[Skip to Content]
Sign In
Individual Sign In
Create an Account
Institutional Sign In
OpenAthens Shibboleth
[Skip to Content Landing]
Table 1. 
Relevant Drugs for Alzheimer Disease Awaiting Approval or Undergoing Phase 3 Trials*
Relevant Drugs for Alzheimer Disease Awaiting Approval or Undergoing Phase 3 Trials*
Table 2. 
Pharmacokinetic and Pharmacodynamic Profiles of Some Drugs Used or in Clinical Development for the Treatment of Alzheimer Disease*
Pharmacokinetic and Pharmacodynamic Profiles of Some Drugs Used or in Clinical Development for the Treatment of Alzheimer Disease*
Table 3. 
Classes of Drugs in Preclinical or Early Clinical Development for the Treatment of Alzheimer Disease (AD)*
Classes of Drugs in Preclinical or Early Clinical Development for the Treatment of Alzheimer Disease (AD)*
1.
Jope  RSSong  LPowers  RE Cholinergic activation of phosphoinositide signaling is impaired in Alzheimer's disease brain. Neurobiol Aging. 1997;18111- 120Article
2.
Nitsch  RMSlack  BEWurtman  RJGrowdon  JH Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. Science. 1992;258304- 307Article
3.
Jossan  SSAdem  AWinblad  BOreland  L Characterisation of dopamine and serotonin uptake inhibitory effects of tetrahydroaminoacridine in rat brain. Pharmacol Toxicol. 1992;71 ((3, pt 1)) 213- 215Article
4.
Knapp  MJKnopman  DSSolomon  PRPendlebury  WWDavis  CSGracon  SITacrine Study Group, A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease. JAMA. 1994;271985- 991Article
5.
Tiseo  PJRogers  SLFriedhoff  LT Pharmacokinetic and pharmacodynamic profile of donepezil HCl following evening administration. Br J Clin Pharmacol. 1998;4613- 18Article
6.
Polinsky  RJ Clinical pharmacology of rivastigmine: a new-generation acetylcholinesterase inhibitor for the treatment of Alzheimer's disease. Clin Ther. 1998;20634- 647Article
7.
Ringman  JMCummings  JL Metrifonate (trichlorform): a review of the pharmacology, pharmacokinetics and clinical experience with a new acetylcholinesterase inhibitor for Alzheimer's disease. Expert Opin Invest Drugs. 1999;8463- 471Article
8.
Rainer  M Galanthamine in Alzheimer's disease: a new alternative to tacrine? CNS Drugs. 1997;789- 97Article
9.
Mielke  RMoller  HJErkinjuntti  TRosenkranz  BRother  MKittner  B Propentofylline in the treatment of vascular dementia and Alzheimer-type dementia: overview of phase I and phase II clinical trials. Alzheimer Dis Assoc Disord. 1998;12(suppl 2)S29- S35Article
10.
Parnetti  L Clinical pharmacokinetics of drugs for Alzheimer's disease. Clin Pharmacokinet. 1995;29110- 129Article
11.
Rogers  SLPerdomo  CFriedhoff  LT Clinical benefits are maintained during long-term treatment of Alzheimer's disease with the acetylcholinesterase inhibitor E2020. Eur Neuropsychopharmacol. 1995;5386- 387Article
12.
Gottwald  MDRozauski  RI Rivastigmine: a brain-region selective acetylcholinesterase inhibitor for treating Alzheimer's disease. Expert Opin Invest Drugs. 1999;81643- 1682
13.
Itoh  ANitta  AKatono  Y  et al.  Effects of metrifonate on memory impairment and cholinergic dysfunction in rats. Eur J Pharmacol. 1997;32211- 19Article
14.
Thomsen  TBickel  UFischer  JPKewitz  H Galantamine hydrobromide in a long-term treatment of Alzheimer's disease. Dementia. 1990;146- 51
15.
Ulrich  JJohannson-Locher  GSeiler  WOStähelin  HB Does smoking protect from Alzheimer's disease? Alzheimer-type changes in 301 unselected brains from patients with known smoking history. Acta Neuropathol (Berl). 1997;94450- 454Article
16.
Müller  WEMutschler  ERiederer  P Noncompetitive NMDA receptor antagonists with fast open-channel blocking kinetics and strong voltage-dependency as potential therapeutic agents for Alzheimer's dementia. Pharmacopsychiatry. 1995;28113- 124Article
17.
Winblad  BPoritis  N Memantine in severe dementia: results of the M-9 BEST Study (Benefit and Efficacy in Severely Demented Patients During Treatment With Memantine). Int J Geriatr Psychiatry. 1999;14135- 146Article
18.
Holtzman  DMLi  YChen  KGage  FHEpstein  CJMobley  WC Nerve growth factor reverses neuronal atrophy in a Down syndrome model of age-related neurodegeneration. Neurology. 1993;432668- 2673Article
19.
Mackenzie  IRMunoz  DG Nonsteroidal anti-inflammatory drug use and Alzheimer-type pathology in aging. Neurology. 1998;50986- 990Article
20.
Breitner  JCWelsh  KAHelms  MJ  et al.  Delayed onset of Alzheimer's disease with nonsteroidal anti-inflammatory and histamine H2 blocking drugs. Neurobiol Aging. 1995;16523- 530Article
21.
Rogers  JKirby  LCHempelman  SR  et al.  Clinical trial of indomethacin in Alzheimer's disease. Neurology. 1993;431609- 1611Article
22.
Marcusson  JRother  MKittener  B  et al. European Propentofylline Study Group, A 12-month, randomized, placebo-controlled trial of propentofylline (HWA 285) in patients with dementia according to DSM III-RDement Geriatr Cogn Disord. 1997;8320- 328Article
23.
Sano  MErnesto  CThomas  RG  et al.  A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. N Engl J Med. 1997;3361216- 1222Article
24.
Gutzmann  HHadler  D Sustained efficacy and safety of idebenone in the treatment of Alzheimer's disease: update on a 2-year double-blind multicentre study. J Neural Transm Suppl. 1998;54301- 310
25.
Xu  HGouras  GKGreenfield  JP  et al.  Estrogen reduces neuronal generation of Alzheimer β-amyloid peptides. Nat Med. 1998;4447- 451Article
26.
Hardy  JIsraël  A Alzheimer's disease: in search of γ-secretase. Nature. 1999;398466- 467Article
27.
Haass  CDe Strooper  B The presenilins in Alzheimer's disease: proteolysis holds the key. Science. 1999;286916- 919Article
28.
Schenck  DBarbour  RDunn  W  et al.  Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature. 1999;400173- 177Article
29.
Richard  FHelbecque  NNeuman  EGuez  DLevy  RAmouyel  P APOE genotyping and response to drug treatment in Alzheimer's disease. Lancet. 1997;34933Article
30.
Paganini-Hill  AHenderson  VW Estrogen replacement therapy and risk of Alzheimer disease. Arch Intern Med. 1996;1562213- 2217Article
Neurological Review
April 2000

Prospects for Pharmacological Intervention in Alzheimer Disease

Author Affiliations

From the Laboratory of Pharmacology (Drs Emilien and Maloteaux) and Department of Neurology (Dr Maloteaux), Université Catholique de Louvain Cliniques Universitaires Saint Luc, Brussels, Belgium; the Centre for Molecular Biology, University of Heidelberg, Heidelberg, Germany (Dr Beyreuther); and the Department of Pathology, University of Melbourne, and the Mental Health Research Institute, Parkville, Australia (Dr Masters).

 

DAVID E.PLEASUREMD

Arch Neurol. 2000;57(4):454-459. doi:10.1001/archneur.57.4.454
Abstract

Alzheimer disease (AD) involves neuronal degeneration with impaired cholinergic transmission in the cerebral cortex and hippocampus in areas of the brain particularly associated with memory and higher intellectual functioning. Other neurotransmitter deficits also occur, but the mechanisms underlying the widespread impairment of synaptic functions remain uncertain. Research on the molecular basis of AD has elucidated a pathogenic pathway from which a range of rational pharmacological interventions has emerged. Although at least 3 cholinesterase inhibitors (tacrine hydrochloride, donepezil, and rivastigmine tartrate) are now available and provide patients with modest relief, the most promising strategy involves approaches to retarding, halting, or preventing the formation or accumulation of β-amyloid (Aβ) plaques. Estrogen is believed to have antioxidant or other anti-Aβ effects, as hormonal replacement therapy in women with menopause is associated with a reduced risk or delayed onset of AD. The association between nonsteroidal anti-inflammatory drugs and a reduced risk of AD has not yet been confirmed, but these agents may protect the brain from the reactive glial and microglial responses associated with Aβ deposition. Also, recent studies suggested that antioxidants, such as vitamin E taken alone or in combination with selegiline hydrochloride, can delay the progression of AD. Despite these encouraging results, no current therapy has been shown to halt or reverse the underlying disease process. The proof of the principle that anti-Aβ drugs will work in the transgenic models of AD is eagerly awaited with the expectation that they will eventually prove successful in humans.

The accumulation of β-amyloid (Aβ) plaques is the pathognomonic feature of Alzheimer disease (AD). How does this accumulation relate to the neuronal degeneration that manifests as a progressive cognitive impairment with widespread neurological and neuropsychiatric disturbances? The slowly emerging answer is that Aβ induces a variety of neurotoxic phenomena, including reactive oxygen species. However, to date only the secondary degenerative effects have been amenable to therapy, as seen in the beneficial effects of cholinergic-boosting strategies. In addition to the 3 licensed compounds (tacrine hydrochloride, donepezil, and rivastigmine tartrate), there are many drugs awaiting approval or undergoing phase 3 trials (Table 1). While drugs specifically targeting the β-amyloidogenic pathway only now are beginning to emerge in a preclinical setting, most other drugs are directed at the cholinergic system. There are many psychotropic agents available to treat the behavioral manifestations of AD, including antipsychotic, agitation-reducing, antidepressant, anxiolytic, and sedative-hypnotic drugs. Interventions in AD include treatment of the underlying disease process and amelioration of neurochemical deficits produced by the cellular changes. This review discusses current perspectives in the pharmacotherapy of AD and examines how the different disciplinary approaches are being incorporated into clinical research for effective drug treatments. Attention is drawn to new compounds with novel mechanisms of action that could have a tremendous impact in the future treatment of AD.

MODULATION OF THE CHOLINERGIC SYSTEM

Different strategies have been developed to boost the cholinergic system, including increased acetylcholine production with cholinergic precursors (choline and lecithin), prevention of synaptic acetylcholine destruction with acetylcholinesterase (AChE) inhibitors, such as tacrine (9-amino-1, 2, 3, 4-tetrahydroacridine, Cognex; Parke-Davis, Morris Plains, NJ), donepezil (developed under the code E2020, Aricept; Pfizer Inc, New York, NY), rivastigmine (developed under the code SDZ ENA 713, Exelon; Novartis Pharmaceuticals, East Hanover, NJ), physostigmine salicylate, and galantamine, or direct stimulation of postsynaptic muscarinic receptors with receptor agonists. However, tacrine and donepezil are the only drugs that have been approved by the Food and Drug Administration (FDA).

Evidence now indicates that some AChE inhibitors also may provide neuroprotective effects, perhaps through the activation of nicotinic receptors, and may even enhance neurotrophic regeneration. Other possible actions include the effect of cholinergic agonists on the processing and secretion of the amyloid precursor protein and Aβ.1,2

Tacrine

After the initial positive and overly optimistic reports in 1986 on the efficacy of tacrine, it was subsequently noted to be an even stronger inhibitor of the butyrylcholinesterase family of enzymes. More recently, apart from AChE inhibition, tacrine has been shown to possess a much broader pharmacological profile, such as blockage of potassium channels, inhibition of the neuronal monoamine uptake processes, and inhibition of monoamine oxidase.3 The heightened efficacy of tacrine in alleviating some of the behavioral symptoms of AD compared with other AChE inhibitors might be related to these other pharmacological actions. The purported cognitive-enhancing effects of tacrine and the AChE inhibitors are often difficult to disentangle from their nonspecific arousal and behavioral effects, which can be expected from all classes of cholinergic stimulants. Serious adverse effects of tacrine, including hepatotoxic effects,4 have weakened its position as a drug of choice.

Tacrine has a mean bioavailability of 17%, with interindividual variability from 2% to 36% (Table 2).10 This low bioavailability is thought to be secondary to large presystemic clearance. Food appears to decrease the rate but not the extent of absorption. Tacrine hydrochloride is rapidly metabolized, with mean half-lives of 1.6 and 2.1 hours after single doses of 25 mg and 50 mg, respectively, which must be taken 4 times a day. Tacrine metabolism appears to be mediated through cytochrome P-450 1A 2 isoenzyme. Clinical dosages of 80 to 160 mg/d usually achieve approximately 30% AChE inhibition.

Donepezil

In November 1996, donepezil (a piperidine-based AChE inhibitor with specificity for AchE) was approved by the FDA as a symptomatic therapy for mild to moderate AD. The bioavailability of donepezil is approximately 100%, with peak plasma concentrations occurring between 2 and 4 hours after an oral dose. Food appears to have no significant effect on the drug absorption. Donepezil has a mean elimination half-life of 70 hours, with significant interindividual variation; a daily dose is recommended. Donepezil is bound highly (93%-96%) to the proteins albumin and α1-acid glycoprotein. The drug is metabolized in the liver by CYP2D6 and CYP3A3/4 and by glucuronidation. A dosage of 5 mg/d yields steady-state AChE inhibition of approximately 64% as determined by cholinesterase inhibition in human red blood cell samples.10 In a 30-week phase 3 clinical trial of donepezil, both the 5- and 10-mg treatment groups had ADAS-Cog (Alzheimer's Disease Assessment Scale-Cognitive subscale) scores superior to the placebo group throughout the 6-month trial. Moreover, more than 80% of the patients in the treatment group showed either improvement or no decline during the 6-month trial. The long-term efficacy of donepezil treatment has not been evaluated yet. However, the efficacy for up to 2 years was evaluated in patients who completed the 30-week phase 3 trial and who underwent a long-term, open-label study with donepezil. For a mean of 40 weeks, patients maintained performance levels better than their original baseline scores. The ADAS-Cog scores collected for more than 2 years suggested that patients receiving donepezil maintained the same magnitude of benefit as in the beginning of the study, indicating that long-term use of donepezil may be beneficial.11

Rivastigmine

Rivastigmine is a neuronal selective AChE inhibitor that is still under clinical investigation. Results of phase 2 trials showed that patients with AD tolerated up to 12 mg/d.12 Adverse effects did not include hepatotoxic effects. The results of a meta-analysis of 3 phase 3 trials demonstrated significant beneficial effects on measures of cognition using the ADAS-Cog scale, global functioning, and activities of daily living. The Swiss regulatory authority approved rivastigmine in August 1997 for the treatment of patients with mild to moderate AD. In May 1998, rivastigmine received marketing approval from the European Medicine Evaluation Agency, London, England, and is currently awaiting approval from the FDA.

Metrifonate

Metrifonate is an AChE inhibitor that acts as a prodrug for the direct, long-acting inhibitor DDVP (2,2-dimethyldichlorovinyl phosphate). In blood samples, metrifonate has a mean half-life of 2.3 hours and DDVP has a half-life of 3.8 hours.7 Thus, prolonged elevation of acetylcholine levels can be achieved.13 Estimates of the half-life for cholinesterase recovery vary depending on study methods, with a mean ± SD of 26.6 ± 15.2 hours. Recently, after some patients in clinical trials experienced muscle weakness, the request for approval for metrifonate in Europe was withdrawn.

Galantamine

Galantamine, a naturally occurring amarylidacea alkaloid, is a long-acting, selective, reversible, and competitive AChE inhibitor. Patients with AD who took galantamine had improved performance on memory tests, and it was well tolerated.14 Galantamine use was approved in Austria.

Nicotinic Cholinergic Strategies

It has been suggested that there is an inverse relationship between smoking and AD.15 Dose dependency has not yet been shown for this protective action. Subcutaneous administration of nicotine has been claimed to improve attention and information processing in patients with AD. Interestingly, these effects were more evident than memory improvement. Further clinical investigations are clearly required to confirm these results.

MODULATION OF OTHER NEUROTRANSMITTER SYSTEMS

There is a growing body of evidence that disturbances of glutamatergic neurotransmission may underlie a mechanism of neurotoxic excitatory amino acids contributing to cognitive deficits in patients with AD.16 Age-related changes in NMDA (N-methyl D-aspartate) receptors have been found in cortical areas and in the hippocampus in many species. Based on these findings, several strategies have been developed to improve cognition by the use of NMDA antagonists as neuroprotective agents to slow the progression of dementia. These antagonists include dextromethorphan hydrobromide, memantine (a congener of amantadine hydrochloride),17 and nitroglycerine. Preliminary clinical evidence suggests that memantine use may improve symptoms of dementia. Functional improvement and reduced care dependence were observed in patients with severe dementia who used memantine. Beneficial effects also were noted in other behavioral patterns. Current drugs in preclinical development include L-701252, LY-235959, and WIN-63480-2 (Table 3).

NEUROTROPHIC GROWTH FACTORS

Nerve growth factor (NGF) as the prototypic neurotrophic growth factor is intimately related to the maintenance of function of the cholinergic basal forebrain system. Forebrain cholinergic neurons are the only cells in the adult brain that express high amounts of the low-affinity p75 receptors for NGF. The NGF increases hippocampal acetylcholine and prevents cholinergic cell loss and atrophy after fornix lesions, indicating the potential utility of NGF as a neuroprotective treatment for basal forebrain cells in AD.18 An innovation in AD therapy may come from NGF-mimetic drugs. Neotrofin or AIT-082 (an analog of hypoxanthine) (NeoTherapeutics, Irvine, Calif) is an orally active compound that is claimed to enhance the levels of various neurotrophic factors, such as NGF, ciliary neurotrophic factor, and neurotrophin-3, and also potentiate the effects of NGF.

DECREASING THE CELLULAR REACTION TO NEURODEGENERATION

Microglial cells, closely related to the macrophage series of cells in the periphery, increase in size and number in the brain with AD. From this observation and the presence of complement in amyloid plaques, the concept of AD as an inflammatory disease has emerged. It has been reported that individuals taking anti-inflammatory drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs), have fewer cerebral microglia19 and are less likely to develop AD, with a fairly consistent risk reduction of about 50%.20 The greatest protection is observed in those individuals with late onset (>70 years of age) and a strong family history of AD. In one randomized, placebo-controlled study21 with indomethacin sodium in 44 patients with mild AD a slight improvement in cognitive function from baseline was noted in the treatment group after 6 months of treatment.

New products with anti-inflammatory properties in clinical development for AD include SC-110 and GR-253035, a cyclooxygenase 2 (COX-2) inhibitor. A DNA-binding protein, NF-κB, has an important role in driving transcription from inflammation-related genes, such as in the production of COX-2, that operate in stressed tissues like the brain with AD. Blocking intervention at this stage may be a potential approach for treatment.

Propentofylline (3-methyl-1-[5-oxohexyl]-7-propyl-xanthine), a xanthine derivative and an inhibitor of the reuptake of adenosine, was reported to inhibit glutamate release, to increase cerebral blood flow, and to act mainly on astrocytes and microglia.9 It appears to delay the progression of mild to moderate dementia in addition to providing symptomatic relief. In a 12-month, randomized, placebo-controlled study22 with propentofylline in patients with AD and vascular dementia, the total patient population showed statistically significant treatment differences in favor of propentofylline for the global measures of dementia and cognitive evaluations. Propentofylline is awaiting registration in the European Union and Canada for use in mild to moderate AD and vascular dementia.

DRUGS THAT REDUCE OXIDATIVE STRESS

There is increasing evidence that the brain with AD is under severe oxidative stress, as a result of either Aβ-mediated generated oxyradicals or perturbed ionic calcium balances within neurons and their mitochondria. Drugs, such as vitamin E,23 idebenone,24 or estrogen, that have strong antioxidant properties are showing variable degrees of efficacy. Newer antioxidants undergoing clinical development include the free radical scavenger ARL-16556, an α-phenyl-t-butylnitrone derivative with spin-trapping effects.

Estrogen replacement therapy in healthy postmenopausal women favorably affects mood and may have modest effects on cognitive function. Many clinical trials are now in progress. In addition to its antioxidant properties, estrogen may promote growth of cholinergic neurons, reduce plasma levels of apolipoprotein E, modify inflammatory responses, or even directly reduce Aβ generation.25

New products undergoing preclinical development include an estrogen-based drug (sustained-release formulation Neurestrol; Endocon Inc, South Walpole, Mass) and ABPI-124, a compound without the adverse effects of feminization. The effects of raloxifene hydrochloride and tamoxifene citrate (nonsteroidal selective estrogen receptor modulators) in AD are yet to be determined.

THERAPEUTIC STRATEGIES IN THE AMYLOID PRECURSOR PROTEIN AND β-AMYLOIDOGENIC PATHWAY

The gene dosage effect of trisomy 21 syndrome has shown that down-regulation of amyloid precursor protein (APP) expression is a theoretical therapeutic strategy, but our understanding of the factors that regulate APP transcription are still too rudimentary. The normal function of APP also remains uncertain, placing some restriction on our ability to predict the unintended adverse effects of APP down-regulation.

Most therapeutic research has been devoted to developing inhibitors of the β- and γ-secretases, which are responsible for the proteolytic cleavage events that generate Aβ. While the identity of these enzymes remains unknown, several pharmaceutical companies have developed compounds that are efficient inhibitors of γ-secretase (Table 3). Most are still undergoing preclinical development, although registration of some compounds may occur in 2000. Studies26,27 that implicate the presenilins in the γ-secretase pathway also are introducing new therapeutic strategies, although the involvement of presenilins in Notch signaling has caused some concern about the potential adverse effects of γ-secretase inhibitors.

Compounds directed at inhibiting the toxic effects of Aβ or stabilizing the aggregated forms of Aβ to promote its clearance from the brain are now undergoing active development. Further insight is required to understand the roles of other proteins or lipids (eg, cholesterol) that interact with Aβ (such as apolipoprotein E and α2-macroglobulin) or with APP as it travels through the cell toward its biogenesis of Aβ. Recently, a remarkable approach was described in which transgenic mice immunized with human Aβ showed attenuation of amyloid plaque formation.28 This attenuation may represent a novel mechanism for promoting the clearance of Aβ from the brain, as the rates of Aβ production were not altered. The prospect of large-scale human immunizations with potential autoantigens raises considerable challenges.

THE EMERGING FIELD OF PHARMACOGENETICS

As in all complex diseases, many genetic elements are responsible for the clinical phenotype. Predicting who, in a mixed population, will respond best to any given therapeutic compound is a challenge for pharmacogeneticists. There are already some indicators that the apolipoprotein E allotype may affect responses to AChE inhibitor therapy.29

CONCLUSIONS

Much has been learned from the first few years of specifically targeted therapy for AD. A comparison of tacrine with other second-generation AChE inhibitors in clinical studies shows that despite these drugs having modest clinical efficacy, their main differences are in the frequency of adverse effects, number of dropouts, and percentage of patients whose conditions improve. Although efficacy may be similar between the AChE inhibitors at effective doses, peripheral cholinergic adverse effects, tolerability, and hepatotoxic effects are severe limitations. The controlled studies using AChE inhibitors have generally been short-term, from 12 weeks to 6 months, and use similar kinds of cognitive outcome measures. Therefore, long-term (>1 year) controlled studies need to be evaluated. Furthermore, reliable controlled data on meaningful outcomes, such as dependency and institutionalization or other aspects of long-term efficacy, are urgently needed.

In contrast to the AChE inhibitors, the beneficial effect of estrogen therapy may delay the progression of AD.30 Since combination therapies may be crucial, it will be interesting to perform trials with combinations of drugs that possess different mechanisms of action; for example, AChE inhibitors and estrogen. Clinical studies are necessary to assess the efficacy and interactive effects of these approaches. With regard to the use of NSAIDs in AD, elderly people with AD are more susceptible to the adverse effects of NSAIDs; therefore, these drugs should be used with caution. The development of COX-2 and leukotriene inhibitors might be very important. The use of antioxidants, such as vitamin E, is worth considering in patients with AD, since they can be obtained over the counter and are relatively nontoxic and inexpensive.

In summary, the knowledge gained to date has served to set the standards by which all future therapies for AD will be measured. Progress in the development of drugs and clinical trials for AD has been remarkable, with every prospect that more effective strategies will emerge in the near future.

Back to top
Article Information

Accepted for publication September 20, 1999.

Reprints: Gérard Emilien, PhD, 127 Rue Henri Prou, 78340 Les Clayes-Sous-Bois, France (e-mail: gemilien@aol.com).

References
1.
Jope  RSSong  LPowers  RE Cholinergic activation of phosphoinositide signaling is impaired in Alzheimer's disease brain. Neurobiol Aging. 1997;18111- 120Article
2.
Nitsch  RMSlack  BEWurtman  RJGrowdon  JH Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. Science. 1992;258304- 307Article
3.
Jossan  SSAdem  AWinblad  BOreland  L Characterisation of dopamine and serotonin uptake inhibitory effects of tetrahydroaminoacridine in rat brain. Pharmacol Toxicol. 1992;71 ((3, pt 1)) 213- 215Article
4.
Knapp  MJKnopman  DSSolomon  PRPendlebury  WWDavis  CSGracon  SITacrine Study Group, A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease. JAMA. 1994;271985- 991Article
5.
Tiseo  PJRogers  SLFriedhoff  LT Pharmacokinetic and pharmacodynamic profile of donepezil HCl following evening administration. Br J Clin Pharmacol. 1998;4613- 18Article
6.
Polinsky  RJ Clinical pharmacology of rivastigmine: a new-generation acetylcholinesterase inhibitor for the treatment of Alzheimer's disease. Clin Ther. 1998;20634- 647Article
7.
Ringman  JMCummings  JL Metrifonate (trichlorform): a review of the pharmacology, pharmacokinetics and clinical experience with a new acetylcholinesterase inhibitor for Alzheimer's disease. Expert Opin Invest Drugs. 1999;8463- 471Article
8.
Rainer  M Galanthamine in Alzheimer's disease: a new alternative to tacrine? CNS Drugs. 1997;789- 97Article
9.
Mielke  RMoller  HJErkinjuntti  TRosenkranz  BRother  MKittner  B Propentofylline in the treatment of vascular dementia and Alzheimer-type dementia: overview of phase I and phase II clinical trials. Alzheimer Dis Assoc Disord. 1998;12(suppl 2)S29- S35Article
10.
Parnetti  L Clinical pharmacokinetics of drugs for Alzheimer's disease. Clin Pharmacokinet. 1995;29110- 129Article
11.
Rogers  SLPerdomo  CFriedhoff  LT Clinical benefits are maintained during long-term treatment of Alzheimer's disease with the acetylcholinesterase inhibitor E2020. Eur Neuropsychopharmacol. 1995;5386- 387Article
12.
Gottwald  MDRozauski  RI Rivastigmine: a brain-region selective acetylcholinesterase inhibitor for treating Alzheimer's disease. Expert Opin Invest Drugs. 1999;81643- 1682
13.
Itoh  ANitta  AKatono  Y  et al.  Effects of metrifonate on memory impairment and cholinergic dysfunction in rats. Eur J Pharmacol. 1997;32211- 19Article
14.
Thomsen  TBickel  UFischer  JPKewitz  H Galantamine hydrobromide in a long-term treatment of Alzheimer's disease. Dementia. 1990;146- 51
15.
Ulrich  JJohannson-Locher  GSeiler  WOStähelin  HB Does smoking protect from Alzheimer's disease? Alzheimer-type changes in 301 unselected brains from patients with known smoking history. Acta Neuropathol (Berl). 1997;94450- 454Article
16.
Müller  WEMutschler  ERiederer  P Noncompetitive NMDA receptor antagonists with fast open-channel blocking kinetics and strong voltage-dependency as potential therapeutic agents for Alzheimer's dementia. Pharmacopsychiatry. 1995;28113- 124Article
17.
Winblad  BPoritis  N Memantine in severe dementia: results of the M-9 BEST Study (Benefit and Efficacy in Severely Demented Patients During Treatment With Memantine). Int J Geriatr Psychiatry. 1999;14135- 146Article
18.
Holtzman  DMLi  YChen  KGage  FHEpstein  CJMobley  WC Nerve growth factor reverses neuronal atrophy in a Down syndrome model of age-related neurodegeneration. Neurology. 1993;432668- 2673Article
19.
Mackenzie  IRMunoz  DG Nonsteroidal anti-inflammatory drug use and Alzheimer-type pathology in aging. Neurology. 1998;50986- 990Article
20.
Breitner  JCWelsh  KAHelms  MJ  et al.  Delayed onset of Alzheimer's disease with nonsteroidal anti-inflammatory and histamine H2 blocking drugs. Neurobiol Aging. 1995;16523- 530Article
21.
Rogers  JKirby  LCHempelman  SR  et al.  Clinical trial of indomethacin in Alzheimer's disease. Neurology. 1993;431609- 1611Article
22.
Marcusson  JRother  MKittener  B  et al. European Propentofylline Study Group, A 12-month, randomized, placebo-controlled trial of propentofylline (HWA 285) in patients with dementia according to DSM III-RDement Geriatr Cogn Disord. 1997;8320- 328Article
23.
Sano  MErnesto  CThomas  RG  et al.  A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. N Engl J Med. 1997;3361216- 1222Article
24.
Gutzmann  HHadler  D Sustained efficacy and safety of idebenone in the treatment of Alzheimer's disease: update on a 2-year double-blind multicentre study. J Neural Transm Suppl. 1998;54301- 310
25.
Xu  HGouras  GKGreenfield  JP  et al.  Estrogen reduces neuronal generation of Alzheimer β-amyloid peptides. Nat Med. 1998;4447- 451Article
26.
Hardy  JIsraël  A Alzheimer's disease: in search of γ-secretase. Nature. 1999;398466- 467Article
27.
Haass  CDe Strooper  B The presenilins in Alzheimer's disease: proteolysis holds the key. Science. 1999;286916- 919Article
28.
Schenck  DBarbour  RDunn  W  et al.  Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature. 1999;400173- 177Article
29.
Richard  FHelbecque  NNeuman  EGuez  DLevy  RAmouyel  P APOE genotyping and response to drug treatment in Alzheimer's disease. Lancet. 1997;34933Article
30.
Paganini-Hill  AHenderson  VW Estrogen replacement therapy and risk of Alzheimer disease. Arch Intern Med. 1996;1562213- 2217Article
×