence of the disease in arthritis clinics was about 0.4 per cent, whereas the incidence in the general population of 64 or more years was estimated at 2.4±10.3 per cent. Conversely, in a post mortem study on a group of patients with Alzheimer's disease, only 0.7 per cent had a history of rheumatoid arthritis. Thus potent nonsteroidal anti-inflammatory drugs (NSAIDs) such as indo- methacin may protect against Alzheimer's disease by reducing the local inflammatory processes that results from the increase in the prostaglandin and leukotriene pathways activated by the cytokines (Rogers et al., 1993).
Finally, accumulated evidence suggests that free- radicals induce amyloid aggregation and deposition (characteristic features of the plaques) and nerve membrane damage may make an important con- tribution to the pathophysiology of Alzheimer's disease. Thus drugs reducing free-radical formation within the brain, and protecting neurons from the toxic effects of free-radicals, could provide a useful therapeutic approach to slowing the degenerative process (Hall, 1992). Besides vitamin E supple- ments, the free radical scavengers idebenone and tirilizad mesylate have already undergone limited therapeutic trials and iron chelating agent desfer- rioxamine has been claimed to have therapeutic benefit (Crapper-McLachan et al., 1991; Nappi et al., 1992; Senin et al., 1992).
In conclusion, it would appear that there are several different approaches which are being made to prevent or reduce the neurodegenerative process which characterises Alzheimer's disease. If it is assumed that the main causative factor in the development of Alzheimer's disease is the excessive formation of the beta-amyloid protein, which may be associated with cellular damage and cytokine mediated inflammation, those drugs which block the formation of beta-amyloid and/ or reduce the localised inflammatory processes could be of therapeutic value. So far only NSAIDs have been shown to offer some potential protection in this regard. Other fundamental approaches, which are currently in the early stages of clinical development, include the administration of specific growth factors (such as NGF) that may assist in the survival and growth of damaged neurons. How- ever, these preventative approaches are still largely experimental and drug treatment currently rests with the use of drugs that treat the symptoms of the disease by increasing cholinergic transmission. Such approaches, while of limited clinical benefit to a minority of patients, do appear to delay the onset of the major symptoms of the disease if administered early in its development. Perhaps we must wait until the developments in the field of gene substitution therapy can be usefully applied before a really effective treatment of this devastat- ing disease can be obtained.
