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Primary Care Companion to The Journal of Clinical Psychiatry logoLink to Primary Care Companion to The Journal of Clinical Psychiatry
. 2006;8(3):158–159. doi: 10.4088/pcc.v08n0306

A Systematic Review of Assessment and Treatment of Moderate to Severe Alzheimer's Disease

Frederick A Schmitt 1,✉, Christine H Wichems 1
PMCID: PMC1540387  PMID: 16912819

Abstract

Objective: The systematic, large-scale study of therapies for moderate to severe Alzheimer's disease (AD) is a relatively recent advancement in the field. This review describes for the general practitioner the characterization of moderate to severe AD, discusses the development of metrics sensitive to the constellation of symptoms in these patients, and critically evaluates the use of those measures in moderate to severe AD clinical trials.

Data Sources: Published clinical trials obtained by MEDLINE searches used the following key words: moderate AD, severe AD, donepezil, rivastigmine, galantamine, memantine, and anti-dementia agents. Clinical trials were limited by language (English), study type (clinical trial), and publication dates (1990–2005).

Study Selection: Nine clinical trials comprise the studies conducted to date in moderate to severe AD and include 5 prospective randomized clinical trials (3 for memantine, 2 for donepezil) and 4 retrospective subanalyses (2 for galantamine, 2 for rivastigmine) of primary datasets.

Data Extraction: Clinical trials are summarized and major findings are reviewed.

Data Synthesis: The data reviewed support the decision to initiate and maintain treatment in moderate to severe AD patients.

Conclusions: The development and implementation of improved metrics for moderate to severe AD patients has revealed that meaningful benefits are attainable in this patient population by treatment with the N-methyl-D-aspartate receptor antagonist memantine. Evidence also indicates a benefit from cholinesterase inhibitor treatment, although further study of these agents in this patient population is warranted.

It has been estimated that over one half of community-dwelling patients diagnosed with Alzheimer's disease (AD) are in the moderate to severe stages of the disease,1 and almost 90% of institutionalized patients with AD have been graded as moderate or severe.2 Despite the large proportion of patients estimated to be in the moderate and severe stages of AD (31% moderate and 21% severe),1 most clinical trials have examined antidementia drug effects earlier in the disease, leading to the approval of the cholinesterase inhibitors (ChEIs) for patients with mild or moderate AD. Given the inevitable decline of the AD patient from mild to moderate and ultimately to severe stages of the disease, clinicians are faced not only with the challenge of determining the proper treatment regimen for their individual AD patients but also with the responsibility of effectively communicating realistic short- and long-term treatment expectations to the patient and/or caregiver.

Previously, a lack of metrics capable of detecting therapeutic efficacy in more advanced AD contributed to the perception that clinical benefit of an antidementia agent was unlikely, or at best immeasurable, in patients with moderate to severe AD. Over the past several years, instruments have been developed and existing tools have been modified, allowing for the accurate characterization and tracking of patients beyond the mild stages of the disease. Incorporation of these tools into clinical trials has provided meaningful data and expanded the study of AD beyond mild to moderate severity, as demonstrated by the positive results of prospective clinical trials examining the efficacy of the ChEI donepezil3 and the moderate affinity N-methyl-D-aspartate receptor antagonist memantine in moderate to severe AD.4,5 The 2003 Food and Drug Administration (FDA) approval of memantine made available for the first time a treatment indicated specifically for moderate to severe stages of AD, and the data supporting this decision utilized rating scales and outcome measures specific to a patient population with more advanced AD.

This review describes for the general practitioner the concept of advanced AD, discusses the development of metrics sensitive to the range of symptoms seen in these patients, and critically evaluates the use of such measures in clinical trials of antidementia agents in moderate to severe AD.

DISEASE PROGRESSION: MODERATE TO SEVERE ALZHEIMER'S DISEASE

The clinical spectrum of AD resides on a continuum whereby the initial signs may be barely detectable and the later symptoms are both obvious and complex.6–8 AD disease progression is not a uniform process; rates of decline vary widely, and there is an enormous range of disability that is largely dependent on the stage of severity.

Early clinical manifestations may present as memory loss, progressing to language and communication impairments, deteriorating executive function, and social withdrawal. Unlike the cognitive impairment that dominates early stage AD, patients with advanced AD are beset by multiple, heterogeneous deficits that complicate the clinical picture. Increasing cognitive loss is accompanied by progressive functional deficits and eroding motor skills. Most sources agree that about 90% of patients will develop various behavioral and psychological symptoms at some point in the illness.9–12 Anxiety, delusions, depression, restlessness, aggression, and pacing have been shown to be prevalent in the later stages of AD.7,13

STAGING TOOLS FOR DETERMINING ALZHEIMER'S DISEASE SEVERITY

A number of longitudinal AD studies have been used as the basis for developing staging systems.8,14 Staging tools delineate the course of AD and provide a means whereby an individual with AD may be placed along a continuum of decline. Because multiple domains are affected by AD, a variety of staging tools have been developed; some evaluate cognition, others assess global severity, and others focus on functional status.15 While staging the severity of AD does not necessarily assist with a prediction of future disease course (e.g., the rate of decline), assessing severity might aid a physician in understanding what particular groups of symptoms can be expected.

Clinical trials in AD use staging tools as inclusion criteria to define the severity of the patient population to be studied. The tools most commonly used in AD clinical trials include the Mini-Mental State Examination (MMSE),16 probably the most widely used assessment of cognitive function employed in both clinical practice and clinical trials; the Clinical Dementia Rating Scale (CDR)17,18; the Global Deterioration Scale (GDS)19; and the Functional Assessment Staging Scale (FAST).20 Brief descriptions of the utility and limitations of each of these tools are provided in Table 1.

Table 1.

Staging Tools in Dementia

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The ideal definitions of moderate and severe AD would encompass the domains of cognition, function, behavior, global status, and caregiver burden. However, the heterogeneous nature of symptoms associated with AD, coupled with limitations inherent to staging tools (e.g., variability, ceiling and floor effects), argues against narrowly defining discrete stages in disease progression. Illustrating this point, Figure 1 highlights the variability in the range of MMSE scores for levels of severity globally determined by clinicians (based on the CDR).18 In spite of these challenges, broad operational definitions of AD progression using staging tools as surrogate markers of disease severity are summarized in Table 2.

Figure 1.

Figure 1.

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Mean and Range of MMSE Scores (box plot) for Levels of Impairment Defined by CDR Stages of Dementia Severitya

Table 2.

Operational Definitions of Alzheimer's Disease (AD) Stages

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EVALUATING TREATMENT EFFICACY IN ADVANCED ALZHEIMER'S DISEASE

Subsequent to concerns regarding the insufficient testing of putative antidementia agents, the FDA proposed draft guidelines in 1990 for establishing whether a drug possessed antidementia efficacy.29 As cognitive impairment is a core feature of AD, it was reasoned that a putative agent must demonstrate efficacy by improving cognition or retarding its deterioration. The FDA also requested that a clinically meaningful (global) measure be included as a second primary outcome to ensure that changes in cognitive test results are mirrored by clinical changes detectable by a physician, independently of psychometric tests. This established the dual-outcome criteria that were to become the de facto standard subsequent to the marketing approval of tacrine in the United States in 1996. The guidelines were limited, however, in their failure to recognize that improvement in behavior or function alone may be legitimate therapeutic goals, particularly in advanced AD patients who are unable to perform standard cognitive tests. Thus, the FDA requirements have guided the development of assessment tools, including those specific for advanced AD.30

The development of metrics appropriate for patients with moderate to severe AD has made it possible to define and evaluate the cognitive, functional, and behavioral status in more advanced patients. Incorporation of these tools into clinical trials has resulted in the quantification of treatment benefits that previously went undetected. Since the choice of assessment tools in clinical trials and the variability of symptoms in more advanced AD patients can affect both the interpretation of trial data and the ability of primary care physicians to apply trial results to the clinic, it is important to gain an understanding of currently employed assessment tools.

The scales that have been developed or modified for use in moderate to severe AD clinical trials include the Severe Impairment Battery (SIB),31 the Alzheimer's Disease Cooperative Study-Activities of Daily Living inventory modified for Severe Patients (ADCS-ADL19),32 the modified Instrumental Activities of Daily Living (IADL+),33 the modified Physical Self-Maintenance Scale (PSMS+),33 and the Disability Assessment in Dementia (DAD).34 Details of each scale are summarized in Table 3.

Table 3.

Rating Scales Used in Moderate to Severe Alzheimer's Disease (AD) Trials

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Although the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) has been the most commonly used outcome measure of cognitive function in antidementia clinical trials,42 it was specifically developed to assess treatment effects in mild to moderate AD patients.43,44 As AD progresses and patients experience a dissolution of expressive and receptive language skills, performance on measures like the MMSE or ADAS-cog may be subject to floor effects, making it difficult to quantify and assess change in patients with moderate to severe AD.

For this reason, the SIB was designed for use in patients with more advanced dementia31 and provides an accurate assessment of change in cognition over time in patients with MMSE scores below 15. Due to the limited comprehension and language skills of this patient population, the assessment employs simple verbal commands accompanied by gestures.45 In addition, credit for nonverbal and partially correct responses is given, which allows for a finer assessment of cognitive function in this highly impaired group. For example, an 85-year-old man with an 8-year history of AD obtained an MMSE score of 5 based on repetition of 3 objects and orientation to city and state (note that only 17% of the MMSE remains to describe disease progression). However, when the SIB is obtained, his score is a 74. The SIB subscales reveal that his primary areas of dysfunction are in praxis (25% completed), orientation (50% correct), memory (71%), and language (76%), with essentially no impairments in basic skills of attention, social interaction, and simple constructions. Given his ability to function on the SIB, and given the wide range of skills identified by the SIB items, cognition can be tracked more carefully in response to treatment and disease progression. Similar to the use of the ADAS-cog in pivotal trials of mild to moderate AD, the SIB has become the de facto standard for assessing cognition in trials of moderate to severe AD.

The PSMS and IADL were among the first scales developed to evaluate function in elderly patients and are validated measures for the assessment of basic (i.e., personal care activities such as walking, feeding, and toileting) and instrumental (i.e., more complicated tasks such as handling finances, shopping, and food preparation) activities of daily living (ADLs), respectively.33 These scales have been modified to enhance their sensitivity for use in clinical trials of moderate to severe AD (IADL+ and PSMS+).3,41 As reported by Feldman et al.,41 these modified instruments are sufficiently sensitive to measure drug treatment effects in moderate to severe AD patients; however, notable limitations of these scales include coarse rating increments that impede their sensitivity to change and the need for concurrent use of both scales to obtain information on basic and instrumental ADLs.46 Other limitations of these and other available assessments of function include the use of gender-specific items, subjective questioning, and inclusion of behavioral as well as functional information.

In response to the limitations, the ADCS-ADL32 and DAD34 were developed to assess the performance of both basic and instrumental ADLs in AD patients. The ADCS-ADL was further modified, and the resulting 19-item version, the ADCS-ADLsev (referred to as the ADCS-ADL19 in this article), was shown to be appropriate for the assessment of functional change in clinical trials of patients with moderate to severe dementia.40

CLINICAL TRIALS IN MODERATE TO SEVERE ALZHEIMER'S DISEASE

Published clinical trials obtained by MEDLINE searches used the following key words: moderate AD, severe AD, donepezil, rivastigmine, galantamine, memantine, and antidementia agents. Clinical trials were limited by language (English), study type (clinical trial), and publication dates (1990–2005).

Clinical trial results published to date with memantine, the ChEIs, or both in moderate to severe AD patients are summarized in Tables 4 and 5 and are described in detail below.

Table 4.

Memantine in Moderate to Severe Alzheimer's Disease (AD)

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Table 5.

Cholinesterase Inhibitors in Moderate to Severe Alzheimer's Disease (AD)

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Efficacy of Memantine in Moderate to Severe Alzheimer's Disease

Cholinesterase inhibitors have been used for AD treatment for about a decade. Memantine is the first treatment from a new class of compounds that has been approved for use in patients with AD. Memantine represents a new approach to AD therapy and offers the first approved treatment option for those patients in the moderate to severe stages of the disease. The safety and efficacy of memantine in moderate to severe AD were supported by 3 pivotal trials, and the developmental history of memantine mirrors the advances in outcome measures over the last decade.

The first large-scale placebo-controlled trial of memantine in dementia was initiated in the early 1990s. It was designed to investigate the clinical efficacy and safety of memantine (10 mg/day) over the course of 12 weeks in nursing home patients with severe dementia of the Alzheimer's type or vascular dementia.47 This population was of interest as there were no therapies approved or in development for this patient population. At the time the study was initiated, the primary outcome measures of interest that could be reliably tested were related to patient function and global performance: the care dependency subscale of the Behavioral Rating Scale for Geriatric Patients (BGP-care) and the Clinical Global Impressions of Change (CGI-C) scale. The BGP was adapted from the Stockton Geriatric Rating scale,52 an investigator-rated scale that provides an objective behavioral assessment of geriatric patients. The BGP has been used in Europe since 1971 and has good reliability and the ability to measure longitudinal change.53 The superiority of treatment with memantine over placebo demonstrated on both the BGP-care and CGI-C became the “proof-of-principle” that initiated further investigation of memantine efficacy in patients with later stages of AD.

In the next trial designed to assess the clinical efficacy and safety of memantine in patients with moderate to severe AD, Reisberg and colleagues performed a 28-week, randomized, double-blind, placebo-controlled trial in 252 AD patients.4 At the time the trial was conducted, the SIB and the ADCS-ADL19 had been validated by the ADCS. Primary outcome measures included a global measure, the Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC+), and a modified functional measure (ADCS-ADL19). Secondary outcomes included a cognitive measure (assessed by the SIB and MMSE), a behavioral measure (Neuropsychiatric Inventory [NPI]),54 and additional functional ratings (FAST, GDS) by the clinicians. The benefits of memantine (10 mg b.i.d.) over placebo in patients with moderate to severe AD were clinically meaningful as determined by the CIBIC+ (p = .03 for observed cases [OC]; p = .06 for last observation carried forward [LOCF]) with 45% of memantine-treated patients either improving or not changing, compared with only 27% of patients receiving placebo. Patients treated with memantine also had better preservation of cognition (as measured by the SIB; p < .001, LOCF; p < .002, OC), especially in the areas of memory and visuospatial activity. Functional preservation was greater with memantine (ADCS-ADL19; p = .02, LOCF; p = .03, OC) compared with placebo, including improvements in conversing. Finally, the effect of memantine on behavioral outcome (as measured by the NPI) was superior to placebo treatment over the study period, reaching statistical significance at week 12.55

In a more recent trial, Tariot and colleagues published the first prospective, double-blind, placebo-controlled trial examining the benefits of memantine in patients with moderate to severe AD who also were receiving a stable dose of the ChEI donepezil.5 Prior to study initiation, patients had been taking donepezil for an average of 2 years (minimum of 6 months). Primary outcome assessments in this 24-week trial included the SIB and the ADCS-ADL19; secondary outcome measures included the CIBIC+, FAST, NPI, and BGP. This trial randomly assigned 403 patients to memantine 10 mg b.i.d. (N = 202) or placebo (N = 201). Significantly more memantinetreated patients (85% vs. 75%) completed the trial (p = .01). At week 24, patients treated with memantine/donepezil showed statistically significant improvement (p < .001) in cognitive function (SIB) compared to patients treated with placebo/donepezil, notably in the areas of memory, language, and praxis. Furthermore, memantine-treated patients displayed significantly less decline (p = .028) in daily function (ADCS-ADL19), and additional analyses showed the maintenance of higher-level functions such as grooming, finding belongings, and turning faucets/lights on and off.56 A significant difference in favor of memantine/donepezil was also seen on the CIBIC+ (p = .027), NPI (p = .002), and BGP-care (p = .001). Taken together, these data suggest that treatment with memantine in patients stabilized on donepezil is superior to donepezil alone.

In addition, a recently completed phase 3 trial of similar design to the monotherapy study by Reisberg and colleagues4 did not demonstrate statistical significance at trial end-point on primary outcomes (data on file, Forest Laboratories, New York, N.Y.).57 Potential confounding factors included less than normal rates of disease progression with placebo treatment and nonnormal distribution of outcome scores. Nevertheless, numerical superiority of memantine was seen over placebo on all outcomes (data on file, Forest Laboratories, New York, N.Y.).57 While these data support the safety and efficacy of memantine treatment in moderate to severe AD, further analyses are underway to fully understand the implications of the findings of this trial. Additional investigations with memantine in mild to moderate AD patients have provided evidence that memantine may be efficacious across the full spectrum of AD (data on file, Forest Laboratories, New York, N.Y.).57

Efficacy of Cholinesterase Inhibitors in Moderate to Severe Alzheimer's Disease

Cholinesterase inhibitors were the first evidence-based treatments available for patients with AD. Although they currently are indicated for the treatment of mild to moderate AD, several lines of evidence support the hypothesis that ChEIs would be beneficial across a wider spectrum of AD, including moderate to severe AD.58,59 The clinical trials of ChEIs conducted in moderate to severe AD patients have varied in design, duration, patient status, inclusion criteria, and outcome measures, reflecting the lack of standardized approaches to the study of this patient population.

The first trial to evaluate a currently available ChEI in more advanced AD investigated the safety and efficacy of donepezil in patients with moderate to severe AD.3 This study was a prospective, randomized, double-blind, placebo-controlled trial in which 290 patients with moderate to severe AD received donepezil 10 mg/day (after 28 days of 5 mg/day) for a 6-month period. The majority of the patients resided in the community (≈87%), with the remainder in assisted living situations (≈13%). The CIBIC+ was selected as the primary outcome measure as there were reservations concerning the perceived clinical relevance of a small but significant change on a cognitive outcome measure at this stage of the disease. Secondary outcome measures, with the exception of the modified standardized MMSE, were selected for their utility in advanced AD in hopes of avoiding floor effects. These secondary measures included assessments of cognition with the SIB; function as measured by the DAD, the IADL+, and the PSMS+; behavioral symptoms as evaluated by using the NPI; and an additional global assessment with an instrument known as the Functional Rating Scale (FRS).60

Patients receiving donepezil demonstrated significant, clinically meaningful benefits as determined by the CIBIC+ compared with placebo at all visits up to week 24 (p < .001). All other secondary measures (including MMSE, SIB, DAD, IADL+, PSMS+, FRS, and NPI) showed significant differences between the groups in favor of donepezil at week 24 (p < .05). Of particular interest to the study of moderate to severe patients were the findings on the 2 cognitive measures, the SIB and the MMSE. The SIB demonstrated a significant sensitivity to change in either direction, allowing for a detection of both a decline from baseline in the placebo group and an improvement from baseline in the donepezil group. This contrasts with the MMSE results, which exhibited floor effects in the placebo group. Together, these results underscore the utility of the SIB and its sensitivity as a measure of cognition with this advanced population and demonstrate the impact of instrument selection on the evaluation of AD treatment outcomes.

Further analysis of this trial revealed a sensitivity of the modified metrics (IADL+, PSMS+, DAD) to detect a significantly slower decline associated with donepezil than placebo in both instrumental and basic ADLs.41 Additional benefits of the delayed functional decline seen with done-pezil treatment included less time spent in provision of care and lower levels of caregiver stress, thus extending the effects of donepezil in moderate to severe patients to include measurable effects on caregivers.

Tariot and colleagues48 reported the results of a double-blind, randomized, placebo-controlled trial of donepezil in 208 nursing home patients with mild to moderately severe AD. The primary outcome measure, a modified version of the NPI adapted for nursing home settings, revealed no significant treatment effect on behavioral symptoms. The authors attributed the paucity of effect on the larger than expected placebo effect and high rate of concomitant psychotropic medication use. Perhaps most striking in this trial is the impact that wide ranges of symptom variability and disease severity have on AD trial outcomes, a reminder of the inherent difficulties involved in studying a disease with a high degree of heterogeneity. Although approximately one third of the patients had advanced AD (MMSE < 10), the study was not powered to focus specifically on this patient subgroup, warranting further study with this patient population in this setting.

Data regarding the efficacy of the other currently marketed ChEIs, rivastigmine and galantamine, are derived from post hoc analyses of pivotal clinical trials in patients with mild to moderate AD. In these analyses, data were extracted from patients who, at baseline, were at the more advanced end of the mild to moderate spectrum (“advanced-moderate” patients). While outcomes of these trials are encouraging and support the evidence for efficacy in moderate to severe AD, there are some inherent limitations to the scope of interpretation of these studies. These limitations typify the challenges of studying more advanced AD and will be discussed in detail below.

In the study reported by Wilkinson et al.,50 data from 4 phase 3 pivotal trials61–64 with galantamine in mild to moderate AD were pooled, and a post hoc analysis was performed on the subgroup of “advanced-moderate” patients. Once pooled, advanced-moderate patients were defined in one of 2 ways, resulting in 2 overlapping groups. Over a 6-month time period, galantamine (24 mg/day) had significant benefits over placebo on cognition (as measured by the ADAS-cog scale) in both subpopulations of advanced-moderate patients. Similar results were seen on measures of function (assessed by the ADCS-ADL) and behavior (measured by the NPI) in the subpopulation of advanced-moderate patients defined on the basis of ADAS-cog scores.

Blesa and colleagues51 performed a similar post hoc analysis of the 4 pivotal trials with galantamine but also included data from the open-label extension trials to assess the longitudinal effects (1 year) of galantamine on advanced-moderate patients. Patients were required to fulfill one of 2 criteria for advanced-moderate AD: either a baseline ADAS-cog score greater than 30 or a baseline MMSE score below 15. Historical placebo data were obtained from similar subsets of patients in previous clinical trials with sabeluzole to model the placebo decline from 6–12 months, corresponding with the timing and duration of the open-label extension studies. Similar to the 6-month report, cognitive abilities (assessed using the ADAS-cog) of patients with advanced-moderate AD who received galantamine for 12 months were maintained at baseline levels after 12 months and were significantly better than those of the placebo group (p < .001). Responder analyses revealed that at 12 months, 51% of advanced-moderate patients with baseline ADAS-cog scores > 30 maintained or improved their ADAS-cog scores; similarly, 48% of the subgroup of patients with baseline MMSE scores ≤ 14 met this same criterion for response. Functional abilities, as measured by the DAD, also demonstrated significant benefits in galantamine-treated patients compared with placebo.

The long-term efficacy of 2 dosage groups of rivastigmine (1–4 or 6–12 mg/day) was assessed in a post hoc analysis of a 26-week pivotal trial and subsequent 26-week open-label extension study.49 The subset of moderately severe AD patients in this year-long study was chosen based upon a baseline GDS score of 5 or more. (Of note, only 3 of the 159 patients that completed the double-blind portion of the trial had a GDS score > 5). After 52 weeks, patients in both dosage groups experienced significantly smaller declines in ADAS-cog scores from baseline than the projected decline in the placebo group. Further analyses revealed benefits associated with earlier initiation of treatment.

These post hoc analyses were constrained by the criteria and outcomes originally defined in the mild to moderate AD trials. For example, considerable variation exists in defining criteria for “advanced-moderate” and “moderately severe” AD and in the outcome measures used (ADAS-cog and other metrics less specific for moderate to severe AD populations). Therefore, caution must be exercised when interpreting these data.

The length of 2 of the reports (1 year) raised the possibility that traditional efficacy measures of cognition (e.g., MMSE and ADAS-cog) may suffer from measurement effects, including floor effects resulting from eroding verbal capacity that affect the applicability of common metrics of cognition. Prior to the development of tools appropriate for more advanced AD, this lack of a valid and reliable measure represented one reason for the paucity of studies with this population.

Furthermore, longer-term trials, while useful in evaluating drug safety, often raise more questions than answers regarding efficacy, owing largely to the open-trial design, lack of randomization, and use of historical/projected placebo controls. The differences in the manner in which placebo controls were generated in the 2 yearlong analyses highlight this point; in the galantamine trial, historical placebo data from similar patients in another drug trial were used, whereas the rivastigmine analysis used placebo controls projected from the rate of decline by the placebo arm in the first 6 months of double-blind treatment.

Results from such post hoc analyses need to be confirmed in prospective clinical investigations of sufficient power using inclusion criteria and outcome measures specific to the moderate to severe AD population. Nevertheless, the findings from these post hoc analyses are consistent with the positive results from the donepezil trial and further support the use of ChEIs in patients with moderate to severe AD.

LIMITATIONS OF ACROSS-TRIAL COMPARISONS

Review of the clinical trials performed in moderate to severe AD reveals a number of challenges as we move toward the future in the study of AD in severely demented individuals. The observation that patients prospectively described as moderate to severe differed in certain baseline characteristics underscores the importance of having a consensus on secondary staging tools. For example, although patients are described as “moderate to severe” in the Feldman donepezil trial (FAST ≤ 6),3 they are quite different functionally from those in the Reisberg memantine trial (FAST ≥ 6a).4 Furthermore, variation in baseline severity may influence the rate of progression in AD as measured by different instruments. For example, Figure 2 depicts the effect that baseline MMSE scores may have on the rates of decline in clinical trials. Despite the variability often seen with MMSE scores at different severity levels, lower mean baseline MMSE scores were associated with more obvious progression as reflected in SIB scores for the placebo group in the Reisberg trial compared with the Tariot and Feldman trials (Figure 2).

Figure 2.

Figure 2.

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Impact of Baseline MMSE Scores on SIB Score Decline in Placebo Patients

Secondly, patients with more advanced AD, such as those included in the reviewed studies, necessitate the use of specialized scales designed to detect changes as a result of treatment. The use of the ADAS-cog, for example, to track cognitive decline in more advanced patients has limitations, and the same limitations apply for other domains as well. Prior to the use of specialized scales, the tangible benefits patients experience with antidementia treatment may have been unrealized. Similarly, if outcomes are evaluated using modified scales, changes that are perhaps immeasurable in the “big picture” may have a large impact in this patient population. Clinically, relatively minor changes due to treatment may have a major impact on symptoms and function. Even small gains in day-to-day living capabilities can be clinically meaningful from the standpoint of quality of life for the patient as well as the caregiver. For example, maintaining toileting skills can reduce caregiver stress and the need for supervision and can potentially reduce the need for nursing facility placement.

CONCLUSIONS

The clinical trial data reviewed above support the decision to initiate and maintain treatment in moderate to severe AD patients, with important, albeit modest, benefits observed across multiple domains. Indeed, the clinical value of treating a moderate to severe AD patient population was supported by the FDA with the October 2003 approval of memantine. Although similar conclusions for the ChEIs are currently limited by trial design heterogeneity, the data summarized above provide evidence to support their continued study in later stages of AD.

Preservation of cognitive and functional abilities as well as “suppression” of behavioral symptoms improves the quality of life for both patients and caregivers. Furthermore, functions that are preserved in advanced AD are just as important, if not more so, than those that are lost. Alzheimer's disease patients, even beyond the moderate stages of disease, usually have some abilities worth preserving, and a plan of care may be implemented that focuses on optimizing patient autonomy and quality of life. Both memantine and the ChEIs have demonstrated an ability to stabilize or slow the decline of key areas affected by AD. For the individual patient, it appears to be crucial to target behaviors, functions, and cognitive skills that the patient may still attempt independently (compare ADCS-ADL19 development40). Then, these behaviors and skills may be used to monitor treatment response.

For many years, it has been a popular opinion that patients with more advanced AD would not benefit from therapeutic interventions; however, the development and implementation of improved metrics for advanced AD over the last several years have revealed clinical evidence that meaningful benefits are attainable in moderate to severe AD. While efforts to identify preventative treatment offer hope for reducing incidence of or a potential cure for AD, no such therapies are currently available. Thus, continued efforts to improve metrics and conduct prospectively designed clinical trials across the spectrum of AD severity are warranted in order to provide additional information and to ensure that the treatment needs of this sizeable AD patient subset are not neglected.

Drug names: donepezil (Aricept), galantamine (Razadyne), memantine (Namenda), rivastigmine (Exelon), tacrine (Cognex).

Disclosure of off-label usage: The authors have determined that, to the best of their knowledge, donepezil, galantamine, rivastigmine, and tacrine are not approved by the U.S. Food and Drug Administration for the treatment of severe Alzheimer's disease and memantine is not approved for the treatment of mild Alzheimer's disease.

Acknowledgments

The authors wish to thank the following individuals for their contributions to the manuscript: Allison Caban-Holt, Ph.D., from the Sanders-Brown Center on Aging, for reviews of the manuscript; Jason T. Olin, Ph.D., from Forest Laboratories, who provided editorial and technical support for the manuscript; and Jennifer Hepker, Ph.D., Kristen A. Andersen, Ph.D., and Merrilee Johnstone, Ph.D., from Prescott Medical Communications Group, for editorial support.

Pretest and Objectives

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Instructions and Posttest

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Registration Form

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Footnotes

Supported by National Institute on Aging Alzheimer's Disease Research Center grants P50 AG05144 and R01 AG19241.

In the spirit of full disclosure and in compliance with all ACCME Essential Areas and Policies, the faculty for this CME article were asked to complete a statement regarding all relevant financial relationships between themselves or their spouse/partner and any commercial interest (i.e., any proprietary entity producing health care goods or services consumed by, or used on, patients) occurring within at least 12 months prior to joining this activity. The CME Institute has resolved any conflicts of interest that were identified. The disclosures are as follows: Dr. Schmitt is a consultant for, has received grant/research support from, and is a member of the speakers or advisory boards for Forest and Pfizer. Dr. Wichems has no personal affiliations or financial relationships with any proprietary entity producing health care goods or services consumed by, or used on, patients to disclose relative to this article.

Acknowledgments appear at the end of the article.

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