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Alzheimer's disease: therapeutic strategies for the 1990s
Neurobiologyof Aging,Vol. 15, No. 2, 287-289, 1994 Copyright© 1994 ElsevierScienceLtd Printed in the USA. All rightsreserved 0197-4580/94 $6.00 + .00
Pergamon
Alzheimer's Disease: Therapeutic Strategies for the 1990s W I L L I A M W . PENDLEBURY* A N D P A U L R. SOLOMONI"
*Department of Pathology, University of Vermont, Medical Alumni Building, Burlington, VT 05405 ~Program in Neuroscience and Department of Psychology, Williams College, Williamstown, MA 01267
ALZHEIMER'S disease (AD) is a chronic neurodegenerative disease that causes progressive dementia and is of unknown etiology and pathogenesis. AD's recognition as the fourth leading cause of death in the United States, and its profound morbidity, has led to the development of therapeutic strategies aimed at palliation if not prevention of the disorder. Most strategies have focused on replacement therapy of known neurotransmitter deficits in patients with AD, in particular, the cholinergic deficit first described in the mid 1970s. This brief report describes the limited success of neurotransmitter therapy for AD and speculates on potential new therapies in light of recent molecular genetic and biologic research. It emphasizes that, in spite of progress in understanding the molecular basis of AD, supportive therapy remains the single most successful approach for treating its victims. AD is the leading cause of progressive dementia in the United States and the fourth leading cause of death (6). Despite recent advances in understanding the molecular foundation of AD (7), little progress has been made regarding treatment or prevention of the disorder. Treatment strategies that were developed in the 1980's focused on replacement therapy for a deficit of central cholinergic neurotransmission (2). The recognition of additional central neurotransmitter deficits, including those of noradrenalin, serotonin, somatostatin, corticotropin releasing factor, and glutamate among others, led to the realization that therapy directed at replacing or augmenting a single neurotransmitter in patients with AD has limited long-term efficacy. A large number of clinical trials, using various classes of drugs to facilitate central neurotransmission in AD patients, validated this realization (1). Treatment for AD can be classified into symptomatic, biologic, and "etiologic specific" therapy. Given the early stage of development of novel biologic therapies such as neuroprotective drugs, neurotrophic drugs, and neural transplants, coupled with the limited success of neurotransmitter therapy, symptomatic therapy constitutes the backbone of AD treatment. This is likely to be the case for the foreseeable future. A variety of anti-anxiety, antidepression, and anti-psychotic drugs are used to treat the behavioral aberrations that frequently accompany AD. Nocturnal wantiering, agitation, aggressiveness, and frank belligerence often respond to pharmacological intervention that may serve as a useful adjunct to AD treatment when drugs are judiciously selected and used in appropriate dosages. In particular, the depression that often accompanies AD in the early and middle stages of the disorder may respond to tricyclic, serotonergic, or monoamine oxidase inhibiting agents, leading to a modest but temporary improvement in cognitive dysfunction. Without question, the most important corn-
ponent of supportive therapy for AD is caregiver counseling and support. The emotional and health status of the primary caregiver ultimately determines the outcome of AD patient care, and it is the most significant factor predicting how long the patient will function independent of institutional intervention. In our Memory Disorders Clinic, we devote considerable effort to ensure that the primary caregiver is fully educated about AD and its ramifications, and about appropriate community-based resources such as support groups and adult day care programs. Potential biologic therapy for AD includes neurotransmitter therapy, cognition enhancement therapy, neuroprotective/ neurotrophic therapy, and neural transplants. Of these, only neurotransmitter therapy has been exploited for extensive, multicenter testing of efficacy and safety in AD patients, and the majority of these studies have concerned central cholinergic replacement or augmentation (2). Cholinomimetic therapies include the use of choline precursors (e.g., lecithin), cholinergic agonists (e.g., bethanecol), and cholinesterase inhibitors (e.g., physostigmine and tetrahydroaminoacridine). Novel cholinomimetic agents that have been tested in more limited studies include 4-aminopyridine and DuP 996, both acting to increase the release of acetylcholine into the synaptic space. Initial enthusiasm for many of these drugs has been dimmed by subsequent studies involving larger numbers of AD patients across a wider spectrum of clinical severity. Probably the most publicized of these agents is tetrahydroaminoacridine (THA, Tacrine, Cognex ®) that was first reported to show efficacy in 16/17 patients with the clinical diagnosis of AD (13). In spite of widespread criticism of this study, THA has been used in several multicenter clinical trials, both in the United States and Europe, designed to demonstrate its efficacy and safety. In spite of a lack of conclusive evidence that THA retards progression of the disorder, the drug was made available to a limited number of AD patients under a treatment IND program, and was the object of an additional multicenter clinical trial begun in October 1991. The result of this study (33 centers, 663 patients) led to the approval of THA by the Food and Drug Administration for use in the treatment of mild to moderate AD in September 1993. Other cholinomimetic therapies, including choline precursors or cholinergic (muscarinic) agonist agents, offer little efficacy for the treatment of AD based on experience in a large number of clinical trials. Future manipulation of the cholinergic deficit ..r. AD patients may depend on the use of a drug that combines the properties of both a muscarinic receptor M~ agonist and an M2 antagonist. Because part of the activity of the presynaptically located M2 receptor is to retard the release of acetylcholine into the syn287
288 aptic space, nonselective muscarinic agonists may decrease the beneficial effect of stimulation of postsynaptic Mj receptors. An M~ agonist and M 2 antagonist combination that readily crosses the blood-brain barrier would maximize the therapeutic potential of this cholinomimetic therapy while minimizing peripheral side effects in AD patients (1). Regarding other neurotransmitter therapeutic strategies, limited experience with manipulation of monoaminergic and neuropeptide systems in AD patients has produced no convincing beneficial effects. Finally, the use of nootropic and other "so-called" cognition-enhancingdrugs has produced disappointing results thus far. Future therapeutic strategies for AD may depend on the development of agents that provide neuroprotective or neurotrophic mediation for selected neuronal systems. Excitatory amino acid (EAA) neurotransmission in AD has been intensively investigated in the past few years (11,12). Neuronal systems using the EAA glutamate have been shown to be involved in long term potentiation, a mechanism that is likely important for learning and memory. Cortical pyramidal neurons, particularly those in cortical layers three and five, provide the bulk of corticocortical associative connections, and glutamate may be the primary neurotransmitter of these neurons. Of interest is that neurons in cortical layers three and five are selectively vulnerable to the degenerative changes of AD, and a glutamatergic deficit has been described in the disorder (1 li. Contrasting this line of evidence, EAA neurotoxicity is a well described pathogenic mechanism. EAA neurotoxicity may mediate the neuronal necrosis that occurs in cerebral ischemia and status epilepticus, a lesion that can be blocked experimentally by agents that modify the activity of EAA impacting on the NMDA receptor. Whether an endogenous EAA such as glutamate, or an intrinsic defect of the NMDA receptor, plays a role in the chronic neurodegeneration characteristic of AD is at present speculative. A primary issue regarding the potential use of NMDA antagonists in the long term treatment of AD is their well documented amnestic effects. It is clear that any manipulation of the glutamatergic system in AD must have benefits that balance its positive role in learning and memory and intercortical connectivity, and the potential for chronic endogenous glutamate neurotoxicity affecting selective neuronal systems that degenerate in AD. Therapeutic agents that balance these two considerations (perhaps taking into account specific EAA receptor subtypes) might be developed to enhance both intra- and intercortical connectivity, facilitate learning and memory, and yet protect against putative EAA neurotoxicity. Drugs that simply block or mediate NMDA receptors are unlikely to provide significant therapeutic benefit. Related to this strategy is the use of calcium channel blockers such as nimodipine. Nimodipine has been found to augment the acquisition of the classically conditioned eyeblink response in aged rabbits (3). In addition, EAA neurotoxicity has been found to be mediated in part by increased influx of calcium into the cell, leading to calciummediated neuronal dysfunction and cell death. Based on these two lines of evidence, nonselective calcium channel blockade may be an efficacious therapy for AD without significantly adversely affecting the positive role of glutamatergic neurotransmission. A recent report suggests that nimodipine may have a beneficial effect in AD (14), but this result awaits further clinical trials. Neurotrophic factors are widely believed to promote neuronal survival, maintain neuronal phenotype, and promote regeneration. The potential of neurotrophic therapy for AD is based in part on evidence that nerve growth factor (NGF) prevents cholinergic degeneration and promotes neuronal sprouting in experimental animals, including primates, following lesions of the fornix (I 5). Unfortunately, NGF must be considered to have limited efficacy in the treatment of AD given the fact that only a few neuronal sub-
PFNDLEBI.IR~, AND SOLOMO~"~ types are responsive to NGF. Nevertheless, the discover)' ot ne'er. neurotrophic substances (e.g., brain-derived neurotrophic factor) with a broad range of neurotrophic influence holds the promise ,,~f advancement in this therapeutic arena. It i~ possible that novel approaches to the delivery of neurotrophic factors, such as tran~ plantation of genetically engineered fibroblasts that secrete a broad spectrum neurotrophic factor, will become feasible. Given, however, the large number of neuronal subtypes that degenerate in AD, it is unlikely that neural transplants containing a single neu ronal subtype or a narrow spectrum neurotrophic factor, will play any role in AD therapy in the future (4,9). Of the etiologic and pathogenic hypotheses that have been a d vocated for AD, only two are truly etiologic in character, and these include genetic and environmental considerations. Recent molcc. ular studies have identified genetic loci on chromosomes 21 and 19 in kindreds of familial AD (FAD), and three missense mutations of the gene coding for the amyloid precursor protein have been de scribed in at least ten kindreds of early onset FAD (see below) ~7). Aluminum has been advanced as a putative environmental toxin playing either an etiologic or pathogenic role in AD (5). "Etiologic specific" therapy directed against environmental agents likely will be used for AD treatment in the future. For example, chelation of aluminum in AD patients recently has been shown to slow the clinical progression of the disease as measured by activities of daily living (10). [3amyloid protein ([3AP) is a 42 to 43 amino acid fragment (carboxyl terminus) of a membrane spanning glycoprotein known as the amyloid precursor protein (APP). The several isoforms of APP (770,751, 714, 695, 563, and 365 amino acids) are all encoded by a single gene located on chromosome 21.13AP accumulates in the brain both in vascular walls and in association with neuritic plaques in virtually 100% of AD and FAD cases (7) Factors that lead to this accumulation are not clearly understood, but the putative cause has been described in at least 10 FAD kindreds as a missense mutation of exon 17 of the APP gene (7). It has been suggested that abnormal processing of APP, duc either to missense mutations or to other factors (7), leads to the accumulation of [3AP in the brains of patients with AD and FAD. [3AP had been found to be toxic to neurons both in vitro (16) and in vivo (8), toxicity that can be blocked by tachykinin neuropeptides (8,16). This evidence suggests that therapeutic strategies directed against 13AP should potentially include the inhibition of a [3AP forming enzyme, the blockade of [3AP release, the prevention of [3AP aggregation, or interference with the toxic response of ~AP. In summary, there are a number of potential therapeutic strategies for AD. Nevertheless, in the near future, supportive therapy for both the patient and the family will continue to be the primary treatment. As we learn more about various pharmacological approaches, they will be used increasingly in conjunction with supportive therapy. It is likely that initially these approaches will be limited to single drugs, but perhaps the best hope lies in combinations of pharmacotherapies. As we become more sophisticated in our therapeutic strategies for AD, it should be possible to begin to understand what drugs are most efficacious for the various cognitive and behavioral problems that present in AD and to use this information in an attempt to design individualized treatment programs. Future therapeutic strategies for AD will require not only a consideration of clinical, pathologic, and biologic features of the disease but also a more complete characterization of the molecular pathogenesis of AD and the identification of its etiologic initiators and promoters. It is likely that genetic and environmental factors play a causal role in AD and in some instances act in concert to initiate the cascade of events leading to its full clinical and pathologic expression.
FHERAPY OF ALZHE1MER'S DISEASE
289
REFERENCES 1. Davidson, M.; Stem, R. G. The treatment of cognitive impairment in Alzheimer's disease: Beyond the cholinergic approach. Psychiatr. Clin. N. Am. 14:461-482; 1991. 2. Davidson, M.; Stern, R. G.; Bierer, L. M.; Horvath, T. B.; Zemishlani, Z.; Markofsky, R.; R. C. Cholinergic strategies in the treatment of Alzheimer's disease. Acta. Psychiatr. Scand. Suppl. 366:47-51; 1991. 3. Deyo, R. A.; Straube, K. T.; Disterhoft, J. F. Nimodipine facilitates associative learning in aging rabbits. Science 243:80%811; 1989. 4. Dunnett, S. B. Neural transplants as a treatment for Alzheimer's disease. Psychol. Med. 21:825-830; 1991. 5. Good, P. F.; Perl, D. P.; Bierer, L. M.; Schmeidler, J, Selective accumulation of aluminum and iron in the neurofibrillary tangles of Alzheimer's disease: A laser microprobe (LAMMA) study. Ann Neurol, 31:286-292; 1976. 6. Katzman, R. The prevalence and malignancy of A|zheimer's disease: A major killer. Arch. Neurol. 33:217-218; 1976. 7. Kosik, K. S. Alzheimer's disease: A cell biological perspective. Science 256:780-783; 1992. 8. Kowall, N. W.; Beal, M. F.; Busciglio, J.; Duffy, L. K.; Yanker, B. A. An in vivo model for the neurodegenerative effects of B amyloid and protection by substance P. Proc. Nat. Acad. Sci. USA 88: 7247-7251; 1991.
9. Lindvall, O. Prospects of transplantation in human neurodegenerative diseases. Trends Neurosci. 14:376--384; 1991, 10. McLachlan, D. R. C.; Dalton, A. J.; Kruck, T. P. A.; Bell, M. Y.; Smith, W. L.; Kalow, W.; Andrews, D. F. Intramuscular desferrioxamine desferrioxamine in patients with Alzheimer's disease. Lancet 337:1304-1308; 1991. 11. Palmer, A. M.; Gershon, S. Is the neuronal basis of Alzheimer's disease cholinergic or glutamatergic? FASEB. J. 4:2745-2752; 1990. 12. Pomara, N.; Singh, R.; Deptula, D,; Chou, J. C.-Y.; Schwartz, M. B.; LeWitt, P. A. Glutamate and other CSF amino acids in Alzheimer's disease. Am. J. Psychiatr. 149:251-254; 1992. 13. Summers, W. K.; Majovski, L. V.; Marsh, G. M.; Tachiki, K,; Kling, A. Oral tetrahydroaminoacridine in long-term treatment of senile dementia, Alzheimer type. N. Engl, J. Med. 315:1241-1245; 1986. 14. Tollefson, G. D. Short-term effects of the calcium channel blocker nimodipine (Bay-e-9736) in the management of primary degenerative dementia. Biol. Psychiatr. 27:1133-1142; 1990. 15. Tuszynski, M. H.; Sang, H.; Yoshida, K.; Gage, F. H. Recombinant human nerve growth factor infusions prevent cholinergic neuronal degeneration in the adult primate brain. Ann. Neurol. 30:625--636; 1991. 16. Yanker, B. A.; Duffy, L. K.; Kirschner, D. A. Neurotrophic and neurotoxic effects of Amyloid'B protein: reversal by tachykinin neuropeptides. Science 250:27%282; 1990.
Pergamon
Alzheimer's Disease: Therapeutic Strategies for the 1990s W I L L I A M W . PENDLEBURY* A N D P A U L R. SOLOMONI"
*Department of Pathology, University of Vermont, Medical Alumni Building, Burlington, VT 05405 ~Program in Neuroscience and Department of Psychology, Williams College, Williamstown, MA 01267
ALZHEIMER'S disease (AD) is a chronic neurodegenerative disease that causes progressive dementia and is of unknown etiology and pathogenesis. AD's recognition as the fourth leading cause of death in the United States, and its profound morbidity, has led to the development of therapeutic strategies aimed at palliation if not prevention of the disorder. Most strategies have focused on replacement therapy of known neurotransmitter deficits in patients with AD, in particular, the cholinergic deficit first described in the mid 1970s. This brief report describes the limited success of neurotransmitter therapy for AD and speculates on potential new therapies in light of recent molecular genetic and biologic research. It emphasizes that, in spite of progress in understanding the molecular basis of AD, supportive therapy remains the single most successful approach for treating its victims. AD is the leading cause of progressive dementia in the United States and the fourth leading cause of death (6). Despite recent advances in understanding the molecular foundation of AD (7), little progress has been made regarding treatment or prevention of the disorder. Treatment strategies that were developed in the 1980's focused on replacement therapy for a deficit of central cholinergic neurotransmission (2). The recognition of additional central neurotransmitter deficits, including those of noradrenalin, serotonin, somatostatin, corticotropin releasing factor, and glutamate among others, led to the realization that therapy directed at replacing or augmenting a single neurotransmitter in patients with AD has limited long-term efficacy. A large number of clinical trials, using various classes of drugs to facilitate central neurotransmission in AD patients, validated this realization (1). Treatment for AD can be classified into symptomatic, biologic, and "etiologic specific" therapy. Given the early stage of development of novel biologic therapies such as neuroprotective drugs, neurotrophic drugs, and neural transplants, coupled with the limited success of neurotransmitter therapy, symptomatic therapy constitutes the backbone of AD treatment. This is likely to be the case for the foreseeable future. A variety of anti-anxiety, antidepression, and anti-psychotic drugs are used to treat the behavioral aberrations that frequently accompany AD. Nocturnal wantiering, agitation, aggressiveness, and frank belligerence often respond to pharmacological intervention that may serve as a useful adjunct to AD treatment when drugs are judiciously selected and used in appropriate dosages. In particular, the depression that often accompanies AD in the early and middle stages of the disorder may respond to tricyclic, serotonergic, or monoamine oxidase inhibiting agents, leading to a modest but temporary improvement in cognitive dysfunction. Without question, the most important corn-
ponent of supportive therapy for AD is caregiver counseling and support. The emotional and health status of the primary caregiver ultimately determines the outcome of AD patient care, and it is the most significant factor predicting how long the patient will function independent of institutional intervention. In our Memory Disorders Clinic, we devote considerable effort to ensure that the primary caregiver is fully educated about AD and its ramifications, and about appropriate community-based resources such as support groups and adult day care programs. Potential biologic therapy for AD includes neurotransmitter therapy, cognition enhancement therapy, neuroprotective/ neurotrophic therapy, and neural transplants. Of these, only neurotransmitter therapy has been exploited for extensive, multicenter testing of efficacy and safety in AD patients, and the majority of these studies have concerned central cholinergic replacement or augmentation (2). Cholinomimetic therapies include the use of choline precursors (e.g., lecithin), cholinergic agonists (e.g., bethanecol), and cholinesterase inhibitors (e.g., physostigmine and tetrahydroaminoacridine). Novel cholinomimetic agents that have been tested in more limited studies include 4-aminopyridine and DuP 996, both acting to increase the release of acetylcholine into the synaptic space. Initial enthusiasm for many of these drugs has been dimmed by subsequent studies involving larger numbers of AD patients across a wider spectrum of clinical severity. Probably the most publicized of these agents is tetrahydroaminoacridine (THA, Tacrine, Cognex ®) that was first reported to show efficacy in 16/17 patients with the clinical diagnosis of AD (13). In spite of widespread criticism of this study, THA has been used in several multicenter clinical trials, both in the United States and Europe, designed to demonstrate its efficacy and safety. In spite of a lack of conclusive evidence that THA retards progression of the disorder, the drug was made available to a limited number of AD patients under a treatment IND program, and was the object of an additional multicenter clinical trial begun in October 1991. The result of this study (33 centers, 663 patients) led to the approval of THA by the Food and Drug Administration for use in the treatment of mild to moderate AD in September 1993. Other cholinomimetic therapies, including choline precursors or cholinergic (muscarinic) agonist agents, offer little efficacy for the treatment of AD based on experience in a large number of clinical trials. Future manipulation of the cholinergic deficit ..r. AD patients may depend on the use of a drug that combines the properties of both a muscarinic receptor M~ agonist and an M2 antagonist. Because part of the activity of the presynaptically located M2 receptor is to retard the release of acetylcholine into the syn287
288 aptic space, nonselective muscarinic agonists may decrease the beneficial effect of stimulation of postsynaptic Mj receptors. An M~ agonist and M 2 antagonist combination that readily crosses the blood-brain barrier would maximize the therapeutic potential of this cholinomimetic therapy while minimizing peripheral side effects in AD patients (1). Regarding other neurotransmitter therapeutic strategies, limited experience with manipulation of monoaminergic and neuropeptide systems in AD patients has produced no convincing beneficial effects. Finally, the use of nootropic and other "so-called" cognition-enhancingdrugs has produced disappointing results thus far. Future therapeutic strategies for AD may depend on the development of agents that provide neuroprotective or neurotrophic mediation for selected neuronal systems. Excitatory amino acid (EAA) neurotransmission in AD has been intensively investigated in the past few years (11,12). Neuronal systems using the EAA glutamate have been shown to be involved in long term potentiation, a mechanism that is likely important for learning and memory. Cortical pyramidal neurons, particularly those in cortical layers three and five, provide the bulk of corticocortical associative connections, and glutamate may be the primary neurotransmitter of these neurons. Of interest is that neurons in cortical layers three and five are selectively vulnerable to the degenerative changes of AD, and a glutamatergic deficit has been described in the disorder (1 li. Contrasting this line of evidence, EAA neurotoxicity is a well described pathogenic mechanism. EAA neurotoxicity may mediate the neuronal necrosis that occurs in cerebral ischemia and status epilepticus, a lesion that can be blocked experimentally by agents that modify the activity of EAA impacting on the NMDA receptor. Whether an endogenous EAA such as glutamate, or an intrinsic defect of the NMDA receptor, plays a role in the chronic neurodegeneration characteristic of AD is at present speculative. A primary issue regarding the potential use of NMDA antagonists in the long term treatment of AD is their well documented amnestic effects. It is clear that any manipulation of the glutamatergic system in AD must have benefits that balance its positive role in learning and memory and intercortical connectivity, and the potential for chronic endogenous glutamate neurotoxicity affecting selective neuronal systems that degenerate in AD. Therapeutic agents that balance these two considerations (perhaps taking into account specific EAA receptor subtypes) might be developed to enhance both intra- and intercortical connectivity, facilitate learning and memory, and yet protect against putative EAA neurotoxicity. Drugs that simply block or mediate NMDA receptors are unlikely to provide significant therapeutic benefit. Related to this strategy is the use of calcium channel blockers such as nimodipine. Nimodipine has been found to augment the acquisition of the classically conditioned eyeblink response in aged rabbits (3). In addition, EAA neurotoxicity has been found to be mediated in part by increased influx of calcium into the cell, leading to calciummediated neuronal dysfunction and cell death. Based on these two lines of evidence, nonselective calcium channel blockade may be an efficacious therapy for AD without significantly adversely affecting the positive role of glutamatergic neurotransmission. A recent report suggests that nimodipine may have a beneficial effect in AD (14), but this result awaits further clinical trials. Neurotrophic factors are widely believed to promote neuronal survival, maintain neuronal phenotype, and promote regeneration. The potential of neurotrophic therapy for AD is based in part on evidence that nerve growth factor (NGF) prevents cholinergic degeneration and promotes neuronal sprouting in experimental animals, including primates, following lesions of the fornix (I 5). Unfortunately, NGF must be considered to have limited efficacy in the treatment of AD given the fact that only a few neuronal sub-
PFNDLEBI.IR~, AND SOLOMO~"~ types are responsive to NGF. Nevertheless, the discover)' ot ne'er. neurotrophic substances (e.g., brain-derived neurotrophic factor) with a broad range of neurotrophic influence holds the promise ,,~f advancement in this therapeutic arena. It i~ possible that novel approaches to the delivery of neurotrophic factors, such as tran~ plantation of genetically engineered fibroblasts that secrete a broad spectrum neurotrophic factor, will become feasible. Given, however, the large number of neuronal subtypes that degenerate in AD, it is unlikely that neural transplants containing a single neu ronal subtype or a narrow spectrum neurotrophic factor, will play any role in AD therapy in the future (4,9). Of the etiologic and pathogenic hypotheses that have been a d vocated for AD, only two are truly etiologic in character, and these include genetic and environmental considerations. Recent molcc. ular studies have identified genetic loci on chromosomes 21 and 19 in kindreds of familial AD (FAD), and three missense mutations of the gene coding for the amyloid precursor protein have been de scribed in at least ten kindreds of early onset FAD (see below) ~7). Aluminum has been advanced as a putative environmental toxin playing either an etiologic or pathogenic role in AD (5). "Etiologic specific" therapy directed against environmental agents likely will be used for AD treatment in the future. For example, chelation of aluminum in AD patients recently has been shown to slow the clinical progression of the disease as measured by activities of daily living (10). [3amyloid protein ([3AP) is a 42 to 43 amino acid fragment (carboxyl terminus) of a membrane spanning glycoprotein known as the amyloid precursor protein (APP). The several isoforms of APP (770,751, 714, 695, 563, and 365 amino acids) are all encoded by a single gene located on chromosome 21.13AP accumulates in the brain both in vascular walls and in association with neuritic plaques in virtually 100% of AD and FAD cases (7) Factors that lead to this accumulation are not clearly understood, but the putative cause has been described in at least 10 FAD kindreds as a missense mutation of exon 17 of the APP gene (7). It has been suggested that abnormal processing of APP, duc either to missense mutations or to other factors (7), leads to the accumulation of [3AP in the brains of patients with AD and FAD. [3AP had been found to be toxic to neurons both in vitro (16) and in vivo (8), toxicity that can be blocked by tachykinin neuropeptides (8,16). This evidence suggests that therapeutic strategies directed against 13AP should potentially include the inhibition of a [3AP forming enzyme, the blockade of [3AP release, the prevention of [3AP aggregation, or interference with the toxic response of ~AP. In summary, there are a number of potential therapeutic strategies for AD. Nevertheless, in the near future, supportive therapy for both the patient and the family will continue to be the primary treatment. As we learn more about various pharmacological approaches, they will be used increasingly in conjunction with supportive therapy. It is likely that initially these approaches will be limited to single drugs, but perhaps the best hope lies in combinations of pharmacotherapies. As we become more sophisticated in our therapeutic strategies for AD, it should be possible to begin to understand what drugs are most efficacious for the various cognitive and behavioral problems that present in AD and to use this information in an attempt to design individualized treatment programs. Future therapeutic strategies for AD will require not only a consideration of clinical, pathologic, and biologic features of the disease but also a more complete characterization of the molecular pathogenesis of AD and the identification of its etiologic initiators and promoters. It is likely that genetic and environmental factors play a causal role in AD and in some instances act in concert to initiate the cascade of events leading to its full clinical and pathologic expression.
FHERAPY OF ALZHE1MER'S DISEASE
289
REFERENCES 1. Davidson, M.; Stem, R. G. The treatment of cognitive impairment in Alzheimer's disease: Beyond the cholinergic approach. Psychiatr. Clin. N. Am. 14:461-482; 1991. 2. Davidson, M.; Stern, R. G.; Bierer, L. M.; Horvath, T. B.; Zemishlani, Z.; Markofsky, R.; R. C. Cholinergic strategies in the treatment of Alzheimer's disease. Acta. Psychiatr. Scand. Suppl. 366:47-51; 1991. 3. Deyo, R. A.; Straube, K. T.; Disterhoft, J. F. Nimodipine facilitates associative learning in aging rabbits. Science 243:80%811; 1989. 4. Dunnett, S. B. Neural transplants as a treatment for Alzheimer's disease. Psychol. Med. 21:825-830; 1991. 5. Good, P. F.; Perl, D. P.; Bierer, L. M.; Schmeidler, J, Selective accumulation of aluminum and iron in the neurofibrillary tangles of Alzheimer's disease: A laser microprobe (LAMMA) study. Ann Neurol, 31:286-292; 1976. 6. Katzman, R. The prevalence and malignancy of A|zheimer's disease: A major killer. Arch. Neurol. 33:217-218; 1976. 7. Kosik, K. S. Alzheimer's disease: A cell biological perspective. Science 256:780-783; 1992. 8. Kowall, N. W.; Beal, M. F.; Busciglio, J.; Duffy, L. K.; Yanker, B. A. An in vivo model for the neurodegenerative effects of B amyloid and protection by substance P. Proc. Nat. Acad. Sci. USA 88: 7247-7251; 1991.
9. Lindvall, O. Prospects of transplantation in human neurodegenerative diseases. Trends Neurosci. 14:376--384; 1991, 10. McLachlan, D. R. C.; Dalton, A. J.; Kruck, T. P. A.; Bell, M. Y.; Smith, W. L.; Kalow, W.; Andrews, D. F. Intramuscular desferrioxamine desferrioxamine in patients with Alzheimer's disease. Lancet 337:1304-1308; 1991. 11. Palmer, A. M.; Gershon, S. Is the neuronal basis of Alzheimer's disease cholinergic or glutamatergic? FASEB. J. 4:2745-2752; 1990. 12. Pomara, N.; Singh, R.; Deptula, D,; Chou, J. C.-Y.; Schwartz, M. B.; LeWitt, P. A. Glutamate and other CSF amino acids in Alzheimer's disease. Am. J. Psychiatr. 149:251-254; 1992. 13. Summers, W. K.; Majovski, L. V.; Marsh, G. M.; Tachiki, K,; Kling, A. Oral tetrahydroaminoacridine in long-term treatment of senile dementia, Alzheimer type. N. Engl, J. Med. 315:1241-1245; 1986. 14. Tollefson, G. D. Short-term effects of the calcium channel blocker nimodipine (Bay-e-9736) in the management of primary degenerative dementia. Biol. Psychiatr. 27:1133-1142; 1990. 15. Tuszynski, M. H.; Sang, H.; Yoshida, K.; Gage, F. H. Recombinant human nerve growth factor infusions prevent cholinergic neuronal degeneration in the adult primate brain. Ann. Neurol. 30:625--636; 1991. 16. Yanker, B. A.; Duffy, L. K.; Kirschner, D. A. Neurotrophic and neurotoxic effects of Amyloid'B protein: reversal by tachykinin neuropeptides. Science 250:27%282; 1990.