Alzheimer's Disease
Overview and Pharmacologic Treatment

Release Date: January 1, 2015

Expiration Date: January 31, 2017


Jennifer Confer, PharmD, BCPS
Critical Care Clinical Specialist Cabell Huntington Hospital Clinical Assistant Professor
West Virginia University School of Pharmacy
Huntington, West Virginia

Kimberly M. Tzintzun, BS in Nutritional Sciences University of Arizona
College of Agriculture and Life Sciences
Tucson, Arizona


Dr. Confer and Ms. Tzintzun have no actual or potential conflicts of interest in relation to this activity.

Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.


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Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.


To familiarize pharmacists with the pathophysiology of and treatment options for Alzheimer’s disease (AD).


After completing this activity, the participant should be able to:

  1. Discuss the pathophysiology and natural progression of AD.
  2. Identify risk factors that may positively or negatively impact the progression of AD.
  3. Summarize current treatment options available for AD.
  4. Examine future therapeutic options in development for AD.

ABSTRACT: Affecting over 5 million Americans, Alzheimer’s disease (AD) is an incurable, neurodegenerative disease. AD occurs in two forms: early-onset, which is genetically determined, and late-onset, influenced by cardiovascular, lifestyle, and genetic risk factors. In either case, AD results in cognitive dysfunction and memory impairment that affects a person’s ability to perform everyday functions. Key pathologic changes have been identified in brain tissue that demonstrate increased levels of both the extracellular beta-amyloid peptide and the intracellular hyperphosphorylated microtubule-binding tau protein. Current treatment options for AD are limited and include cholinesterase inhibitors and memantine. These agents are utilized to improve symptoms, decrease memory impairment, and enhance cognition. Several ongoing clinical trials are being conducted with a specific focus on the beta-amyloid and tau hypotheses.

Dementia is a general term for diseases and conditions characterized by a decline in function, cognition, behavior, and other thinking skills that affects a person’s ability to perform everyday activities. This decline is primarily caused by damage to nerve cells in the brain. First described by German psychiatrist and neuropathologist Alois Alzheimer in 1906, Alzheimer’s disease (AD) is the most common form of dementia, with an estimated prevalence of 5.2 million Americans of all ages affected in 2014.1 This includes an estimated 5 million people aged ≥65 years. It is estimated that approximately 500,000 people in this age group will develop AD this year alone, with that number expected to double or triple by the year 2050.1

The cost of providing care for patients with AD, including routine healthcare, long-term care, and hospice, are estimated at $214 billion, with Medicare expected to cover approximately 70% and out-of-pocket expenses accounting for 17% of total payments.1 As of 2010, AD was officially listed as the sixth leading cause of death in the United States.2 Specifically for those ≥65 years of age, AD is the fifth leading cause of death. Due to underdiagnosis, AD may cause more deaths than official sources recognize.2 In addition, for a death to be attributed to AD, it must be given as the official cause of death on the death certificate. Often, acute conditions such as pneumonia or heart disease are listed as the primary cause of death rather than AD, so that these individuals are not being counted among the number who died of AD.

At this time, there are no therapeutic treatments available to stop or reverse the progression of AD. Treatment of the disease includes five major components: nonpharmacologic interventions, cholinesterase inhibitors, memantine, neuroprotective approaches, and psychopharmacological medications to improve cognition, increase functional ability, and decrease further progression of memory decline. This review aims to examine the efficacy and safety of currently available medications and emerging treatment options for AD.


The cause for AD in people remains mostly unknown (aside from 2% to 5% of cases in which a genetic mutation has been identified).1 Several hypotheses have been proposed and studied to further explain the cause of AD. Two characteristic pathologies essential for a definitive diagnosis of AD are the extracellular neuritic plaque deposits of the beta-amyloid (Ab) peptide and the flame-shaped neurofibrillary tangles of the microtubule-binding tau protein.3 For a confirmed, definitive diagnosis, these pathologies are only obtainable through an autopsy and brain tissue evaluation. Ab peptides are derived by sequential proteolytic processing from a large type I transmembrane protein, the amyloid precursor protein (APP).4 APP, located within the cell membrane of a neuron, is important in cellular signaling. As commonly identified, APP is cleaved in two places: first by beta-secretase, a membrane-bound aspartyl protease, and then by gamma-secretase, an enzyme complex composed of four subunits.3,4

Normal physiologic function of the resulting derived Ab peptide is not fully understood, but several potential benefits include prevention of oxidative stress, as well as the ability to function as a transcription factor and control cholesterol transport.5-7 Mutations within the Ab peptide domain accelerate disease progression through diverse mechanisms, resulting in an increase of total Ab peptide production, increased production of longer Ab peptide species, and changes within the structure of the peptide. The accumulation of Ab peptides begins to form amyloid fibrils and nonfibrillar aggregates designated Ab oligomers.8 It is unclear whether intracellular or extracellular aggregation of these plaques is responsible for cognitive decline, but Ab oligomers or fibrils have been demonstrated to have an inhibitory effect on synaptic transmission and can reduce the number of synapses in the brain.9 This accumulation of peptides may be an initiating factor in AD and is termed the amyloid hypothesis.10

The formation of intraneuronal neurofibrillary tangles is associated with the tubulin-binding protein, tau.11 The tau protein is found within the axons of the central nervous system and promotes stability of microtubules and other cells. The tau protein consists largely of six different isoforms that are generated by alternative splicing of its mRNA. The protein is characteristically hydrophilic, contains minimal secondary structures, and has activity that is highly regulated by phosphorylation. These characteristics lead to a disorganized structure that is highly responsive to changes in phosphorylation, resulting in hyperphosphorylation of the tau protein.

Tau interaction with tubulin dimers promotes the formation of microtubules. These protein polymers function as tracks for intracellular transport and help stabilize cell shape.9-11 In the normal adult brain, there are approximately two phosphate molecules per tau molecule, whereas in a person with AD the ratio within the brain is approximately eight phosphate molecules for every tau molecule. Hyperphosphorylation of the tau protein significantly decreases its affinity for microtubules. The hyper-phosphorylated tau protein disassociates from the tubulin dimers and disrupts the normal function of microtubules. The accumulation of hyperphosphorylated tau becomes insoluble, forming neurofibrillary tangles within the neuron, ultimately causing the death of the cell.11,12

Parallel to (or as a consequence of) these neuro-pathological modifications, various neurotransmitter systems are altered in the brain tissue of individuals with AD.13 Among the numerous neurochemical abnormalities described for the brains of AD patients, the decrease in the activity of the acetylcholine (ACh)-synthesizing enzyme, choline O-acetyltransferase, is the most prominent and provides an excellent biochemical correlate of the severity of dementia in this disorder.14 Although aging itself causes a loss of synaptic function, as people with AD demonstrate advancing disease the extent of synaptic failure best correlates with the severity of cognitive decline.


Early Onset

While quite rare, 1% to 6% of all AD cases are early onset, with cognitive dysfunction displayed before age 65 years, usually between ages 30 and 60 years.15 Early-onset AD is the most frequent form of dementia under the age of 65.14 About 60% of early-onset AD is familial, with 13% appearing to be inherited in an autosomal dominant manner affecting first-degree relatives.15 The causes of familial AD are linked to mutations on chromosomes 21, 14, and 1. Mutations on chromo some 21 cause the formation of abnormal APP. Mutations on chromosomes 14 and 1 lead to abnormal production of presenilin 1 and 2 (PSEN1 and PSEN2), respectively. PSEN1 and PSEN2 are genes that provide instructions for the production of APP. The PSEN1 protein makes up one subunit of the gamma-secretase complex. PSEN2 protein works together with PSEN1 in the proteolytic cleavage of many proteins, including APP.15-18

Essentially all individuals with Down syndrome will develop AD by age 40 years.18 Down syndrome is a chromosomal condition most often caused by trisomy 21, meaning that each cell in the body has three copies of chromosome 21 instead of the usual two copies.18 The association between Down syndrome and AD is thought to be the overexpression of the APP gene on chromosome 21, which encodes the amyloid precursor protein. The resultant overproduction of Ab in the brain, resulting in the Ab plaques associated with AD, may begin in the first decade of life in persons with Down syndrome.15

Late Onset

The late-onset form of AD is far more common than early-onset, accounting for an estimated 95% of all AD cases.15 Approximately 10% of persons aged >70 years have significant memory loss, and more than half of these individuals have AD.15 The etiology of late-onset AD is not fully understood, but it is likely that environmental, genetic, and lifestyle factors contribute to the development of the disease.1 The etiology of late-onset AD is not fully understood, but it is likely that environmental, genetic, and lifestyle factors contribute to the development of the disease.

Although late-onset AD is not genetically determined as is the early-onset type, evidence implies that possession of various alleles on the apolipoprotein (APOE ) gene on chromosome 19 is a risk factor for the development of late-onset AD.19 Normal function of the APOE gene provides instruction for the production of APOE protein, which is responsible for the proper distribution of cholesterol and other lipids in the bloodstream. There are five different alleles of the APOE gene: E1 to E5. Two of them, E1 and E5, are extremely rare, while the rest, E2 to E4, are more common. Possession of the E4 allele has specifically been identified as a risk factor for the development of late-onset AD. The E4 allele is present in approximately 20% to 30% of the population, yet not all those who possess this allele will develop AD.1,19 A single E4 allele can increase the risk of AD by a factor of four, and two E4 alleles can increase the risk by a factor of 19.10 The E2 variant allele might possibly provide protective properties against the disease, while the E3 variant remains neutral, displaying neither positive nor negative effects specific to AD.

In addition to the genetic risk factors of the APOE gene, evidence has demonstrated that AD is multi-factorial and results from a combination of cardiovascular risk factors including aging, hypertension, and hyperlipidemia, and lifestyle risks such as physical inactivity, dietary patterns, and exposure to one or more environmental agents, such as viruses and/or toxins.15 TABLE 1 further depicts the genetic involvement in early-onset AD and the implications of gene mutations.14-19


The clinical manifestation of AD is dementia that typically begins with a subtle and poorly recognized failure of memory that slowly becomes more severe and, eventually, incapacitating. The progression of AD can be classified into a series of stages: predementia, mild, moderate, and severe.20 The predementia stage is often underrecognized, as it commonly mimics normal aging or other stress-related issues. Typically, in this stage intermittent memory loss may occur, but overall, a person remains rather independent. During mild stages of AD, increases in memory loss become more apparent, communication may decline as common words and phrases are difficult to recall, but independence remains. Progressing into the moderate stage of AD, individuals begin to exhibit such characteristics as cognitive decline, agitation, withdrawal, and depression.

Last, in the severe stage of AD, memory loss is common, deterioration in communication is exhibited, and there is a loss of both simple functional tasks (e.g., feeding oneself, bathing) and high-level daily activities (e.g., check writing); individuals are generally no longer independent at this stage.20 Other common findings throughout AD stage progression include confusion, poor judgment, language disturbance, and hallucinations. Additionally, seizures, parkinsonian features, increased muscle tone, myoclonus, incontinence, and mutism may occur.21

The key classification for the diagnosis of AD has been the uniform set of criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS–ADRDA).22 The criteria were developed with the intent of accurately associating the clinical symptoms of AD with the neuropathological manifestations after death. The levels of certainty when establishing the severity of AD were labeled as definite for autopsy-confirmed disease, probable for the typical clinical syndrome without intervening issues, and possible for diagnoses complicated by other disorders that might contribute to the dementia. These specific criteria are currently under evaluation, as the mechanisms involved with the progression of AD are much broader than initially observed and are now acknowledged to include pathological changes other than Ab plaques and neurofibrillary tangles.22

TABLE 2 provides a summary of the factors that are known to increase or decrease the risk of developing AD.22-26


While there are no pharmacologic treatments available for AD that will slow or stop the progression of the disease, several medications have been approved by the FDA that aim to improve symptoms associated with AD, decrease memory impairment, and enhance cognition through cholinergic and glutamatergic neurotransmission.27 Clinical trials are currently being conducted with focus on inhibition of the enzymes responsible for proteolysis of APP, as well as on treatments based on tau pathology.

In addition to the approved and upcoming agents, there are several medications frequently prescribed for other labeled indications, which are suggested to have demonstrated efficacy in providing neuroprotective effects in patients with AD. Epidemiologic studies have suggested that adjunctive therapy with conventional medications, such as HMG-CoA reductase inhibitors (statins), nicotine replacement, nonsteroidal anti-inflammatory drugs (NSAIDs), estrogen, and omega-3 fatty acids, may reduce cognitive decline and decrease risk factors associated with AD development.28 There is currently insufficient evidence to confirm regular use of these medications in the treatment of AD, and it is recommended that further trials be conducted to provide optimal doses specific for this indication. TABLE 3 lists the FDA-approved pharmacologic treatment options for managing AD.29-34

Cholinesterase Inhibitors

With a decrease in the ACh-synthesizing enzyme, choline O-acetyltransferase, there is a decrease in cholinergic transmission and an increase in the hydrolysis of ACh by acetylcholinesterase, leading to an increase in cognitive impairment and Ab plaque production. Cholinesterase inhibitors elevate levels of ACh in the synaptic cleft by inhibiting the hydrolyzing activity of acetylcholinesterase, thereby improving central cholinergic transmission. Other mechanisms have been examined emphasizing the benefits of cholinesterase inhibitors for AD, including the ability to influence the expression of various forms of ACh, increase expression of nicotinic ACh receptors, and mediate the APP processing and lessen Ab-induced toxicity.29

Indicated for the treatment of mild-to-severe AD, cholinesterase inhibitors should be considered standard of care for patients with AD. Currently, four cholinesterase inhibitors have been FDA-approved: tacrine, donepezil, rivastigmine, and galantamine. Approved in 1993, tacrine, a first-generation cholinesterase inhibitor, is no longer utilized as it demonstrated significant hepato toxicity and controversial efficacy.29,30 Cholinesterase inhibitors may demonstrate vagotonic effects, which may cause bradycardia and/or heart block with or without an underlying cardiac disease history. Because of this concern, centrally active cholinesterase inhibitors are contraindicated in patients with bradycardia (<50 bpm) or syncope.29

Donepezil: Approved in 1996, donepezil is a second-generation cholinesterase inhibitor that reversibly binds in a noncompetitive manner to acetylcholinesterase and, as a result, is hydrolyzed instead of ACh.29 Donepezil is highly selective for central acetylcholinesterase with limited peripheral activity. Due to this limited peripheral activity and a long plasma half-life, donepezil can be administered once daily. Approved for all stages of AD, donepezil is available in a conventional immediate-release tablet and a sustained-release formulation, both of which can be taken without regard to meals.29

Rivastigmine: Approved in 2000, rivastigmine is indicated for mild-to-moderate (oral capsule) and severe AD (transdermal patch). The inhibitory effect on acetylcholine, termed pseudo-irreversible, is due to the carbamyl moiety, as it remains bound to its substrate after the acetyl moiety dissociates following hydrolysis, resulting in acetylcholinesterase inactivation for greater than 24 hours.29 Although it demonstrates some selectivity for acetylcholinesterase, rivastigmine is also known to inhibit butyrylcholinesterase; this is considered to play a minor role in regulation of brain acetylcholine and butyrylcholine levels. Available as an oral capsule, oral solution (taken twice daily with food), and a transdermal patch (applied once daily), rivastigmine is not significantly metabolized by CYP450 enzymes and is not plasma protein–bound, therefore exhibiting few drug-drug interactions.29

Galantamine: Approved in 2001 for mild-to-moderate AD, galantamine is a reversible and competitive cholinesterase inhibitor that demonstrates modulation and stimulation of the nicotinic acetylcholine receptors, improving nicotinic transmission and increasing release of more ACh, another pathway associated with neurodegenerative disorders. Taken without regard to meals, galantamine is available as an immediate-release tablet taken twice daily, an oral solution, and an extended-release capsule taken once daily.29

Safety and Efficacy: To avoid adverse effects associated with cholinesterase inhibitors (see TABLE 3), a slow escalation of the dose should be done when initiating the medication. If there is a lack of response to treatment or a loss of response to long-term treatment, consideration should be given to switching to another cholinesterase inhibitor. If a switch is needed due to safety or tolerability to one agent, a washout period of 7 days is recommended before initiation of the new agent. For patients who do not have problems with tolerability but may have a lack of response to treatment, no washout period is required.29 Prior to initiation of a cholinesterase inhibitor, current medication regimens should be thoroughly reviewed by physicians and any unnecessary anticholinergic or interacting medication be discontinued to decrease the risk of adverse effects.

To date, an abundance of studies have been conducted that examined the clinical efficacy and safety of the cholinesterase inhibitors for AD, as well as numerous review articles published that correlate the data identified in the conducted studies. This discussion will be limited to the review of two meta-analyses of the cholinesterase inhibitors for AD. In 2006, the Cochran collaboration assessed the evaluation of the efficacy and safety of the three cholinesterase inhibitors described above (donepezil, rivastigmine, galantamine).35 At this time, 13 trials met the inclusion criteria for review. All trials were multicenter, randomized, double-blind, parallel group trials with a total of 7,298 patients randomized. Ten of the 13 trials described the stage of AD to be mild-to-moderate. The results of the trials establish a favorable effect of the cholinesterase inhibitors compared to placebo on cognitive function with treatment for 6 months or more (P <.00001). In addition, overall similar benefits were observed with all three medications regarding their impact on measures of activities of daily living and behavior.35

Regarding safety, the analysis of the trials reported that more patients receiving treatment with a cholinesterase inhibitor (29%) versus placebo (18%) discontinued treatment, primarily because of common adverse effects seen with these drugs, including nausea, vomiting, and diarrhea. The analysis concluded that in spite of slight differences between the mechanisms of action of the three cholinesterase inhibitors, there is no evidence to suggest any differences between their efficacies on AD.35

A second analysis, conducted in 2008 by Hansen et al, reviewed the efficacy and safety of donepezil, rivastigmine, and galantamine through an analysis of 26 studies.36 Results of the analysis demonstrated that the data from these studies support the use of cholinesterase inhibitors in AD by providing benefits in stabilizing or slowing the deterioration of cognition, function, and behavior. While these results were reported to not be statistically significant with regard to cognition, the authors found that the relative risk of global response was better with donepezil and rivastigmine compared to galantamine (P < .005 and P < .05, respectively) but did not differ between donepezil and rivastigmine (P = .4). Comparisons were also noted to favor donepezil over galantamine with regard to behavior (P = .003). As seen with the Cochran collaboration, the incidence of adverse effects was higher in those individuals taking a cholinesterase inhibitor compared to placebo, with 76% of participants reporting at least one adverse effect, of which the most frequently reported were nausea, vomiting, diarrhea, dizziness, and weight loss.36

Many of these studies compared one agent to placebo, and there are few trials that directly compare one agent to another. Thus, there is no noticeable evidence to suggest one cholinesterase inhibitor over another.29,36

N-Methyl-d-Aspartate (NMDA) Receptor Antagonist

Memantine, an NMDA receptor antagonist, first approved in Europe in 2002 and in the U.S. in 2003, is indicated for the treatment of moderate-to-severe AD.29 Glutamate is the primary excitatory neurotransmitter within the brain and can stimulate several postsynaptic receptors, including the NMDA receptor, which has been associated with memory impairment and dementia in people with AD. Overactivity of the NMDA receptor, secondary to excessive glutamate release, leads to an increased entry of calcium ions into the cell. Calcium ion entry is normally blocked by magnesium ions. This glutamate release and calcium influx may overstimulate the glutamate receptors, thus leading to excitotoxicity and neuronal cell death and further worsening the memory impairment in people with AD. Memantine has moderate affinity for and is a noncompetitive antagonist of the NMDA type of glutamate receptor. Through the antagonism of the receptor, magnesium ions are able to enter the NMDA receptor ion channel, leading to a decrease in calcium influx and a decrease in receptor stimulation. Memantine is available as an immediate-release tablet, an extended-release capsule, and an oral solution (TABLE 3).29

Reisberg and colleagues conducted a 28-week, double-blind, parallel-group study to assess efficacy in which patients with moderate-to-severe AD were randomly assigned to receive either memantine 20 mg daily or placebo.37 Primary outcomes examined differences in variables in the Clinician’s Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus) and the Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory modified for severe dementia (ADCS-ADLsev), obtained at baseline and at the study endpoint. A total of 252 participants were enrolled in the study. Of these, 181 patients completed the study and were evaluated at week 28. Patients who received memantine demonstrated a better outcome than those of the patients who received placebo based on results of the CIBIC-Plus (P = .03) and the ADCS-ADLsev (P = .02).37

Although a majority of patients experienced a mild-to-moderate adverse event (84% with memantine and 87% with placebo), these events were determined to be either unrelated or unlikely to be related to the study medication. Other listed adverse events leading to discontinuation of memantine included agitation, urinary incontinence, urinary tract infection, insomnia, and diarrhea. Overall, the authors concluded that memantine is associated with a reduction in clinical deterioration in patients with moderate-to-severe AD.37

On December 23, 2014, the FDA approved Namzaric, a fixed-dose combination of extended-release memantine and donepezil. It is indicated for the treatment of moderate-to-severe AD in patients already taking the two drugs, which are often prescribed together.38


In addition to the neurotransmitter targets of the cholinesterase inhibitors and memantine, several ongoing phase II and III trials are being conducted with a specific focus on the beta-amyloid and tau hypotheses.39 Specifically targeting the inhibition of alpha-, beta-, and gamma-secretase enzymes, secondary prevention of AD can be made through the decrease in Ab production, as these enzymes are known to cleave APP, which leads to increases in Ab. In addition, to decrease the neurotoxicity due to Ab aggregates, inhibition to suppress this aggregation and formulation of enzymes to degrade Ab peptides may support an increase in memory and a decrease in amyloid plaque deposits. Parallel to trials being conducted for targets of the amyloid hypothesis, a number of studies for treatment based on tau pathology, including prevention of tau phosphorylation, tau aggregation, and tau misfolding, are emerging.28,29 Many of these trials have been conducted in cell models and/ or mice, and although several demonstrate promising results, additional research is required to demonstrate efficacy and safety in human patients.


Many aspects of AD are not fully understood. With further investigation of the physiological and pathologic mechanisms involved with early- and late-onset AD, it may be possible to expand pharmacologic therapies to include treatment that may stop progression or reverse the complications of this disease. Evaluation of the criteria for risk factors associated with AD may uncover new mechanisms of action, other than the two well-known hallmarks—Ab plaque deposits and tau protein tangles. Current therapies for patients with AD can alleviate symptoms, reduce cognitive decline, and provide temporary improvement, and should be considered first-line agents.


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