NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Hansen RA, Gartlehner G, Kaufer DJ, et al. Drug Class Review: Alzheimer's Drugs: Final Report [Internet]. Portland (OR): Oregon Health & Science University; 2006 Jun.

Cover of Drug Class Review: Alzheimer's Drugs

Drug Class Review: Alzheimer's Drugs: Final Report [Internet].

Show details


A. Overview

Alzheimer's disease (AD), the most common adult form of dementia, is an age-associated neurodegenerative disorder pathologically characterized by the abnormal accumulation of intracellular neurofibrillary tangles and extracellular amyloid plaques in selected brain regions. Primary clinical manifestations of AD include the insidious onset and gradual progression of cognitive impairment affecting multiple domains. Impaired recent memory (difficulty learning new information) is the clinical hallmark of AD; other associated cognitive signs include disturbances in language, visuospatial processes, and executive control functions such as insight and judgment. Alterations in behavior (e.g., irritability, paranoia), mood (e.g., depression), and personality (e.g., apathy) frequently occur in AD, are more variable than cognitive symptoms, and often contribute disproportionately to caregiver distress. Following the original case description in 1907 AD was initially viewed as a "pre-senile" dementia, with onset below age 65 years. Over time the term "senile dementia of the Alzheimer type" arose to acknowledge that dementia with AD-like clinical and pathological features occurred more commonly after age 65 years.

The historical distinction between pre-senile and senile forms of AD was abandoned in standard diagnostic criteria for AD developed over the last 25 years; the Diagnostic and Statistical Manual of Psychiatric Disorders (DSM-IV) and the National Institute of Neurological and Communicative Disorders and Stroke, and Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) have eliminated the historical distinction. The two main types of AD currently recognized are a generally later-onset sporadic form, representing about 95% of all cases, and autosomal-dominant familial forms involving specific mutations in one of three genetic loci (APP, presenilin 1, and presenilin 2) and typically associated with the early-onset of AD symptoms. Genetic polymorphism of the apolipoprotein epsilon locus (apo E4 allele) increases the risk of developing AD two to three-fold and is associated with an earlier age of onset in sporadic AD. Within the last decade, a syndrome referred to as "Mild Cognitive Impairment" (MCI) has gained recognition as a prodrome of AD in many but not all cases.1 MCI is distinguished from AD by the presence of only short-term memory deficits and the absence of clear-cut functional limitations independent of memory difficulties.

Research diagnostic criteria for AD generally have been shown to be accurate and reliable based upon pathological confirmation studies;2 nonetheless, the boundaries between MCI and early AD are not always clear. Furthermore, among all dementia cases with AD pathology a significant minority will have concomitant cerebrovascular lesions (infarctions or small-vessel ischemic lesions of the white matter) or Lewy body pathology akin to Parkinson's disease (PD). The presence of multiple pathological substrates associated with AD also can contribute to diagnostic ambiguity. Further developments in structural and functional neuroimaging techniques, genetic susceptibility testing, and validating biomarker assays will help clarify diagnostic efforts and inform therapeutic drug testing and monitoring.

AD is estimated to affect 4.5 million individuals in the United States with an average course of about 8 to 10 years.3 Of all individuals over age 65 years, an estimated 6% to 8% have AD or another form of dementia and this rate exceeds 30% at age 85 years and older. Although different estimates vary, roughly half of all AD patients are in the early or mild disease stage and the other half are in the moderate to severe range of severity.4 The projected prevalence of AD will approximately double over the next 20 years, as a result of the aging of the post-WWII baby-boomer generation.

Since the total current economic burden posed by AD, including direct costs (medical, hospital, and nursing home care) and indirect costs (lost productivity of caregivers) is estimated to exceed $85 billion a year, the current and looming economic impact of AD is staggering.5 The overall cost of managing AD is significantly greater for patients with severe disease than for those with mild to moderate; the reasons are largely greater dependency needs, higher resource utilization, and increased rate of institutionalization.

The comprehensive management of AD entails both nonpharmacologic and pharmacologic interventions. Nonpharmacologic interventions primarily address behavioral disturbances (e.g., task simplification, environmental modification, minimal excess stimulation, etc.) and other sources of cognitive impairment (e.g., treating comorbid medical conditions, minimizing or eliminating drugs with deleterious cognitive side effects).6 Pharmacologic strategies have focused on modulating disease-associated neurotransmitter alterations; strategies can be characterized as symptomatic or neuroprotective. Although a symptomatic and a neuroprotective pharmacologic treatment may have similar outcome characteristics in a clinical trial, the key difference is that a neuroprotective therapy will have a cumulative benefit that persists after the treatment is discontinued. Currently available pharmacologic therapies, including cholinesterase inhibitors (ChEIs) and N-methyl-D-aspartate (NMDA) receptor antagonists, are considered symptomatic treatments based on their ability to slow the clinical progression of symptoms across cognitive, behavioral, and functional domains.

Initial pharmacologic strategies for AD focused on increasing cholinergic transmission in the brain based on the "cholinergic hypothesis" of memory dysfunction. Among different strategies employed to increase synaptic levels of acetylcholine (ACh), blocking the breakdown of ACh by inhibiting acetylcholinesterase (AChE) has proven most successful to date. Inhibiting the enzyme butyrylcholinesterase (BuChE), which is a minor constituent in normal brains but in the brains of AD patients is increased in association with plaques and tangles, may also improve cholinergic transmission.7

Centrally active ChEIs, which differ in targeting AChE alone or affecting both AChE and BuChE, were the first class of drugs approved by the US Food and Drug Administration (FDA) for the treatment of AD. Currently available ChEIs include donepezil hydrochloride (donepezil), galantamine hydrochloride (galantamine), rivastigmine tartrate (rivastigmine), and tacrine hydrochloride (tacrine). Among these agents galantamine also acts as an allosteric nicotinic receptor modulator, which has been shown to stimulate the presynaptic release of acetylcholine and other neurotransmitters in laboratory preparations.8 Because of their more favorable therapeutic profiles, greater convenience, and absence of liver toxicity, the second-generation ChEI agents (i.e., donepezil, galantamine, and rivastigmine) largely have supplanted the first approved drug in this class, tacrine. Neuropharmacologic and pharmacokinetic properties of the currently available ChEIs are summarized in Table 1.

Table 1. Current drug treatments for Alzheimer's disease.

Table 1

Current drug treatments for Alzheimer's disease.

More recent evidence implicates the excitatory neurotransmitter glutamate as playing a role in the pathophysiology of AD.9–11 Currently, the only available drug targeting cognitive symptoms via a putative glutamatergic mechanism is memantine hydrochloride (memantine). Memantine has been widely used in Germany for more than two decades to treat a variety of conditions, including dementia, PD, neurogenic bladder, and neuropathic pain.12, 13 Memantine has been promoted as a treatment for dementia in Germany since 1989; in 2002 the European Union approved its use in AD. Memantine is a low-affinity noncompetitive NMDA receptor antagonist that blocks pathologic neural toxicity associated with prolonged glutamate release without interfering with the normal physiologic actions of glutamate required for learning and memory functions.14, 15 Neuropharmacologic and pharmacokinetic properties of memantine are summarized in Table 1.

Other more poorly documented pharmacologic approaches include drugs like nicotine, selegiline, vitamin E, ginkgo biloba, piracetam, hormone replacement therapy, anti-inflammatory drugs, statins, and folic acid;14, 16 these will not be considered in this review.

B. Scope and key questions

The purpose of this review is to help policy makers and clinicians make informed choices about the use of the four ChEIs and memantine in the treatment of AD. We compare the efficacy, effectiveness, and safety (adverse events) of donepezil, galantamine, rivastigmine, tacrine, and memantine in patients with mild to severe AD. Although we will emphasize comparative head-to-head studies, the few published ones do not allow for a comprehensive evaluation. Accordingly, we will also include supplementary data from individual placebo-controlled trials and observational studies.

The participating organizations of the Drug Effectiveness Review Project (DERP) are responsible for ensuring that the scope of the review reflects the populations, drugs, and outcome measures of interest to their constituencies. The Oregon Evidence-based Practice Center initially prepared preliminary key questions identifying the populations, interventions, and outcomes of interest, and we based the eligibility criteria for studies on these preliminary questions. Representatives of organizations participating in the DERP, in conjunction with experts in the fields of health policy, neurology, pharmacotherapy, and research methods reviewed, revised, and approved the questions and outcome measures. The participating organizations approved the following key questions:

  1. How do donepezil, galantamine, rivastigmine, tacrine, and memantine or combinations of these drugs (i.e., acetylcholinesterase inhibitor plus memantine) compare in their efficacy or effectiveness for stabilizing symptoms and treating behavioral disturbances in patients with AD?
  2. How do donepezil, galantamine, rivastigmine, tacrine, and memantine (or combinations of these drugs) compare in their time to effect and in the time required to assess the clinical response?
  3. What are the comparative incidence and severity of complications of donepezil, galantamine, rivastigmine, tacrine, and memantine (or combinations of these drugs)?
  4. Does efficacy, effectiveness, or adverse events of donepezil, galantamine, rivastigmine, tacrine, or memantine (or combinations of these drugs) differ in subgroups of patients with (1) different demographic profiles (age, race, or gender), (2) Parkinsonian features or vascular dementia, or (3) use of other commonly prescribed drugs?

The first key question addresses the issue of effectiveness: do drugs used to treat AD differ in their effects under real-life circumstances? This report addresses both efficacy (i.e., do AD drugs differ in their effects under ideal or highly controlled circumstances) and effectiveness. We distinguish between efficacy (explanatory) studies and effectiveness (pragmatic) studies; studies conducted in primary care or office-based settings that use less stringent eligibility criteria (i.e., broad range of population characteristics and disease severity) have long follow-up periods (i.e., greater than one year), and assess health outcomes are characterized as effectiveness studies. Studies conducted in more highly selected populations over shorter periods of time are characterized as efficacy studies. We summarize the results of efficacy and effectiveness studies separately as the results of effectiveness studies are more generalizable than results from highly selected populations (i.e., efficacy studies).

For assessing efficacy and effectiveness, our review includes methodologically valid comparative evidence from controlled clinical trials and fair- or good-quality systematic reviews. For evaluating safety we include controlled clinical trials, systematic reviews, and observational studies. A summary of outcome measures and study eligibility criteria can be found in Table 2; a more complete description of commonly used scales and outcome measures can be found in Appendix B.

Table 2. Outcome measures and study eligibility criteria.

Table 2

Outcome measures and study eligibility criteria.

The second key question specifically addresses the time to achieve statistical and clinical differences between available drugs. Although we searched for direct and indirect evidence addressing time to statistical and clinical differences, several points should be considered. In general, determining time to effect and time required to assess clinical response are both difficult tasks given the progressive nature of AD, the design of most trials, and the nature of measurement scales. Because limited evidence compares one AD drug to another and because placebo-controlled trials are too heterogeneous with respect to study design, outcomes assessment, and populations to allow any inferences about the comparative time to effect, drawing conclusions about one drug compared to another is similarly difficult. Furthermore, given the fact that changes in cognition and global assessment can be reached only with sustained treatment with ChEIs and memantine, the clinical significance of time to effect is likely to be of minimal importance to physicians and patients. We review the available evidence below, but we caution readers about interpretation given the nature of the evidence and questionable significance of any differences reported across trials.

Given the progressive nature of AD it is important to note the distinction between clinical improvement and slowing the progression of disease. Although a treatment may not demonstrate clinical improvement from baseline over time, it may be able to slow the rate of cognitive or behavioral deterioration. In this review we use the term "improvement" to reflect the degree to which patients improve with respect to their comparator. Because most of the evidence for these drugs stems from placebo-controlled trials, "improvement" commonly reflects differences between active- and placebo-treated patients. These patients, in reality, may not be significantly better than they were when they started treatment, but have demonstrated slower deterioration than patients in the other study groups.

As equipotency among the reviewed antidementia drugs is not well established, we assume that dose comparisons made within the recommended daily dosing range are comparable (Table 1). Dose comparisons made outside the recommended daily dosing range are acknowledged in our report, but we do not use them to determine the quality of the evidence. Furthermore, we evaluate studies that assess only initial treatment with these drugs as independent agents; we do not consider the issue of switching from a ChEI to memantine or vice versa. Although some clinicians may use a combination of drugs in clinical practice, we do not specifically consider combination therapy in this report. However, because combination therapy has been addressed by at least one clinical trial, we contrast this trial with other available evidence.

Considerations governing our work on key question 1 and 2 (i.e., dose equivalency, operational definitions) pertain as well (as appropriate) to key questions 3 and 4.

Copyright © 2006, Oregon Health & Science University, Portland, Oregon.
Bookshelf ID: NBK10314


Other titles in this collection

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...