The incidence of Alzheimer's disease is expected to increase through the year 2050 with an estimated prevalence of 11 to 16 million cases. Two classes of medications are FDA approved for managing symptoms of AD, cholinesterase inhibitors and an N-methyl-D-aspartase receptor antagonist..
The incidence of Alzheimer's disease (AD) is expected to increase through the year 2050 with an estimated prevalence of 11 to 16 million cases. Two classes of medications are FDA approved for managing symptoms of AD, cholinesterase inhibitors (ChEIs) and an N-methyl-D-aspartase (NMDA) receptor antagonist. ChEIs are commonly used as initial treatment on diagnosis. Memantine, the only NMDA receptor antagonist, can be used as monotherapy as well as an adjuvant to ChEIs. New doses and formulations of these medications have recently gained FDA approval. New compounds under development target the amyloid pathway, tau phosphorylation, or acetylcholine levels, and it is hoped that they will not only improve symptoms but also slow disease progression or even lead to a cure. (Formulary. 2011;46:268–284.)
TYPES OF DEMENTIA
A combination of neuropathology and clinical criteria is used to differentiate between the causes of dementia.3 In the brain, behavior and mood are controlled by the serotonergic, dopaminergic, and noradrenergic pathways, while memory is thought to be controlled by the cholinergic pathway.4 The types of neurotransmitters and different areas of the brain affected dictate the presenting symptoms and corresponding type of dementia.
The pathology of AD involves deficits in acetylcholine, the presence of neurofibrillary tangles, and the excess formation of neuritic plaques.3,4 The disease affects neurons in the basal forebrain, amygdala, hippocampus, and cerebral cortex, all of which correspond to clinical deficits in learning, memory, reasoning, behavior, and emotional control.3 The Diagnostic and Statistical Manual of Mental Disorders IVth Edition (DSM-IV) defines the diagnostic criteria for dementia of the Alzheimer type as the development of multiple cognitive deficits manifested by both memory impairment (inability to learn new, or recall old, information) and at least one of the following: aphasia, apraxia, agnosia, or disturbance in executive functioning. These cognitive deficits must significantly impair social/occupational functioning and represent a significant decline from a previous level of functioning. Dementia of the Alzheimer type is also characterized by gradual onset, continuing cognitive decline, cannot be due to other causes of progressive cognitive decline, and cannot occur exclusively during the course of delirium.5
Although AD is still the most common cause of dementia, dementia with mixed etiologies, such as AD and vascular dementia or DLB, is becoming more common than previously thought.2,4 Vascular dementia can have 2 pathologies: large-vessel disease or small-vessel disease. Large-vessel disease leads to infarctions in the cortical region of the brain, whereas small-vessel disease is seen in the subcortical brain regions and is often the result of hypertension, diabetes, or blood vessel damage.6 Early symptoms of vascular dementia include apathy, personality changes, and executive functioning deficits that are similar to symptoms seen with frontotemporal dementia, owing to the effect on the frontal subcortical regions.4,6 As its name implies, frontotemporal dementia is caused by damage to the anterior frontal and temporal lobes of the brain, and early symptoms are often behavioral and language-based.4 DLB is characterized by the presence of alpha-synuclein protein aggregates (Lewy bodies) in the substantia nigra and cortex.4 Because these aggregates are also seen in idiopathic Parkinson's disease, DLB can present with features of Parkinson's disease, such as tremor, bradykinesia, rigidity, and postural instability.4 Other defining clinical symptoms of DLB are visual hallucinations and memory loss attributed to an acetylcholine deficit.4
In addition to the irreversible neuronal changes that cause dementia, a complete differential diagnosis also considers reversible causes. Reversible causes of dementia include vitamin deficiencies (B12, thiamine), hypothyroidism, infections (HIV, syphilis, Lyme disease), normal-pressure hydrocephalus, subdural hematoma, depression, alcohol, and drugs (sedatives, tranquilizers, analgesics).4
As research continues to uncover details of the disease process of dementia and AD, previously known pathophysiology is coming to the forefront of treatment. Of note, the roles of tau proteins in neurofibrillary tangles and beta amyloid in neuritic plaques (also known as amyloid or senile plaques) are being explored. Neurofibrillary tangles and plaques are found predominantly in AD, but are also present in frontotemporal dementia and other diseases.3 Both the tangles and plaques occur naturally in the aging process, but are seen in excess in AD. In the formation of plaques, the larger precursor protein known as amyloid precursor protein (APP) is cleaved into smaller protein fragments.7 The largest of these fragments is a 42 amino acid peptide chain called beta amyloid. The misfolding of this protein leads to the neurotoxic plaques, although there is increasing evidence to indicate that soluble amyloid fibrils of the beta amyloid protein called oligomers are the true cause of neuronal damage.4 Genetic mutations in genes encoding for APP, presenilin-1, and presenilin-2 (the cause of familial AD) cause an increase in beta amyloid plaques as well.7 Tau is a protein that has a role in assembling and stabilizing microtubules in neurons.4 Tau protein has to be phosphorylated to bind to the microtubules, and overphosphorylation inhibits the tau protein from binding to the microtubules. As a result, the microtubules collapse, and the tau protein filaments aggregate in the cytoplasm forming tangles.3 Overall, these neuronal abnormalities cause cell death and play a significant role in the disease process.
CURRENT TREATMENTS FOR AD
Duration of therapy is highly individualized. There are varying recommendations for when to discontinue medications. For accurate assessment, monitor after 2 to 4 weeks for adverse drug reactions, 3 to 6 months for improvement of cognition and function, and 6 to 12 months for delayed progression of disease.
The ChEIs-donepezil, rivastigmine, galantamine, and tacrine-are indicated for mild-to-moderate AD; only donepezil is approved for the severe stage. These medications reversibly bind the enzyme acetylcholinesterase, allowing for more available concentrations of acetylcholine, a neurotransmitter associated with thought, learning, memory, and other cognitive processes.3 Although available, tacrine is not recommended because it has a high risk for hepatotoxicity and drug interactions (cytochrome P450), requiring frequent monitoring.
There have only been a few strong, head-to-head studies comparing the efficacy of all the ChEIs, and they have had conflicting results. Each of the medications, however, has been shown to make overall small, but significant improvements in slowing the rate of cognitive and functional decline, when compared with placebo. A meta-analysis reviewed 14 clinical trials of donepezil, galantamine, and rivastigmine from 1980 to 2007; in these trials, manufacturer-recommended dosing was used and patients were followed for 3 to 6 months.11 This meta-analysis found that there was no difference between treatments as the reported change in the 70-point Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) score was -2.67 (95% CI, -3.28 to -2.06) for donepezil, -2.76 (95% CI, -3.17 to -2.34) for galantamine, and -3.01 (95% CI, -3.80 to -2.21) for rivastigmine. Within this analysis, 2 studies compared donepezil with galantamine and 2 compared donepezil with rivastigmine in open-label, head-to-head, clinical trials. These head-to-head trials reported conflicting results depending on funding for the clinical trial, duration of treatment, and severity of AD. The most common side effects noted were diarrhea, nausea, vomiting, dizziness, and weight loss. Donepezil was associated with a higher rate of diarrhea (12%); however, rivastigmine had the highest rates of nausea (44%), vomiting (30%), dizziness (22%), and weight loss (11%). In the indirect comparison of the ChEIs, no difference was seen in their modest effect on cognition, with only a slight increase in adverse drug reactions (ADRs) in the rivastigmine treatment group.
A 2006 Cochrane review compared the results of 10 randomized, double blind, placebo-controlled trials of donepezil, galantamine, or rivastigmine.12 Patients with mild, moderate, and severe AD were treated with manufacturer recommended doses for 6 months. This review found the ADAS-cog score improved on average -2.7 points (95% CI, -3.0 to -2.3). Although the review included only a small number of severe AD cases, the results appeared to be similar to those in patients with mild-to-moderate AD. There was a higher rate of withdrawal (29% compared with 18%) and increased rates of reported nausea, vomiting, diarrhea, abdominal pain, anorexia, dizziness, headache, and insomnia in patients treated with ChEIs. No differences in cognition were seen between the treatment groups; however, there was a slightly higher rate of adverse events with rivastigmine than with other ChEIs. Only two 6-month Northern European trials reviewed healthcare costs associated with donepezil use. Although these trials did not include enough information and their duration was too short for a complete cost-benefit analysis, both trials found no benefit or disadvantage for total healthcare resources.11
The main difference between the ChEIs is in available formulations, drug interactions, and side-effect profiles. The most common side effects of this class are gastrointestinal ADRs, such as nausea, vomiting, and diarrhea.3 A study comparing donepezil and rivastigmine in patients (n=111) with mild-to-moderate AD assessed patients at 4 and 12 weeks using ADAS-cog and found both treatments to be equally efficacious.13 The rivastigmine group, however, had a higher rate of reported ADRs (58%) compared with donepezil (43%), specifically nausea and vomiting (rivastigmine, 11% vs donepezil, 7%). These ADRs were typically mild with a low discontinuation rate. ChEIs may also exacerbate certain medical conditions such as uncontrolled bradycardia, bradyarrythmia, asthma, chronic obstructive pulmonary disease, and seizures.3
In July 2010, FDA approved donepezil 23 mg for the treatment of moderate-to-severe AD with product labeling similar to that for the 5-mg and 10-mg tablet strengths. Donepezil 23 mg is given once daily and should be titrated from a starting dose of 10 mg daily after at least 3 months.14
Donepezil 23 mg was studied in a 24-week, multicenter, randomized, double-blind trial.14 The objective was to determine the effectiveness of the higher-dose compared with standard-dose donepezil in moderate-to-severe AD. The effectiveness of high-dose donepezil was measured using the Severe Impairment Battery (SIB) for cognition and the Clinician's Interview-Based Impression of Change Plus Caregiver Input Scale (CIBIC+) for global function rating. Tolerability and adverse events were assessed using an open-ended patient/caregiver reporting system. After 24 weeks, a statistically significant difference was seen in the higher dose donepezil group (+2.2, P<.001) on SIB scale; however, it is unclear whether this represents a significant clinical difference. SIB is a 133-point scale and was found to have a range from 6 to 81 for patients with a Mini-Mental State Examination (MMSE) score less than 6.15 The CIBIC+ was not different between the high-dose and standard-dose groups. There was a higher rate of withdrawal due to adverse events in the donepezil 23-mg group than in the donepezil 10-mg group (18.6%, 182 patients vs 7.9%).14 With the recent patent expiration of donepezil 10 mg and the availability of generic formulations, the price difference between brand donepezil 23 mg and generic donepezil 10 mg is expected to be significant. If an increase to donepezil 23 mg daily is considered, it must be done so taking into account the unknown meaningful improvement in cognition and global functioning, potential increased risk of side effects, and, of course, potential cost difference.
NMDA RECEPTOR ANTAGONIST
Memantine is indicated for patients with moderate-to-severe AD. This medication is a noncompetitive antagonist to the NMDA receptor-controlled cation channels. It also binds the 5-hydroxytryptamine-3 receptor and nicotinic acetylcholine receptors. By binding to the NMDA receptor, glutamate is regulated, which, in turn, regulates long-term potentiation, a central mechanism in learning and memory.8 Glutamate moderation also prevents excessive amounts of calcium that can lead to cell death.3
Memantine use in moderate-to-severe AD and mild-to-moderate AD was evaluated in a 2009 Cochrane review.16 Overall, the difference in CIBIC+ for patients with moderate-to-severe AD was small but statistically significant (0.28 points; 95% CI, 0.15-0.41). The effect for patients with mild-to-moderate AD was even smaller (0.13 points; 95% CI, 0.01-0.25), yet still statistically significant. The review did not find a difference in withdrawal rates or adverse events; however a decreased rate of agitation was seen in patients with moderate-to-severe AD treated with memantine.
Evidence exists supporting the use of combination therapy of memantine and a ChEI for moderate-to-severe AD.17 The Alzheimer's Drug Discovery Foundation expert panel recommends the initiation of combination therapy in patients diagnosed with moderate-to-severe AD.18 The American College of Physicians /American Academy of Family Physicians clinical practice guidelines do not specifically address combination therapy and recommend the choice of pharmacologic agents based on individual tolerability, ease of use, and cost.19 Combination therapy has been shown to be effective in improving cognition, activities of daily living, and behavior compared with ChEIs alone in patients with moderate-to-severe AD.8,9 Often, the strategy is patient specific, for example, if increasing the dose of donepezil is causing worsening gastrointestinal side effects that are not self-limiting, using the 5-mg dose and adding memantine may be more appropriate.
One epidemiologic study followed patients in the Alzheimer's Research Program (1983 to 1988) and the Alzheimer Disease Research Center at the University of Pittsburgh (1985 to present).20 This study found a prolonged time to nursing home placement for patients on combination therapy compared with those who had not used cognitive enhancers or those treated with ChEIs only. This study included a much longer duration of follow-up than previous studies, in which follow-up averaged only 24 weeks. The study had some limitations, however, because of the epidemiologic design. Patients on combination treatment began the study period with higher MMSE scores and higher levels of education, which may have also affected time to nursing home placement.
Memantine is generally well tolerated when initiated at 5 mg once daily and increased by 5-mg increments once weekly until the target dose of 10 mg twice daily is achieved. A lower target dose of 5 mg twice daily is needed in patients with renal dysfunction (defined as a creatinine clearance less than 30 mL/min).3 Unlike the common gastrointestinal ADRs seen with ChEIs, the most common ADRs reported with memantine are headache, constipation, and dizziness.3, 15 This medication can have antagonistic effects on serotonin receptor-type 3, which may protect against the gastrointestinal effects of ChEIs when used in combination therapy.8 Memantine is currently under patent and will not be available for generic manufacturing until 2015.
In June 2010, memantine hydrochloride extended-release capsules gained FDA approval for treatment of moderate-to-severe AD. Approval was granted based on 1 placebo-controlled trial using memantine 28 mg once daily over 24 weeks in patients currently treated with a ChEI.21 Memantine was initiated at 7 mg once daily and titrated each week by 7 mg/d until the target dose of 28 mg was achieved. On the primary outcome, change in SIB scale, memantine was superior to placebo, with a difference of 2.8 points (P=.001). The study did not find an increased rate of adverse events in the memantine extended-release group, despite the 1.5 times higher maximum concentration of drug. Although the trial included only patients actively treated with ChEIs, FDA approved memantine extended-release with the same indications as the immediate-release formulation.
β-secretase inhibitors. Inhibition of -secretase has become a target of drug development since it cleaves APP to A . However, this new class has faced design challenges. The compounds must cross the blood-brain barrier and not disrupt the b-secretase substrate neuregulin-1, which is thought to be involved in myelination. Two drugs, rosiglitazone and pioglitazone, decrease b-secretase expression by stimulating the nuclear peroxisome proliferator-activated receptor g.22 In trials in patients without ApoE4, rosiglitazone treatment improved CIBIC+ scores; however, further investigation of rosiglitazone in AD have been halted because of concerns about increased cardiovascular risk.24 Pioglitazone easily crosses the blood-brain barrier and is currently undergoing phase 3 trial in patients with mild cognitive impairment. Among other investigational b-secretase inhibitors, KMI-429 is under development, and CTS-21166 was found to reduce Ab protein levels in healthy adults during a phase 1 trial.21
g-secretase inhibitors. Another drug class under clinical development is the g-secretase inhibitors. Based on their pharmacology, these compounds are predicted to decrease Ab proteins in the cerebral spinal fluid (CSF), which will decrease the development of neuritic plaques and progression of AD. The first drug in this class was tarenflurbil (MPC-7869, Flurizan), which failed to show a benefit in phase 3 trials on the ADAS-cog so its development was halted.23 Development of another compound, semagacestat, was halted during phase 3 trials because of a negative effect in the treatment group compared with controls. This led to the hypothesis that g-secretase is crucial to maintain membrane homeostasis and that decreased activity of this enzyme may actually worsen AD symptoms.25 Despite this hypothesis, other medications within this drug class are still under investigation, including BMS-708163, a Notch-sparing, second-generation g-secretase inhibitor, which led to a decrease in CSF Ab in patients with mild-to-moderate AD. Begacestat (GSI-953) and PF-3084014 are other Notch-sparing, second-generation g-secretase inhibitors under investigation. NIC5-15, a naturally-occurring monosaccharide found in foods, also acts as a Notch-sparing g-secretase inhibitor as well as an insulin sensitizer, which may improve AD symptomology.22
a-secretase stimulators. Another drug class under development is the a-secretase stimulators. a-secretase is important as it cleaves APP and leads to the reduction in Ab proteins. Phase 1 testing of the investigational compound etazolate (EHT-0202), which modulates the gamma aminobutyric acid receptor thus stimulating a-secretase, has begun phase 2 testing for mild to moderate AD.22 Epigallocatechin-3-gallate, developed as Sunphenon EGCg, is a polyphenol extract from green tea, which induces a-secretase while decreasing Ab aggregation. Studies are currently recruiting patients with early mild AD.26 Byrostatin-1, a protein kinase C activator that also stimulates a-secretase, has decreased Ab protein levels in animal studies, and a phase 2 trial in patients with mild-to-moderate AD is planned. Exebryl-1 modulates both b-secretase and a-secretase activity, has decreased Ab formation in mouse models, and phase I trials are expected to begin.22
APP inhibitors. Posiphen represents another drug class, the APP inhibitors. Posiphen, a (+)-phenserine enanatiomer, is an acetylcholinesterase inhibitor. It has poor affinity for acetylcholinesterase but substantially decreases APP by reducing its messenger ribonucleic acid translation. Although posiphen was well tolerated with some benefit seen in cognition in patients with mild-to-moderate AD, the primary outcomes of ADAS-cog and CIBIC+ were not improved. The lack of significant improvement has hindered interest in future, larger randomized clinical trials of this drug.22
Ab protein aggregation inhibitors. A fifth drug class under development inhibits Ab protein aggregation, which decreases the synaptotoxic activity of Ab oligomers by reacting, neutralizing, and eliminating them. It has been challenging, however, to develop these agents because of difficulty in crossing the blood-brain barrier and the high possibility of toxicity.21 One such medication was tramiprosate (Alzhemed), which did not change Ab protein levels or have clinical effects on cognition in the phase 3 Alphase trial because of low CNS penetrability and weak potency.22,25 Nonetheless, this compound, found in certain seaweeds, is now being marketed as homotaurine, a nutraceutical for memory protection available in the United States and Canada.25 The next generation of Ab aggregation inhibitors, PBT2, scyllo-inosital (AZD-103, ELND005) is currently under development.27,28
AD vaccines can stimulate cellular and humoral immune responses to generate anti-Ab antibodies, which then remove Ab proteins from the CNS.29 One such vaccine, which has garnered much media coverage, is AN-1792. Unfortunately, during a phase 3 trial, 18 (6%) of the 300 patients on active treatment developed aseptic encephalitis. This was hypothesized to be due to cytotoxic T-cell activation or an autoimmune reaction.21,29 Despite this set back, other active immunity vaccines are being developed. Phase 1 trials of one such vaccine, affitope (AD-01), have been completed, and trials of another, AD-02, are actively recruiting.30
To help minimize the T-cell activation, passive immunity, or the direct administration of anti-Ab antibodies, is under development. A phase 3 trial of bapineuzumab, a humanized anti-Ab monocloncal antibody, is actively recruiting. Also recruiting are phase 2 trials of solanezumab, ponezumab (PF-04360365), gantenerumab (R-1450), GSK-933776, and MABT-5102A for either prodromal AD or mild-to-moderate AD.22
The nonspecific passive immunity, IVIg, which includes naturally occurring polyclonal anti-Ab antibodies in immunoglobulins from donors, is a final area of AD immunotherapy. Phase 2 trials demonstrated a decrease in total Ab protein levels and evidence of stabilized cognitive functions.22
The other major hypothesis, that tau protein dysfunction leads to dementia, has generated additional AD drug design. In dementia, the tau protein becomes abnormally phosphorylated forming microtubule-associated protein tau (MAPT), which then forms neurofibrillary tangles. Inhibition of GSK3 decreases the amount of active tau-phosphorylating kinase, decreasing MAPT.23 Valproate and lithium inhibit GSK3; however, both had disappointing results when tested in patients with mild dementia. NP-03112 is a thiadiazolidinone-derived GSK-3 inhibitor in phase 2 trials. Davunetide intranasal and IV formulations have improved cognition in amnestic mild cognitive impairment. Nicotinamide is the biologically active niacin (vitamin B3) and has been shown to decrease phosphorylated tau concentrations.22
Methylioninium chloride (methylene blue, Rember) is a tau antiaggregate.23 A 60-mg dose of methylene blue was shown to improve cognitive function in a phase 2 trial. After 1 year, a decline in disease progression was seen. Leuco-methyl-thioninium, a new formulation of methylene blue, has a higher bioavailability and is now undergoing phase 3 trials.22
Since a decrease in muscarinic binding sites in presynaptic cholinergic terminals have been seen in AD, muscarinic receptors are another target for drug development. Talsaclidine (WAL-2014) and cevimeline (AF-102B) are muscarinic receptor agonists that did cause a decline in Ab concentrations. Both entities, however, had undesirable cholinergic side effects, such as increased salivary flow. Cevimeline is now being tested in xerostomia.22
Nicotine receptors are also believed to be important in cholinesterase transmission and may play a role in Ab protein toxicity.23 EVP-6124 is a nicotinic a7 receptor agonist currently undergoing phase 2 trials in mild-to-moderate AD.31
Latripirdine (Dimebon, dimebolin) is a nonselective antihistamine, which is thought to improve mitochondrial function. This helps AD symptoms because mitochondrial dysfunction occurs in early AD and leads to synaptic damage and apoptosis. In the phase 3 CONNECTION study, however, latripirdine showed no benefit in mild-to-moderate AD.22
Nerve growth factor (NGF) may be linked to deactivation of the amyloid pathway and prevention of neurodegeneration. NGF is difficult to administer because of difficulty in crossing the blood-brain barrier. In original trials, NGF was administered as an intracerebroventricular infusion with positive effects on cognition and physiological measurements. However, patients experienced adverse events such as subcortical haemorrhage, weight loss, and pain. Phase 2 trials for innovative NGF delivery devices are planned.22
Histamine H3 antagonists are thought to decrease acetylcholine in the prefontal cortex. Early drug development included compounds GT-2331, ciprofan, and thioperamide, which because of imidazole-like structures, led to CYP450 inhibition and low CNS permeability. Phase 2 trials of newer compounds, including PF-03654746, GSK239512, MK-0249, and ABT-288, have been completed.32
Since the number of AD cases is predicted to rise over the next 30 years, large increases in healthcare costs and care burden due to AD are also expected. Thus, cost-effective treatment is essential. Current treatment guidelines recommend ChEIs for mild-to-moderate AD and NMDA receptor antagonists for severe AD. The ChEIs do not differ in efficacy; however, therapy can be individualized based on tolerability, ease of use, and cost. Donepezil 23 mg once daily may not be a cost-effective therapy since it resulted in only a small benefit with higher rates of withdrawal and ADRs compared with donepezil 10 mg. It is also expected to cost significantly more than generic donepezil 10-mg tablets. Memantine XR may be a viable alternative therapy to memantine IR since it resulted in small but significant benefit without worsening ADR rates. Depending on actual drug acquisition costs, memantine XR may be useful for patients who find it difficult to adhere to twice-daily dosing. Although these medications have been shown to slow worsening of cognition, they do not modify the disease. Therapies under development are attempting to do this. It is hoped that, in the future, multiple drug classes will prove to be safe and effective in reversing the neurodegeneration seen in AD.
Dr Tiedeman is ambulatory care clinical pharmacy specialist, Veteran Affairs Maryland Health Care System. Dr Kim is geriatric clinical pharmacy specialist, Veteran Affairs Maryland Health Care System, Baltimore. Ms Flurie is a PharmD candidate 2012, University of Maryland School of Pharmacy, Baltimore. Dr Korch-Black is PGY-2 ambulatory care residency director, ambulatory care clinical pharmacy specialist, Veteran Affairs Maryland Health Care System. Dr Brandt is an associate professor of geriatric pharmacotherapy, director of clinical and educational programs at the Peter Lamy Center on Drug Therapy and Aging, Department of Pharmacy Practice and Science, University of Maryland School of Pharmacy.
Disclosure Information: The authors report no financial disclosures as related to products discussed in this article.
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