Alzheimer's disease (AD) is the most common of several central nervous system deteriorative progressive disorders. AD currently affects 4 million Americans, but is projected to affect 14 million by the year 2040. Similar increases are expected in other developed countries.1 Although memory loss is the most consistent symptom in AD, decline of multiple cognitive functions, such as judgment, attention, praxis, and language, is gradual. The disorder eventually leads to a pronounced impairment in level of functioning, with quality of life reduced for both patient and caregivers. The economic impact of AD, both direct and indirect, has been estimated at approximately $58 billion annually.2
Although the memory and cognitive deficits are central clinical features of AD, most patients also exhibit behavioral manifestations during the course of their illness. A recent review indicated that more than half of AD patients with mild cognitive impairment presented with at least one psychiatric symptom and one third presented with two or move symptoms.3 Psychiatric symptoms common in AD patients include anxiety, depression, paranoia, hallucinalions, delusions, agitation, and diurnal disturbances. Although treatment is currently focused on symptomatic treatment of AD patients with both pharmacologie leg, antidepressants and antipsychotics 1 and nonpharmaco logic strategies, until recently, no specific therapy for the cognitive deficits has been available.
The AD pathophysiology has received intense research attention in the past decade. Although biologic markers are still not available, it is now possible to establish a clinical diagnosis with uniformity. 4 Definite diagnosis is by ncuropathology: neuritic plaques and neurofibrillary tangles spread diffusely throughout the cerebral cortex and hippocampus. Biochemical studies of post-mortem brain and cerebrospinal fluid (CSFi have also shown deficiencies in several neurotransmitters and neuropeptides in AD compared with normal aging,5-7 but the cholinergic deficiency has boon most consistent and directly linked to the memory loss in AD. 8 The recent molecular genetic approaches have provided another tool to understand risk factors in AD.9
This article presents a brief summary of emerging pharmacotherapies specifically for the memory and cognitive deficits in AD. New drug development for AD has also been covered in previous reviews. HI~U! The Table shows a summary of clinical trials with tacrine (each involving 50 or more AD patients), the only US Food and Drug Administration (FD A !-approved drug for AD. For the purposes of this overview, investigational pharmacologie strategies in AD may be divided into the following overlapping categories: (1) to prevent or put off the onset of the illness in at-risk asymptomatic individuals; (2) to stop or slow the natural course of AD in those already diagnosed; and (3) treatments that enhance cognition and memory. These approaches are discussed further subsequently.
DEVELOPMENT OF AGENTS TO PREVENT OR DELAY THE ONSET OF AD
Despite projected increases in the prevalence rates of AD, the cost of research and development of effective treatment for this mushrooming population is equally daunting. Thus far, the research of large pharmaceutical companies has focused on symptomatic therapy, chiefly replacement of ne uro transmitter deficiencies such as acetylcholine, resulting in approval of tacrine (Cognex), an acetylcholinesterase inhibitor. To prevent or delay the onset of AD, we must be able to identify the exact risk factors of AD to identify individuals at risk.
A good marker, preferably peripheral and minimally invasive, ideally should not only identify individuals at risk for AD, but also predict the age of onset and degree of risk. Several such markers are currently being investigated for the diagnosis, staging, and prognosis of AD and for the assessment of AD risk in families. Some examples include apolipoprotein E (APOE) genotyping,1" measurements of cerebral metabolism using positron emission tomography (PET),1"1 cerebral atrophy on magnetic resonance imaging (MRI ),15·16 neurochemical measurements using magnetic resonance spcctroscopy (MRS),17 CSF assays of various proteins and metabolites, fibro blast-based tests of electrolyte channels, and chotinergic challenges by intravenous, oral, or intraocular route.5 1S
One new avenue of research is the link between the risk of AD and the APOE locus on chromosome 19.l!l APOE is a protein involved in plasma fat transport that has also been proposed to play a role in the central nervous system. APOE has three allelic forms termed as 2. 3, and 4, and people can have one of five APO genotype combinations (2/2, 2/3, 3/3, 3/4, 4/4). Studies have indicated that the APO 4 alíele is strongly associated with late-onset AD familial type. l!) It has also been proposed that APOE may play a role in the structure of a neurofilament protein called tau, and thus alter AD risk.2" However, the actual role of APOE in the molecular pathogenesis remains unknown.
"Brain enhancers OT nootropics leg, cerobrolysin), cerebral vasodilators, and other "smart drugs" have been available for years, even being commonly prescribed abroad, eg, Germany and Italy, No convincing controlled data establish the efficacy of these drugs in delaying the onset of AD. Several, but not all, studies have also suggested that the use of antiinflammatory (both steroidal and nonsteroidal) medications21,22 or estrogen replacement therapy23-25 may iower the rjsk for developing AD. Controlled prospective studies are needed to assess these epidemiologie findings in light of cost-benefit considerations, before they can be recommended as AD therapy. Other potential targets for "preventive therapies" include glial and neuronal events involved in the processing of amyloid, and neurofibrillary tangles.
Currently, no AD preventive therapy is approved by the FDA, and research is still at a preclinical laboratory level. In addition, development of an AD marker in asymptomatic individuals may pose both clinical and ethical problems, especially in the absence of effective treatments.
DEVELOPMENT OF AGENTS TO SLOW THE NATURAL COURSE OF AD
Many agents for slowing the progression of AD are at preclinical and clinical levels of trials. Such a neuTOprotective agent should shield neurons in AD brains from further degeneration, and thus clinically slow the consequences of disease progression. Efficacy of the putative agent could be measured in cognition and functionality of the AD patient.
The actions of the excitatory amino acid neurotransmitter glutamate, acting on the N-methyl D-aspartate iNMDA) receptor, has been postulated to lie behind other neuronal injury as hypoxia or neurotoxins, and this process may also involve calcium influx into the cell. NMDA antagonists (eg, dizocilpine, eliprodil) and calcium channel antagonists (eg, nimodipine) are in trials for their effects in AD. Glycine selective agents are similarly believed to be in development for AD.13
Free radicals are known to play a role in neuronal death.2'' The efficacy of antioxidant free radical scavengers, such as vitamin E and selective MAO-B inhibitors, in neurodegenerative disorders has been studied. Indeed, the search for therapies in AD parallels similar efforts in Parkinson's disease, although neurotransmitter replacement was less successful in AD. The selective MAO-B inhibitor L-deprenyl has been shown to slow disease progression in Parkinson's, and some studies show cognitive efficacy in AD.27 Other selective MAO-B inhibitors (eg, lazabemidel and vitamin C are also being studied for AD efficacy on the basis of scavenger mechanisms.
Drugs with effect on phospholipid metabolism (eg, cycloserine, acetyl-L-camitine), antiinflammatory agents (eg, NSAIDs7 prednisone, coichicine), nerve growth factors (eg, NGF), and estrogena leg, neuroestriol) are among the classes now being clinically tested as neuroprotective agents.
These protective agents are assessed in terms of their ability to enhance memory or cognition and the progression of the illness; however, none has been reported to be able to halt the progression of AD over long periods, and the FDA has not approved any of the previously listed agents for the indication of slowing progression of AD. The vast majority of trials currently being conducted maintain rigorous research conditions only for 6 months, and hence there is no conclusion regarding disease prognosis.
DEVELOPMENT OF AGENTS TO ENHANCE COGNITION INAD
The last decade saw many studies on regional concentrations of the various neurotransmitters and neuropeptides in AD post-mortem brains compared with normal aging. Findings included consistent reductions in the regional concentrations of acetylcholine, neuropeptides such as somatos tatin, and a smaller reduction in some ca techo] a mines. Loss of cholinergic input to the cortex was then hypothesized to explain the cognitive dysfunction in AD. * Therefore, therapy for memory problems in AD patients focused on enhancing cholinergic activity in various ways: by acetylcholine precursors (eg, lecithin, choline), choline esterase inhibitors (AChE) (eg, physostigmine, tacrine), combinations of AChE with precursors (eg. lecithin with tacrine), muscarinic agonists (eg. bethanecol, arecoline, xanomelinei. nicotinic agonists i tig, transdcrmal nicotine patches), or drugs facilitating AChK release (eg, linopc-ridine DUP 996. Dupont Murck0.11,12,26-29
Clinical Trials With Tacrine Involving More Than 50 Patients
Of 22 studies on lecithin/choline, only six showed some mild cognition efficacy. t;i The reason for lack of efficacy in choline appears to he due to the disturbance of the Na+-dependent transport rather than the level of choline in the central nervous system.
Only one drug. 9-amino tetrahydroaminoacridino (THA or tacrine). has been approved by the FDA for routine clinical use to treat AD ' since November 1993). A number of studies with tacrine have been published.-8'30 Six studies, each involving 50 or more patients, have shown varying degrees of positive response (Table). A 12-week study of tacrine involving 215 patients reported that about 15% of the patients showed some improvement for a brief period. ? A long-term multicenter study (30 weeks) of 663 patients unequally randomized to placebo or to one of three tacrine doses (that were then titrated to 80. 120. or 160 mg/dayi led to the approval of THA for (he treatment of AD. This study suggests that, among the patients who could tolerate THA, 30%· to 51% may show improvement in cognitive measures and 25% to 42% may show improvement in clinician-rated global measures. Optimal response was at the highest tacrine dose (160 mg/day), but the dropout rate resulting from side effects was very high at this dose.
At high concentrations, tacrine inhibits both acetylcholinesterase and butyrycholinesterase and may act on several other neurotransmiUer systems and ion channels/11 TtIA is metabolized by the IA2 isoenzyme of the cytochrome P450 in the liver, and the side effects and cognitive benefits are dose-related/10 Hepatotoxicity and peripheral symptoms arc among the most troublesome for patients. Clinical reported side effects include elevated liver enzymes, nausea, vomiting, diarrhea, rash, and bradycardia. More than half of patients enrolled in trials have withdrawn during treatment, mainly because of side effects/111 A recent survey of the 2446 AD patients taking THA revealed that, a quarter had significant elevations (>3 times normal upper limiti in alanine amino transferase (ALTl levels. The liver changes are usually detected in the fìnsi 8 weeks of therapy, returning to normal on drug withdrawal, and patients are then able to be rechallenged with the drug/10
THA dose should be increased gradually from 40 nig/day to 160 mg/day, at 6-week intervals, in increments of 40 mg/day, depending on the patient's tolerance. '" Weekly serum transaminase level monitoring is required for the first 18 weeks of therapy and for 6 weeks after each further increase in dosage.1"1 Dosing is four times a day. These schedules, together with the side effects, make tacrine less than desirable for many patients, caregivers, and physicians.
Therefore, several second-generation choline-esterase inhibitors (eg. ENA 713, Ë2020) and cholinergic agonists are being developed"1 that, based on preliminary data, appear to not have some of tacrine's limitations. H is proposed that a greater selectivity for brain acetycholinesterase as opposed to butyrylcholinesterase and other substrates may account for a better side-effect profile; however, as in the earlier AD cholinergic trials, so far. the effects of the dose tolerated by most patients are overall a disappointment.
Combination therapies, akin to oncology's chemotherapy regimens, are being assessed in AD. Physostigmine, yohimbine, arid low-dose L-deprenyl, which act on both cholinergic and noradrenergic systems, may be useful as cognitive enhancers/12 Such combination therapies have not been examined in multicenter clinical trials to establish their efficacy and long-term safety and hence are not approved by the FDA to treat AD. Neuropeptides have difficulty getting past the blood-brain barrier, and when administered to AD patients, as with adrenocorticotropic hormone (ACTH), no appreciable benefit has been seen.:!:! Emerging data suggests that concurrent use of vitamin E, vitamin C, antiinflammatory agents, or estrogen in aging subjects may be associated with superior cognition. :i~' Prednisone. nonsteroidal antiinfl anima tory drugs, and neuroestrioi (a novel subcutaneous implant that can release hormone for several months) are in large clinical trials. Recent interest in the link between estrogen and AD started with animal studies showing that the cholinergic neurons of basal forebrain contain estrogeni and the incidence of AD in postmenopausal women taking estrogen preparations is reduced.
Those reports suggested that the women with estrogen deficiency may be at risk to develop AD. Unfortunately, the results of some studies36 are not very promising, but obviously further studies to evaluate the efficacy of estrogen in AD are needed. The action mechanism of estrogen remains to be clarified, but an antidepressive effect, improvement of cerebral blood flow, direct neuronal stimulation, proliferations of gliacytes, and suppression of a polipo protei n E have been suggested.37 Some mechanisms may be combined, contributing to some beneficial effects on clinical symptoms. ;H* All of these studies involving estrogen indicate the need For the larger double-blind studies to establish its clinical efficacy. Many more nootropic agents are available outside the US, yet none have been proved to he very effective in improving symptoms of AD.
Beyond tacrine, no agent among all the candidates has been approved by the FDA. The heterogeneous clinical, pathologic, and disease progression variabilities in AD make it difficult to assess treatment efficacy, although we now have a promising animal model oí' AD.3tJ Moreover, practical problems of resources and even ethics in maintaining clearly worsening AD patients in double-blind trials for longer periods arise. The experience gained so far has led to increased understanding of at least the short-term natural history of AD, but we still need long-term, welldesigned studies to answer questions related to the improvement of symptoms, course of the disease, and its prevention.
Despite the last decade's advances in understanding the AD disease process, we are still in large clinical trials with replacement and combination therapies. The field is moving to a more etiologically based approach as evident from the development of the transgeneic mouse model, where amvloid accumulates in areas similar to that in AD brains. The hope is for development of drugs targeting amyloid production and plaque formation.39 Newer transgenic animal models (eg, based on APOE mutations) are presently being developed. The alarming increase in AD prevalence has triggered a significant increase in the commitment of government and industry toward developing effective therapies for AD. Psychiatrists should educate colleagues about the effective use of existing non pharmacologie and pharmacologie therapies for behavioral symptoms associated with AD while waiting for specific therapies to improve memory. Even in the absence of specific cognitive therapy, one can improve the quality of life of both patients and their caregivers.
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Clinical Trials With Tacrine Involving More Than 50 Patients