Alzheimer's Disease

1. Alzheimer's Disease Jawza F. Al-Sabhan PHCL 430

2. Lecture Objectives • On completion of the lecture, the student will be able to: • Distinguish early-onset and late-onset Alzheimer's disease • Discuss genetic and environmental causes that can play a role in the etiology of Alzheimer's disease • Identify the neurotransmitter systems affected by Alzheimer's disease • Describe the signs and symptoms of various stages of Alzheimer's disease • Explain the primary treatment goals of both pharmacologic and nonpharmacologic therapies for Alzheimer's disease

3. I now begin the journey that will lead me into the sunset of my life.Ronald Reagan

4. Introduction • Alzheimer's disease (AD), first characterized by Alois Alzheimer in 1907, is a gradually progressive dementia affecting: • Cognition • Behavior • Functional status.

5. Epidemiology • The incidence increases to 80% if AD in conjunction with other pathologic lesions is considered • Approximately 4.5 million Americans have AD • The prevalence of AD increases exponentially with age, affecting approximately 7% of individuals ages 65 to 74 years, 53% of those ages 75 to 84, and 40% of persons ages 85 years and older.

6. Epidemiology

7. Cognitive • Memory loss (poor recall and losing items) • Aphasia (circumlocution and anomia) • Apraxia • Agnosia • Disorientation (impaired perception of time and unable to recognize familiar people) • Impaired executive function

8. Noncognitive • Depression, psychotic symptoms (hallucinations and delusions) • Behavioral disturbances (physical and verbal aggression, motor hyperactivity, uncooperativeness, wandering, repetitive mannerisms and activities, and combativeness)

9. Functional • Inability to care for self such as: • dressing • bathing • toileting • eating

10. Stages of Alzheimer's Disease

12. Risk Factor • Family history 25%-50% • Increasing age • Down Syndrome • Head trauma

13. Pathophysiology

14. Characteristics of Alzheimer's Disease • Degeneration of cholinergic neurons • The most prominent neurotransmitter • Reduce activity of choline acetyltransferes • Reduce No. of cholinergic neurons • Cortical atrophy • Presence of neurofibrillary tangles • Accumulation of neuritic plaques

15. AD and the Brain • Plaques and Tangles: The Hallmarks of AD • The brains of people with AD have an abundance of two abnormal structures: • beta-amyloid plaques, which are dense deposits of protein and cellular material that accumulate outside and around nerve cells • neurofibrillary tangles, which are twisted fibers that build up inside the nerve cell An actual AD plaque An actual AD tangle

16. AD and the Brain • Beta-amyloid Plaques • Amyloid precursor protein (APP) is the precursor to amyloid plaque. • 1.APP sticks through the neuron membrane. • 2.Enzymes cut the APP into fragments of protein, including beta-amyloid. • 3.Beta-amyloid fragments come together in clumps to form plaques. 1. 2. In AD, many of these clumps form, disrupting the work of neurons. This affects the hippocampus and other areas of the cerebral cortex. 3.

17. AD and the Brain • Neurofibrillary Tangles Neurons have an internal support structure partly made up of microtubules. A protein called tau helps stabilize microtubules. In AD, tau changes, causing microtubules to collapse, and tau proteins clump together to form neurofibrillary tangles.

18. AD and the Brain The Changing Brain in Alzheimer’s Disease No one knows what causes AD to begin, but we do know a lot about what happens in the brain once AD takes hold. Pet Scan of Normal Brain Pet Scan of Alzheimer’s Disease Brain

19. AD and the Brain Preclinical AD • Signs of AD are first noticed in the entorhinal cortex, then proceed to the hippocampus. • Affected regions begin to shrink as nerve cells die. • Changes can begin 10-20 years before symptoms appear. • Memory loss is the first sign of AD.

20. AD and the Brain • AD spreads through the brain. The cerebral cortex begins to shrink as more and more neurons stop working and die. • Mild AD signs can include memory loss, confusion, trouble handling money, poor judgment, mood changes, and increased anxiety. • Moderate AD signs can include increased memory loss and confusion, problems recognizing people, difficulty with language and thoughts, restlessness, agitation, wandering, and repetitive statements. Mild to Moderate AD

21. AD and the Brain Severe AD • In severe AD, extreme shrinkage occurs in the brain. Patients are completely dependent on others for care. • Symptoms can include weight loss, seizures, skin infections, groaning, moaning, or grunting, increased sleeping, loss of bladder and bowel control. • Death usually occurs from aspiration pneumonia or other infections. Caregivers can turn to a hospice for help and palliative care.

22. Diagnosis • Rating scale used to assess AD • MMSE • ADAS • SIB • NPI • GDS • CGL

23. Treatment: Alzheimer's Disease • Desired Outcomes • Nonpharmacologic Therapy • Pharmacologic Therapy • Pharmacotherapy for Cognitive Symptoms • Cholinesterase Inhibitors • Antiglutamatergic Therapy • Other Potential Treatment Approaches

24. Desired Outcomes • The primary goal of treatment in AD is to symptomatically treat cognitive difficulties and preserve patient function as long as possible. • Secondary goals include treating the psychiatric and behavioral sequelae that occur as a result of the disease. • Current AD treatments have not been shown to prolong life, cure AD, or halt or reverse the pathophysiologic processes of the disorder.

25. Nonpharmacologic Therapy Education, communication, and planning are the key nonpharmacologic components of caring for an AD patient.

26. Basic Principles of Care for the Alzheimer's Patient

27. Pharmacologic Therapy • Pharmacotherapy for Cognitive Symptoms • Pharmacotherapy of Noncognitive Symptoms

28. Treatment Options for Cognitive Symptoms in Alzheimer's Disease

29. Cholinesterase Inhibitors • In the early 1980s, researchers began to examine means to enhance cholinergic activity in patients with AD by inhibiting the hydrolysis of acetylcholine through reversible inhibition of cholinesterase. • Tacrine was the first such drug to be examined in a systematic fashion. However, tacrine is fraught with significant side effects, including hepatotoxicity, that severely limit its usefulness. • For all practical purposes the use of tacrine has been replaced by the use of safer, more tolerable cholinesterase

30. Cholinesterase Inhibitors • Newer cholinesterase inhibitors • Donepezil • Rivastigmine • Galantamine • show similar efficacy and adverse event profiles to one another and are generally well tolerated. • The most frequent adverse events associated with these agents are mild to moderate gastrointestinal symptoms (nausea, vomiting, and diarrhea). • Other cholinergic side effects are generally dose-related and include urinary incontinence, dizziness, headache, syncope, bradycardia, muscle weakness, salivation, and sweating • Gradual dose titration over several months can improve tolerability. • Abrupt discontinuation can lead to worsening cognition and behavior in some patients.

31. The mechanism of action

32. Pharmacokinetics of Cholinesterase Inhibitors

33. Dosing of Cholinesterase Inhibitors

34. Antiglutamatergic Therapy • Memantine is the only NMDA-antagonist currently available. • Memantine blocks glutamatergic neurotransmission by antagonizing NMDA receptors. • Glutamate is an excitatory neurotransmitter in the brain implicated in long-term potentiation, a neuronal mechanism important for learning and memory. By blocking NMDA receptors, excitotoxic reactions, which ultimately lead to cell death, may be prevented.

35. Antiglutamatergic Therapy • Memantine has been studied in patients with moderate and severe AD as monotherapy and in combination with donepezil with modest favorable results on cognition and function.It is currently indicated for use in AD patients with moderate to severe illness.

36. Antiglutamatergic Therapy • Memantine has 100% bioavailability regardless of administration with or without food. Protein binding is low. Memantine is not metabolized by the liver and does not inhibit cytochrome P450. Memantine is primarily excreted unchanged in the urine. The half-life ranges from 60 to 80 hours.

37. Antiglutamatergic Therapy • The most common adverse events associated with memantine include constipation, confusion, dizziness, headache, hallucinations, coughing, and hypertension

38. Antiglutamatergic Therapy • Memantine is likely to be used as monotherapy and also in combination with cholinesterase inhibitors in patients with moderate to severe AD. • Memantine should be initiated at 5 mg once a day and increased weekly by 5 mg a day to the effective dose of 10 mg twice daily. • It may be given with or without food. • Dosing of 10 mg daily is recommended in patients with severe renal impairment

39. Role of Combination Therapy • The efficacy of all available AD treatments is limited. Currently, the best possible short-term outcome includes a symptomatic improvement over the pretreatment baseline. Because agents with different mechanisms of action are now available for the treatment of AD, the efficacy of combination therapy has been considered. In the only combination treatment trial published to date, patients receiving donepezil were randomized to receive 20 mg/day of memantine or placebo. During the 6-month course of the trial, those randomized to receive combination therapy performed better on a cognitive scale and an activities of daily living scale than those randomized to donepezil plus placebo.A subsequent report concluded that with donepezil-memantine combination therapy, behavioral benefits were also demonstrable on the Neuropsychiatric Inventory.It is important to note that these studies included subjects with MMSE scores of 5 to 14. Data showing donepezil-memantine combination therapy benefits in AD patients with MMSE scores above 14 are lacking.

40. Management of Brain Vascular Health • Management of brain vascular disease includes monitoring blood pressure, glucose, cholesterol, and homocysteine and initiation of appropriate interventions. • Guidelines recommend initiation of low-dose aspirin therapy in patients with AD with significant brain vascular disease. • Elevated homocysteine levels correlate with decreased performance on cognitive tests, but there remains insufficient evidence of a benefit of B vitamin supplementation (B6, B12, and folic acid) on cognitive function in patients with AD.

41. Other Potential Treatment Approaches Estrogen Antiinflammatory Agents Rofecoxib has been compared to naproxen and placebo with no demonstrated cognitive benefit after 1 year Until clinical trials establish benefit of the cyclooxygenase-2 inhibitors, their general use as preventive treatment for AD cannot be recommended. Market withdrawal of rofecoxib and other safety concerns within this class may limit further study in AD. • Estrogen replacement has been studied extensively for the treatment and prevention for AD. Most, but not all, epidemiologic studies show a lower incidence of AD in women who took estrogen replacement therapy postmenopausally. Results from these epidemiologic surveys prompted researchers to look at the use of estrogen preventively and as a treatment for cognitive decline.

42. Lipid-Lowering Agents • Interest in the potential protective effects in AD patients of lipid-lowering agents, particularly the 3-hydroxy-3-methylglutaryl-coenzyme A-reductase inhibitors, is growing. • Longitudinal epidemiologic studies suggest an association between elevated midlife total cholesterol levels and AD. • Other studies note that the incidence of AD is lower in patients who have taken either a statin or another lipid-lowering agent, but not in patients who were taking other cardiovascular medications. Interestingly, pravastatin and lovastatin, but not simvastatin, were associated with a lower prevalence of AD, suggesting that individual agents rather than a class effect impact AD prevalence. • Although these studies have linked cholesterol levels to increased risk of AD, others have yielded conflicting results

43. Dietary Supplements Vitamin E Ginkgo Biloba Ginkgo is one of the most popular dietary supplements used in AD. Hypothesized mechanisms of action in AD include increasing blood flow, decreasing the viscosity of blood, antagonizing platelet activating factor receptors, increasing tolerance to anoxia, inhibiting monoamine oxidase, antiinfective properties, and preventing the damage of membranes caused by free radicals Therapeutic response may be noted in 2 to 3 weeks, but 12 weeks of consistent dosing may be needed to get a beneficial effect. It is recommended that doses of 120 to 240 mg of the standard leaf extract twice per day be used. • Based on pathophysiologic theories involving oxidative stress and the accumulation of free radicals in AD, significant interest has evolved regarding the use of antioxidants in the treatment of AD. • Vitamin E treatment may also be associated with risks. Side effects observed with vitamin E administration include impaired hemostasis, fatigue, nausea, diarrhea, and abdominal pain. For example, vitamin E can cause thinning of the blood if it is taken with other medications such as aspirin, ibuprofen, and/or naproxen.