Benefits of Early Pharmacological Treatment in Alzheimer Disease

As the aging of the world population continues, the number of people affected by dementia is likely to steadily increase. It is estimated that there are 4.5 million affected people in United States alone and that this number will triple in the first half of this century. Alzheimer disease (AD), the most common form of dementia, remains a major public health challenge internationally. This disease not only exacts a heavy toll on patients but also causes anguish to millions of caregivers and costs society more than $100 billion annually in the United States alone.¹

Dementia refers to a generally chronic syndrome characterized by a decline in intellectual functioning that is substantial enough to interfere with a person's ability to perform usual and daily activities. Depending on the underlying cause, the clinical course can be static or progressive. AD is clinically characterized by an insidious onset and progressive decline. The identified neuropathological hallmarks of this disease include extracellular amyloid plaques, intracellular neurofibrillary tangles, and an associated loss of neurons. Eventually all aspects of the affected individual's life are involved to the extent that he or she becomes dependent on care providers for the most basic activities of daily life (Table 1). The psychiatric symptoms of a patient with AD often result in caregiver burnout and may lead to the patient's placement in a supervised living facility.²

Early treatment begins with early detection
Successful intervention requires an early and timely diagnosis. Caregivers of persons with AD often state that an average of 2 years passes from the onset of symptoms to a formal diagnosis.³ Similarly, it is recognized that pathological changes of AD begin to appear years or decades before a clinical diagnosis is made.⁴ Thus, early diagnosis remains a challenge.⁵ Clinicians may fail to recognize the earliest signs of AD or may feel uncomfortable diagnosing AD because of a lack of standard assessment tools, time and reimbursement constraints, and fears that a diagnosis of dementia may open a Pandora's box. Alternatively, patients and families may not report cognitive problems, either because they are in denial or they fear stigmatization.

We do not know what causes AD, but the past 2 decades have seen remarkable progress in our understanding of its origin and treatment. A major focus of research is to refine our ability to identify the illness at the earliest point by using biological and imaging markers. In terms of treatment, the ideal solution is to effectively prevent the disease and limit the number of new cases. Although some risk factors have been identified,⁶ we may not yet have the ability to prevent the disease before it develops (primary prevention); the focus, therefore, is on maximizing the effectiveness of available treatments for symptomatic patients and identifying those in transition to or at risk for progression to AD (secondary prevention). Current available treatments (cholinesterase inhibitors and memantine) limit the devastation that is unleashed by this disease (tertiary prevention). Mild cognitive impairment (MCI) is increasingly being recognized as a prodrome to dementia but is not an FDA-approved indication for treatment with the above agents. In addition to symptomatic treatments, several disease modification strategies are under clinical investigation.

Defining success
AD is not merely a cognitive disorder (Table 1). The data from regulatory trials of antidementia agents may not look impressive unless success is defined in broader terms. In the absence of a cure, both improvement and slower rate of decline over time are positive therapeutic outcomes (Figure). Recent studies of antidementia agents have addressed some of the limitations of regulatory trials in an effort to enhance their clinical relevance. Inclusion of broader patient populations,^7,8 extended period of observation,^9,10 and use of behavioral, caregiver, and economic outcomes^11-13 have helped redefine "success." On average, untreated patients decline relentlessly, whereas treated patients tend to show a less progressive deterioration. We now have the ability to stabilize cognitive function in a substantial percentage of patients and limit long-term disability for at least 1 year. Put simply, these treatments work reasonably well.^14-16

Rationale for early intervention
In a progressive illness in which symptom severity and disease burden steadily increase, it makes sense to initiate treatment as early as possible. Effective treatments help to preserve cognitive abilities, limit functional dependence and psychological burden.^10-12,15-18 Emerging evidence suggests, but does not prove, that starting treatment early increases the likelihood of better outcomes.^9,19 Early intervention could mean slower progression of the disease process and preservation of neural structures, potentially delaying the emergence of certain symptoms in persons at risk. These benefits could translate into enhanced safety, autonomy, and quality of life for patients and their caregivers. Certainly, in clinical practice treatment decisions need to be individualized and require weighing potential benefits against risks of adverse effects.

In addition, treatment helps lower direct medical costs for both patients and their caregivers^13,20 and can delay nursing home placement.^21,22 In essence, it is logical to start treatment early and continue it as long as it is clinically meaningful. In their study, Trinh and colleagues²³ found that cholinesterase inhibitors have a modest beneficial impact on neuropsychiatric and functional outcomes for patients with AD. Furthermore, the results of a recent meta-analysis showed that patients who were treated with donepezil over a 12-, 24-, or 52-week period, had some benefit in cognitive function, activities of daily living, and behavior.²⁴

A diagnosis of dementia represents a certain threshold that has been crossed in a disease process. Recent treatment studies in patients with MCI reflect the growing emphasis on early intervention. The results of treatment studies with MCI suggest that treatment may delay the progression to AD.^25,26 These results provide another rationale for early intervention. Additional studies in those with very early dementia have demonstrated substantial benefit, furthering the argument "the earlier the better."¹⁹ It is important for clinicians and caregivers to know that not all is lost once a diagnosis of AD is made. In early stages of AD, patients can still learn new information and use it in daily life.²⁷ This helps them remain engaged in their hobbies and enjoy social interactions with the world around them.

Psychopharmacology for AD
There is no magic cure for AD; however, much can be done to limit the suffering and maintain a reasonable quality of life for patients. Once a diagnosis is made, patients and caregivers need guidance and support (Table 2). Pharmacological intervention with antidementia agents is the current standard of therapy. Four acetylcholinesterase inhibitors (AChEIs) and an N-methyl d-aspartate (NMDA) receptor antagonist are currently approved by the FDA for treatment of AD (Table 3).

Among the AChEIs, tacrine was the first marketed in the United States. Data from an observational study of tacrine provided early evidence of long-term benefits of therapy with this class of agents. Patients who received therapeutic doses of tacrine were 2.8 times less likely to be admitted to a nursing home than those who were treated with subtherapeutic doses.²¹ Tacrine is now rarely used in the United States because of safety concerns and an inconvenient dosing schedule. Patients taking tacrine require intensive monitoring of liver enzymes because of its potential to produce hepatic toxicity.²⁸

Donepezil is approved by the FDA for the treatment of patients with mild to moderate, as well as severe AD. In a year-long placebo-controlled study,¹⁵ scores on the Mini-Mental State Examination (MMSE) remained at or close to baseline levels for the group treated with donepezil over the 52 weeks of study, whereas MMSE scores deteriorated by 2.2 points in the group treated with placebo. In another 1-year placebo-controlled study,¹⁶ treatment with donepezil was associated with a 38% reduction in the risk of functional decline compared to treatment with placebo. Further evidence comes from several 6-month, placebo-controlled studies with open-label extensions and studies in patients with greater dementia severity. All suggest outcomes favoring active treatment over placebo.^7,8,29 Some studies raise the hope that treatment with AChEIs in patients with AD may delay nursing home placement,^14,22 although no such effect was seen in a large prospective study.³⁰

Rivastigmine is an AChEI as well as an inhibitor of butyrylcholinesterase. There is no conclusive evidence so far that butyrylcholinesterase inhibition produces clinical benefit. Rivastigmine is currently approved by the FDA for treatment of mild to moderate AD and Parkinson dementia. Several studies (6-month placebo-controlled and longer-term observational) have demonstrated stabilization of cognitive symptoms.¹⁷ Two of the pivotal trials with rivastigmine incorporated measures of functional performance based on caregiver interview.^31,32 Rivastigmine 6 to 12 mg daily was superior to low-dose rivastigmine and placebo treatment in both studies in terms of mainte- nance of functional performance. Patients who received rivastigmine therapy also showed reduction in behavior- al symptoms, including psychosis and disinhibition.¹¹

Galantamine is the latest among the AChEIs. In addition to inhibition of AChEI, it is a modulator of allosteric nicotinic receptors. The clinical significance of this additional effect on nicotinic receptors is not established. Pivotal trials of galantamine indicate favorable effects on both cognition and functional performance.^9,18 Treatment with galantamine reduced the likelihood of emergent psychopathology over the duration of the trial compared with placebo.¹⁸ The "delayed start" data from an open extension phase add to the evidence favoring early initiation of treatment (see below).

Memantine, an NMDA receptor antagonist, is approved by the FDA for treatment of moderate to severe AD-both as monotherapy and as add-on therapy to an AChEI. Available data from studies in moderate to severe AD suggest a slowing of deterioration in cognition, function, and overall dementia severity.^33,34 Memantine has also been shown to improve behavioral symptoms such as aggression, apathy, and nighttime behaviors.¹² Data from studies of memantine in mild to moderate AD have not been as convincing.³⁵

Early treatment influences long-term outcomes
The antidementia treatments produce modest yet consistent benefit in maintaining patients' cognitive abilities, daily function, and behavioral control. How does early treatment differ from delayed treatment and how does continuous treatment alter the natural course of AD? Does initiating treatment very early produce more substantial benefits? Should treatment be initiated for patients with MCI? These questions have been addressed in some of the recent analyses.

Data from 1-year "delayed start" studies and longer-term observational studies suggest that patients who started receiving active treatment after a delay of 6 months did not achieve as optimal an outcome at the end of the study period. In a 6-month placebo-controlled study of galantamine with a 6-month open extension, patients who received placebo in the double-blind phase were crossed over to open treatment.⁷ These patients showed expected initial decline in cognitive performance followed by the expected improvement when galantamine was begun. The cognitive performance in these patients improved but did not "catch up" to the level in those patients who had been receiving continuous therapy. Similar results were also seen in studies of donepezil. Patients for whom active treatment was delayed did experience cognitive benefit, but at the end of the 3-year study, cognitive outcome scores favored early and continuous treatment.¹⁰ These data suggest that delaying therapy might deprive some patients of an optimal response.

In yet another study to support early intervention, 153 patients with AD who had an average MMSE score of 24 (very mild AD) were randomized to receive placebo or donepezil. While the placebo group failed to improve on primary cognitive measures, treatment with donepezil resulted in significant improvements in cognitive function over 24 weeks.¹⁹ This finding is thought-provoking. It is possible that the rate of cognitive decline and potential benefit of intervention in early AD is different from what is typically seen in studies of patients with greater cognitive severity.

The rate of progression in patients with AD is heterogeneous. Lopez and colleagues³⁶ have expanded on their previous report that treatment with AChEIs alters the natural course of AD.¹⁴ Their recent analysis shows that patients taking an AChEI were twice as likely to progress slowly as patients with AD who were not treated with an AChEI. This is clinically meaningful, since the rate of decline can impact the caregiver's ability to provide care, which influences a patient's ability to live in the community.

A critical "tipping point" for caregivers is emergence of unmanageable psychopathology in patients with AD. In another study, open-label donepezil was dispensed for 12 weeks, followed by randomization to placebo or donepezil for another 12 weeks. Patients treated with donepezil showed improvement in behavioral symptoms that was maintained during the randomization phase. Patients who were switched to placebo after 12 weeks experienced behavioral deterioration.³⁷

Mild cognitive impairment: a window of opportunity
In a progressive illness such as AD, it is obvious that individuals move through a transitional phase during which symptoms are not severe enough to warrant a dementia diagnosis. MCI represents that transition between normal aging and dementia. Persons with MCI have a subjective sense of memory decline that is recognized by family or clinical providers. These individuals do not have appreciable functional impairment.³⁸ The concept of amnestic MCI, however imperfect, comes closest to identifying AD before the onset of dementia. This construct has been used in several clinical trials and some have suggested that MCI is very early AD.³⁹ Further validation comes from a recent study in which 99% of participants with amnestic MCI who progressed to dementia were classified as having AD after 3 years of follow-up.⁴⁰

The benefits of treatment are likely to be more substantial if treatment is initiated before the threshold for dementia diagnosis is crossed. Therefore, the concept of MCI has inspired clinicians and researchers to action. Two recent studies have explored the potential for treating patients for MCI. In a 24-week, double-blind, placebo-controlled trial there was a significant difference favoring donepezil on a secondary outcome measure, although the primary measures failed to show benefit for donepezil.²⁶

Encouraging results were also seen from the Alzheimer's Disease Cooperative Study MCI clinical trial.⁴⁰ The results indicate that patients taking donepezil were at reduced risk for progressing to AD during the first 18 months; however, this advantage disappeared at the end of 3 years. The study compared the effects of donepezil 10 mg daily, vitamin E 2100 IU daily, and placebo in delaying the progression from MCI to AD in 769 patients. In a subset of patients who had the apoE4 allele, donepezil appeared to decrease the probability of progression to AD for the full 36 months of the study. Thus, a diagnosis of amnestic MCI may provide a window of opportunity for intervention and for limiting the suffering of patients and their caregivers.

Conclusion
Relentless decline is observed in patients with AD who do not receive treatment. In the absence of a cure, stabilization and slowing the progression are valuable objectives. Early diagnosis and treatment can help us achieve these goals. Recent data point to a broader range of effects of antidementia drug treatment, including favorable effects on behavior, daily functions, and caregiver burden. Data from year-long placebo-controlled studies and observational data converge on the conclusion that long-term benefits are likely with treatment. Patients who received active treatment on average were better off than patients who did not receive treatment. Furthermore, the provocative "delayed start" data suggest that delaying the onset of treatment may result in less favorable outcomes. These findings are strengthened by some, but not all, additional data from studies of very mild AD and MCI.

Laboratory evidence suggests neuroprotective or possible disease-modifying effects of AChEI and memantine therapy. These agents may influence disease progression not only by modifying neurotransmitter abnormalities but by influencing abnormal amyloid and tau processing and neurotoxicity. If these findings are substantiated, our goal of pharmacological intervention will shift from symptom management to disease modification-in which case, early therapy (possibly in patients with MCI) will become more important.