AD progresses through several clinical stages (Figure 1). Loss of recent memory, or forgetfulness, is the most common presenting symptom. This is often accompanied, or shortly followed by, personality and behavioral changes, including disinterest in hobbies and social activities. Complex tasks that involve executive functioning – such as the management of finances, using household appliances, and performing household chores – are often impaired early in the disease, whereas basic ADL – such as grooming and hygiene, toileting, and feeding – are not affected until the dementia is more advanced. Impaired patients will eventually develop decline in other cognitive realms. These include navigational ability (visual-spatial function), recognition of common items (gnosis), and motor programming (praxis) 7.

Multiple risk factors have been proposed for the development of AD. It is generally agreed that advancing age and family history of dementia are the major risk factors in typical, late-onset AD 2. Genetic factors can also be a contributing risk in early-onset disease. While the role of apolipoprotein E (APOE) in AD pathology is unknown, there is a correlation between the risk of AD and APOE genotype 8. The APOE-4 allele has been most closely associated with increasing the risk of AD by three- to fourfold.

AD is a complex neurologic disease that is diagnosed by clinical presentation; however, there are three consistent neuropathologic hallmarks of the disorder that are generally noted on postmortem brain examination: amyloid-rich senile plaques 9, neurofibrillary tangles 10, and neuronal degeneration. The primary cause of AD is still speculative, but AD pathology includes evidence of neuronal cell dysfunction either caused by or resulting in neurofibrillary tangles and/or β-amyloid plaques. In recent years, significant research attention has also been devoted to the roles of inflammation, free radical formation, and oxidative cell damage in the pathogenesis of AD. The progression of AD is related to the disease's effect on neuronal circuitry. Short-term memory loss, usually the first symptom of the disease, reflects a disruption of signaling between the hippocampus and entorhinal cortex, adjacent regions of the brain that are thought to be required for early establishment of memory 11. As AD advances in severity, neuronal signaling in the neocortical areas required for cognitive function and long-term memory storage are affected 11. AD exhibits a large impact on neurotransmission: the most prominent neurotransmitter changes are cholinergic. The effects of AD on the cholinergic system include reduced activity of choline acetyltransferase (ie, reduced synthesis of acetylcholine [ACh]) 12, reduced number of cholinergic neurons in late AD (particularly in the basal forebrain) 13, and selective loss of nicotinic receptor subtypes in the hippocampus and cortex 12.

ACh is the major neurotransmitter affected in AD 12. Its pharmacology is a consequence of its interrelationship with acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), muscarinic receptors, and nicotinic receptors. AChEIs are the only drug class currently approved in the United States for the treatment of AD. AChEIs block the esterase-mediated metabolism of ACh to choline and acetate and result in increased ACh in the synaptic cleft and increased availability of ACh for postsynaptic and presynaptic cholinergic receptors 14. There are four AChEIs currently available in the United States: tacrine (Cognex^®, 1993), donepezil (Aricept^®, 1996), rivastigmine (Exelon^®, 2000), and galantamine (Reminyl^®, 2001). Table 1 identifies prescription share and volume. Each of these agents has undergone extensive clinical trial evaluation throughout the world. Drug efficacy versus placebo has been demonstrated consistently in trials ranging in duration from 12 to 52 weeks. Generally, the majority of clinical trials conducted to establish the efficacy of treating AD with this class of agents have adopted similar outcome measures. The standard psychometric tool used to assess cognition in the majority of these studies is the Alzheimer's Disease Assessment Scale (ADAS) 15. The section of the scale from which scores are most frequently reported is the cognitive subscale (ADAS-cog). In addition to the ADAS-cog, the AD clinical trials also utilize quantified clinical impressions of the patient by a study investigator. These data usually are gleaned from direct examination of the study subject as well as from a caregiver interview. These clinical impressions are most often reported as a Clinical Global Impression (CGI) or Clinician Interview-Based Impression of Change (CIBIC).

While the four available AChEIs are all members of a common drug class, they exhibit many individual differences. The characteristics of these agents are summarized in Table 2.

At present, there exist no clearly established guidelines for determining which specific AChEI to use for which specific patient with AD. Existing clinical trials data do not help to inform this clinical decision making. By and large, the magnitude of the treatment effect observed in the published, placebo-controlled clinical trials for all of the available agents is comparable. The side-effect profiles differ in that rivastigmine, as an example, likely has more gastrointestinal-related adverse events in therapeutic doses than donepezil or galantamine. Donepezil appears to have somewhat more sleep disturbance reported as a side effect than the others. However, for reasons that are still unclear, clinical experience dictates that some patients will be idiosyncratically more tolerant of one agent than another, or perhaps more responsive to one agent versus another. With multiple therapies having become available in the past few years for treatment of AD-related symptoms, this may prompt switches among AChEIs. Reasons for switching among different AChEIs may include one or more of the following: dosing convenience, inefficacy or perceived inefficacy, poor tolerability, physician preference, patient or caregiver request, or economic considerations. Before a switch is made, the physician must consider the pharmacodynamics and pharmacokinetics of the possible options to maximize patient tolerability and minimize loss of established efficacy from the previous regimen.

A drug with a longer elimination half-life, such as donepezil, may require a washout period of 1 to 2 weeks before initiating another AChEI to avoid cholinergic toxicity 56. However, one must also consider that significant functional decline may occur during washout, and significant improvements achieved during therapy may be lost during washout. If the latter occurs, restoring function to pre-washout levels is rare if the drug is reinstated 56. Three studies were done to determine the minimum washout period necessary when switching from donepezil to rivastigmine (1.5 mg twice daily) 57. The first study compared a 2-week washout (n = 5) versus no washout (n = 6) of donepezil before rivastigmine was started. In the second study, patients (n = 105) went through a 4-day donepezil dose reduction, followed by a 4-day washout before initiation of rivastigmine at 1.5 mg daily, and then escalated based on tolerability. The third study compared donepezil washout periods of zero days (n = 57), 3 days (n = 2), and 4 weeks (n = 3). The results of these three studies suggest that long washout periods may not be necessary when switching from donepezil to rivastigmine 57. Larger studies are needed for verification of these findings.

A post hoc analysis of a previously conducted trial 46 was performed to examine the effect of prior AChEI exposure on the efficacy and tolerability of galantamine 42. There was a minimum 2-month washout period between previous AChEI therapy and initiation of galantamine. Regardless of previous AChEI exposure, treatment effects were consistent with galantamine, with patients experiencing significant improvements in cognitive and global function. There were no significant differences between subgroups in terms of adverse events, indicating that galantamine is well tolerated despite prior AChEI use 42.

When determining the length of necessary washout, the physician must weigh the risk for cognitive decline during the washout period against the potential for adverse events without a washout on a patient-by-patient basis 56. It is important to consider individual patient factors, such as current cognitive abilities, health and frailty, use of concomitant medications, potential for drug interactions, and previous sensitivity to AChEI treatment 56. When switching among AChEIs, the goal is to maintain cognitive function while avoiding the emergence of adverse events that may cause patients to discontinue therapy 56.

Vitamin E is an antioxidant that prevents cell damage by inhibiting the oxidation of lipids and the formation of free radicals. There is only one clinical trial investigating its use in patients with AD 58. Though it was safe and well tolerated, there were no improvements in cognition, function, or behavior. However, patients taking vitamin E did show a significant treatment effect, specifically in the delay of institutionalization 58. The American Psychiatric Association recommends the use of 1,000 IU of vitamin E twice daily for patients with moderate AD. Additional trials are needed to test the benefits of vitamin E in patients with milder forms of AD.

Other alternative treatment agents that may have beneficial effects in patients with AD are selegiline, ginkgo biloba, and nonsteroidal anti-inflammatory drugs. Unfortunately, within the nonsteroidal anti-inflammatory class, recently concluded clinical trials of two selective COX-2 inhibitors, refecoxib and celecoxib, failed to show benefit as therapeutic agents. However, based largely on epidemiologic evidence, significant attention is still being directed to whether nonselective agents such as indomethacin, sulindac, and ibuprofen may have a role in the prevention and treatment of AD. Recently, the statin class of compounds as well as agents that lower serum homocysteine levels (eg, folic acid) have been proposed for their possible therapeutic roles in the treatment of AD. More studies need to be conducted before recommendations can be made as to their appropriate use in the AD population.

As the condition of patients with AD progressively deteriorates, they often develop behavioral symptoms that can be very troublesome to the caregiver and/or family. Common psychiatric and behavioral symptoms frequently seen include apathy, agitation, mood lability, blunted affect, disinhibition, withdrawal, delusions, anxiety, suspiciousness, dysphoria, hostility, aggression, and hallucinations 5960. As severity increases, these symptoms can increase caregiver distress and often lead to placement of the patient in a personal care facility 61.

Before treatment of these symptoms is begun, the physician must rule out any medical disorders, physical discomfort, medication effects, or pre-existing psychiatric illness that may be contributing factors. Once target behaviors are identified, appropriate treatment (pharmacologic and/or environmental) can be initiated. While no agents are currently approved for the treatment of behavioral symptoms in patients with AD, physicians commonly prescribe off-label agents to help manage these symptoms. Agents of choice include the atypical antipsychotics (eg, risperidone, olanzapine, quetiapine), serotonergic compounds (eg, citalopram, sertraline), or mood stabilizers, such as sodium valproate. The best clinical trial data gathered to date support the superior efficacy over placebo of risperidone 62 and olanzapine 63 for psychosis and agitation in dementia. Emerging placebo-controlled data also support a role for sodium valproate 64 in the treatment of agitation.

Importantly, the potential psychotropic effects of ChEIs have also been increasingly explored. The cholinergic hypothesis of the 1980s linked the changes in memory and cognition seen in AD with biochemical changes in the brain, changes that included deficits in acetylcholine, norepinephrine, and serotonin. Treatment for AD involved cholinomimetic therapies that block the degradation of acetylcholine available at the synapse. AChEIs were developed to delay the progression of cognitive decline. The deficit in ACh is responsible for some of the neuropsychiatric symptoms presented in AD – agitation, psychosis, personality changes, depression – because emotional behaviors are mediated by the effects of cholinergic action on the frontal and temporal lobes of the brain. AChEIs may create a more favorable neurochemical environment allowing psychotropic agents to be more effective 65. Clinical trials examining the psychotropic effects of these cholinomimetic drugs are being conducted 166566676869. The positive effects that galantamine exhibits on the behavioral aspects of AD illustrates multiple mechanisms by which this class of agents may exert psychotropic effects. One such mechanism is the action to increase ACh: since patients with AD have low levels of ACh in the limbic system 70, enhancing these levels with an AChEI may help to improve behavioral symptoms. With galantamine specifically, its nicotinic-modulatory property may allow for increased arousal and decreased aberrant motor behavior and agitation similar to the mechanism by which psychostimulants act in the treatment of attention deficit disorders in children 71. In addition, improved function of nicotinic thalamofrontal projections by galantamine may reduce agitation, which appears to be frontally mediated 72.

There are several new agents in development with various mechanisms of action for the treatment of AD. The identification of new targets for AD treatment may allow for combination therapy in the near future. While AChEIs are the only approved treatment option for patients with AD, researchers are currently studying other therapies.

Memantine (Merz & Co., Frankfurt/Main, Germany) is a noncompetitive, N-methyl D-aspartate (NMDA) receptor antagonist approved in Germany for more than 10 years for the treatment of dementia. The proposed mechanism by which memantine exerts its effects on dementia is thought to be related to its neuroprotective characteristics 7374. Clinical safety and efficacy have been investigated both in clinical trials and postmarketing surveillance studies 757677. Memantine is generally well tolerated, with the most common adverse events being vertigo, restlessness, hyperexcitation, and fatigue 76. It may become a neuroprotective treatment for dementias in the near future, and it may also be combined with AChEIs for symptomatic relief of AD 78.

An additional option for treatment of AD that has received much attention is immunization against β-amyloid to reduce the levels of β-amyloid plaques 79; studies are still in early development for its applicability to AD treatment. Unfortunately, an ongoing clinical trial of one such vaccine was recently halted due to the emergence of neuroinflammation in treated subjects. Other treatment possibilities include γ – and β-secretase inhibitors to prevent β-amyloid formation 80.