As it currently stands, Alzheimer’s disease is recognized as a progressive and chronic neurological condition that can produce significant cognitive and behavioral impairments in those who are diagnosed. It is reported that about 50 million people around the world have Alzheimer’s disease or another type of dementia (Barba 2019). According to the World Health Organization, the number of individuals who have dementia is projected to rise to about 82 million in 2030 and 152 million by 2050 (Barba 2019). There are an estimated 200,000 people in the United States who have early-onset Alzheimer’s disease (Barba 2019). Additionally, the United States burden of Alzheimer’s disease and related dementia will double by 2060 (Centers for Disease Control and Prevention 2018). While the origin of Alzheimer’s disease is not completely understood, genetic, environmental, and lifestyle factors have been identified as contributors to its development.
Diagnosis of Alzheimer’s Disease
The diagnosis of Alzheimer’s disease is based on clinical assessment, and while an individual is alive there are no laboratory tests or imaging studies that will provide a confirmatory diagnosis. The process of diagnosis can prove to be challenging given the insidious onset and symptom presentation of the condition, which can closely resemble the normal aspects of aging, such as progressive memory loss (Robinson, Tang, and Taylor 2015). However, this is where a thorough medical history, a physical examination, targeted laboratory tests, imaging studies, and neuropsychiatric studies used in combination can aid with a diagnosis. There are a number of clinical guidelines that have been developed to assist with the diagnosis of Alzheimer’s disease, including ones by the National Institute on Aging (NIA); the American Psychiatric Association; and the Consortium to Establish a Registry for Alzheimer’s Disease. In 2011, the NIA and the Alzheimer’s Association workgroup released new research and clinical diagnostic criteria for Alzheimer’s disease (Jack et al. 2011).
Clinical Presentation/Hallmark of Alzheimer’s Disease
To date there is no cure for Alzheimer’s disease, but there are available pharmacological treatments that have been designed to modify the course and symptom presentation of the condition. The prognosis for an individual diagnosed with Alzheimer’s disease is poor, with the average life span post-diagnosis ranging from about eight to 10 years. However, the advent of therapeutic interventions can assist with the management of symptoms.
For each person, the features of Alzheimer’s disease prove to be complex, but a commonality is the four progressive stages of the neurologic disorder: (1) preclinical, (2) mild, (3) moderate, and (4) severe (Dubois et al 2016; U.S. Department of Health and Human Services 2020). One of the most identifiable features that is largely synonymous with Alzheimer’s disease is cognitive impairment, which follows a clear pattern of mild to severe as the individual’s memory and thinking skills begin to deteriorate with the progression of the disease (Christiansen 2018). With Alzheimer’s disease, there are notable pathologic changes that cause impairment and impair the formation of new memories. The neurotransmitter acetylcholine plays a pivotal role in the formation of memory, and a decline in the concentration of acetylcholine, which can result from cellular loss, is targeted by a number of the therapeutic agents that are currently used to treat Alzheimer’s disease (Lane, Potkin, and Enz 2006).
Pharmacological Aspects of Alzheimer’s Disease Medication
Beginning in the 1990s, cognitive enhancers in the form of cholinesterase inhibitors have become the mainstay of drug therapy for Alzheimer’s disease. Acetylcholinesterase (Ache) inhibitors or anti-cholinesterase work by inhibiting cholinesterase enzymes from breaking down acetylcholinesterase, which ultimately increases the duration and level of the neurotransmitter action (Colovic et al. 2013). Acetylcholinesterase inhibitors are categorized into two groups that include irreversible and reversible. For the management of Alzheimer’s disease, the reversible group has more therapeutic implications, while the toxic effects are more likely associated with the irreversible group (Colovic et al. 2013). Regulatory bodies such as the US Food and Drug Administration and the European Medicines Agency have approved the use of donepezil, rivastigmine, and galantamine as reversible acetylcholinesterase inhibitors and N-methyl-d- aspirate (NMDA) receptor antagonist (memantine) to manage the symptoms of Alzheimer’s disease and work toward improved quality of life (Birks 2006; Colovic et al. 2013; Hyde et al. 2013).
In 1993, tacrine was approved as the first reversible acetylcholinesterase inhibitor for the treatment of Alzheimer’s disease, but as a result of its side effect profile, which included hepatotoxicity, it is no longer utilized. After the removal of tacrine from the market, donpezil was approved for use. It is a piperidine-type, centrally acting reversible acetylcholinesterase inhibitor that possesses little peripheral activity as it helps delay the deposit of amyloid plaque (Arce et al. 2009). Donepezil is indicated for mild to moderate Alzheimer’s dementia (Knowles 2006). It is rapidly and well absorbed from the gastrointestinal tract to reach plasma concentrations in three to four hours. The side effect profile of donepezil includes nausea, vomiting, diarrhea, vivid dreams, bradycardia, dizziness, urinary incontinence, and fatigue.
Rivastigmine is a powerful, slow-reversible carbamate inhibitor that works to block cholinesterase activity by binding at the esteratic part of the active site (Colovic et al. 2013). It has the ability to selectively inhibit both acetylcholinesterase and butyrylcholinesterase with good central nervous system penetration (Colovic et al. 2013; Kandiah et al. 2017). It is approved for both mild to moderate Alzheimer’s dementia. It possesses a rapid and complete absorption from the gastrointestinal tract and reaches plasma peak concentration within an hour. Rivastigmine’s administration with food may delay its absorption by 1.5 hours. Lastly, the side effects are comparable to donepezil and can include nausea, vomiting, and diarrhea (usually occurring during titration phase); bradycardia; syncope; weight loss; and dizziness (Seibert et al. 2012). Also, caution is to be exercised in those with peptic ulcer disease, respiratory disease, seizure disorder, and urinary tract obstruction.
Galantamine is an alkaloid that is isolated from the plant Galanthus woronowii (Colovic et al. 2013). It is a selective, rapidly reversible, competitive inhibitor of acetylcholinesterase (centrally acting acetylcholinesterase inhibitor) and acts on nicotinic receptors. It is an allosteric ligand at the nicotinic cholinergic receptors. It is approved for mild to moderate Alzheimer’s dementia to inhibit the degradation of acetylcholine (Lin et al. 2019). There is rapid and complete absorption from the gastrointestinal tract with immediate release formulation reaching serum peak concentration in about one hour without food and about 1.5 hours when taken with food. The absolute oral bioavailability is between 80% and 100%, with a half-life of seven hours. The extended release formulation achieves its median peak time in about 4.5 to 5 hours (Colovic et al. 2013). The side effect profile of galantamine includes nausea, vomiting, and diarrhea (usually occurring during titration phase); bradycardia; syncope; weight loss; and dizziness. When compared with the other acetylcholinesterase inhibitors, galantamine appears to be less tolerable, but gradual titration of dose over a few months can improve this effect (Birks 2006).
Memantine is viewed to be the first uncompetitive N-Methyl-D-asparate (NMDA) receptor antagonist approved for treatment of moderate to severe Alzheimer’s disease (Parsons, Stöffler, and Danysz 2007). It is believed to work by blocking the action of glutamate. It has a moderate affinity to the NMDA receptor and is believed to prevent excessive activation of the NMDA receptors. The side effect profile of memantine includes dizziness, confusion, constipation, insomnia, and hallucination. It may have a synergistic effect when used in combination therapy with the acetylcholinesterase inhibitors.
Alzheimer’s disease continues to be viewed as a varied and complex disease that affects millions of people around the world. Given the chronic nature of the disease, there is ongoing research to find a cure. While there is currently no cure for Alzheimer’s disease, there are therapeutic agents on the market that work to slow down the progressive nature of the disease to help individuals achieve some degree of quality of life. Researchers continue to work diligently to understand the disease progression and formulate new drug treatments that can be added to the use of acetylcholinesterase inhibitors and N-Methyl-D-asparate.
Abimbola Farinde, PharmD, PhD, is a Postdoctoral member of SOT. She currently is an adjunct faculty member in the College of Nursing and Health Care Professions at Grand Canyon University.
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