Alzheimer’s Disease: Overview and Treatment Options Jillian Blair Thomas, Pharm.D. Candidate 2013 Michael W. Frye, Pharm.D. Candidate 2013 Bernie R. Olin, Pharm.D., Associate Clinical Professor and Director Drug Information Center Auburn University, Harrison School of Pharmacy Universal Activity #: 0178-0000-12-114-H04-P | 1.5 credit hours (.15 CEUs) | Expires Dec. 12, 2015 Alabama Pharmacy Association | 334.271.4222 | www.aparx.org | [email protected] Introduction toxicity. The rate of progression of dementia may be slowed by controlling hypertension. Diabetes Alzheimer’s disease (AD) is the most may increase the risk of dementia through common cause of dementia in the United States multiple mechanisms. Glucose metabolites may affecting an estimated 5.4 million people, with have a toxic effect on the brain, specifically over 60% of those diagnosed being women. structures of the hippocampus, and vasculature. Worldwide, an estimated 24.3 million, possibly Insulin itself may increase the risk of AD due to as many as 35 million, people have been disturbances in insulin signaling pathways 1-6 diagnosed with Alzheimer’s disease. It is peripherally and in the brain.2,5 Insulin may also estimated that by the year 2050 between 13 and have a role in the regulation of metabolism of Aβ 2, 3 16 million Americans will be affected by AD. and tau protein.2 Alzheimer’s disease is more prevalent in African Dominantly inherited forms of AD 1 Americans and Hispanics than in whites. The account for only a small percentage of cases; majority of patients with AD are 65 years or however, there is a definite genetic link.1,2,5 older at the time of diagnosis, but about 5% of There is a high familial occurrence of AD linked patients diagnosed with AD are under the age of to autosomal dominant traits on chromosomes 65. Patients who are diagnosed with AD between 21, 14, and 1.1,2,6 Mutations on these age 40 and 64 are considered to have early-onset chromosomes are associated with early-onset 2 AD. The incidence of AD increases exponentially 2,4,5,6 AD. Chromosome 21 contains a gene that 1,2,5 with age. About 1 in 8 Americans age 65 and encodes for amyloid precursor protein (APP). older are affected by AD and nearly half of APP is a protein that is normally found 1-3,7 Americans over age 85. AD reduces life throughout the body. Overproduction and/or expectancy with average survival after diagnosis transcription errors can lead to the production of 1,2 being about 4 to 6 years. an abnormal subunit of APP known as beta- amyloid peptide (Aβ).1,2 Aβ peptides consist of Risk Factors and Genetics 36-43 amino acids. Aβ consisting of 42 amino The primary risk factor associated with acids is more neurotoxic that other amyloid AD is advancing age. Once a person turns 65 forms and is prone to aggregate and form 1,2,4,5 years old, his/her risk for AD doubles every five plaques. In fact, much of the neuronal years.6,7 Other risk factors include head trauma, damage associated with AD is caused by Aβ. metabolic syndrome, diabetes, hypertension, Chromosomes 1 and 14 are home to genes that and family history.1,2,4,5 There is growing code for proteins involved in APP processing. evidence that supports a link between Defects in these genes are associated with the 1,2,4 cardiovascular disease and its risk factors and majority of cases of early-onset AD. Even the incidence of AD.2,8 Risk factors of though there is a definite link between certain cardiovascular disease that are also risk factors genes and AD, the majority of cases of AD are 1,2 for AD are hypertension, high levels of low- considered to be sporadic. density lipoprotein cholesterol (LDL), low levels Sporadic forms of AD may be linked to a of high-density lipoprotein cholesterol (HDL), susceptibility gene, APOE. APOE is found on obesity, atherosclerosis, and diabetes.2,4,5 chromosome 19 and encodes for apolipoprotein 1,2,4,5 Dysfunctional blood vessels in the brain may E (ApoE). ApoE is normally involved in 1 impair nutrient delivery to neurons and may cholesterol and phospholipid metabolism. ApoE reduce beta-amyloid (Aβ) clearance (see is synthesized in the liver, cerebrospinal fluid, discussion below). Elevated levels of cholesterol and central nervous system and acts as a 2,4 in the brain may alter neuronal membrane transporter in the brain. ApoE is associated functioning and contribute to neuritic plaque with increased Aβ deposition and it may also formation. Vascular disease may accelerate the accelerate the progression of vascular dementia; deposition of Aβ in the walls of cerebral it can bind neurofibrillary tangles (NFTs) as 2,5,6,8 vasculature, which may contribute to neuronal well. ApoE may also affect the rate of Aβ 1 Alzheimer’s Disease: Overview & Treatment Options | Alabama Pharmacy Association | www.aparx.org clearance.4,5 The APOE gene occurs in three neurodegeneration associated with Aβ isoforms: *2, *3, and *4.1,2,5 APOE*4 is deposition.1,2,5 Neuritic plaques also contain associated with an increased risk of late-onset ApoE. Neuritic plaques may be found in patients AD.1,2,4-6,8-10 A person may have zero, one, or two without dementia, but plaques found in these APOE alleles; the more APOE*4 alleles present, patients do not contain abnormal proteins.1 The the greater the risk of developing AD.1,2,4-6,8,9 amount of amyloid deposition in neuritic plaques is related to the severity of neuronal damage; Pathophysiology however, Aβ does not correlate with disease severity as strongly as does NFT density.1,8,9 The most obvious findings in a brain Neurotransmitters and enzymes are also affected by AD are atrophy and synapse loss; affected by AD. Acetylcholine (ACh) is one of the however, these features alone are not diagnostic main neurotransmitters affected by AD.1,2 because a certain amount of atrophy and Choline acetyltransferase levels are reduced by synapse loss may occur with normal aging. up to 90% in the cortical and hippocampal Atrophy due to AD is mainly found in the regions.1 The extent of reduction in choline temporal, parietal, and frontal lobes of the brain acetyltransferase concentration is related to and synapse loss is most pronounced in the plaque density and disease severity.1,2,5 ACh and hippocampus.1,2,5 The main changes seen in the acetylcholinesterase concentrations are reduced cerebral cortex of patients with AD are NFTs and in patients with AD. Muscarinic receptors in the neuritic plaques.1,2,4,8 cortex and hippocampus usually remain at NFTs are most likely to form in large normal or near-normal levels until late-disease. pyramidal neurons and, as such, are found AD leads to a reduction in the number of primarily in the pyramidal regions of the nicotinic receptors in the brain. Cholinergic neocortex, hippocampus, and amygdala.1,5 NFTs activity is most significantly altered by AD, but may also be found in the brainstem and locus norepinephrine, serotonin, glutamate, and ceruleus. Typically, NFT formation begins in the gamma-aminobutyric acid activity are also hippocampus and spreads to the neocortex.1,2,6,8 affected.1,2,5 NFTs are composed of paired helical filaments It has been proposed that oxidative containing abnormally phosphorylated tau stress, mitochondrial dysfunction, and protein.1,2,4,6,8 Tau protein normally provides postmenopausal loss of estrogen may have a structural support for microtubules in the cell, role in the pathogenesis of AD. Oxidative stress but cannot bind properly due to abnormal and free-radical build-up may contribute to the phosphorylation.2,3,5 The inability of tau protein development and progression of AD.1,2,5 to function normally results in cell death due to Mitochondrial dysfunction disrupts neuronal an abnormally functioning microtubule system.2,5 energy metabolism and contributes to free Severity of dementia is associated with the radical accumulation, oxidative stress, and density of NFTs which are a sign of neuronal ultimately apoptosis.2,5 Estrogen is involved in death.2,5,8,9 neuronal growth and maintenance of normal Neuritic plaques are spherical bodies of cholinergic activity; it may also have antioxidant tissue composed of granular deposits and the properties. Loss of estrogen due to menopause remnants of neuronal processes. Neuritic results in loss of the normal activities of estrogen plaques have a three-tiered structure consisting in the brain.2 All three of these mechanisms may of a central amyloid core, a middle region of contribute to the pathogenesis of AD. swollen axons and dendrites, and an outer zone 1,6,8 of degenerating neuritic processes. The Diagnosis and Staging amyloid core contains APP which can be cleaved to form neurotoxic Aβ.1,2 Neuritic plaques Currently, a definitive diagnosis can only contain acute-phase inflammatory mediators be made post-mortem, but advances in due to local inflammation and diagnostic technology have made clinical 2 Alzheimer’s Disease: Overview & Treatment Options | Alabama Pharmacy Association | www.aparx.org diagnosis of AD up to 90% accurate when Table 1: Factors that may cause symptoms of compared to post-mortem diagnosis.1,4 When cognitive impairment making a clinical diagnosis, it is important to rule Diseases that may Medications that may out other, potentially reversible, causes of affect cognitive affect cognitive function impaired cognition. There are numerous function medications and diseases that can negatively • Adjustment • Anticholinergic affect cognition (see Table 1).1,2,4,8,9 A thorough disorder agents patient history is important because it • Amnestic • Anticonvulsants syndrome • Antidepressants documents symptoms and progression and it • Delirium • Antihistamines may indicate or help rule out potential causes of • Depression • Antineoplastic agents 2,4,9 cognitive impairment.