Alzheimer's Disease

Jawza F. Al-SabhanPHCL 430

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

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

Ronald Reagan

Introduction

• Alzheimer's disease (AD), first characterized by Alois Alzheimer in 1907, is a gradually progressive dementia affecting:

• Cognition• Behavior• Functional status.

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.

Epidemiology

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

Noncognitive

• Depression, psychotic symptoms (hallucinations and delusions)

• Behavioral disturbances (physical and verbal aggression, motor hyperactivity, uncooperativeness, wandering, repetitive mannerisms and activities, and combativeness)

Functional

• Inability to care for self such as:– dressing– bathing– toileting– eating

Stages of Alzheimer's DiseaseStages

Patient has difficulty remembering recent events. Ability to manage finances, prepare food, and carry out other household activities declines. May get lost while driving. Begins to withdraw from difficult tasks and to give up hobbies. May deny memory problems.

Mild(MMSE score

26–18)

Patient requires assistance with activities of daily living. Frequently disoriented with regard to time (date, year, season). Recall for recent events is severely impaired. May forget some details of past life and names of family and friends. Functioning may fluctuate from day to day. Patient generally denies problems. May become suspicious or tearful. Loses ability to drive safely. Agitation, paranoia, and delusions are common.

Moderate(MMSE score

17–10)

Patient loses ability to speak, walk, and feed self. Incontinent of urine and feces. Requires care 24 hours a day, 7 days a week.

Severe(MMSE score

9–0)

Risk Factor

• Family history 25%-50%• Increasing age• Down Syndrome• Head trauma

Pathophysiology

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

Plaques and Tangles: The Hallmarks of AD

The brains of people with AD have an abundance of two abnormal structures:

An actual AD plaque An actual AD tangle

• 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

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.

3.

AD and the Brain

In AD, many of these clumps form, disrupting the work of neurons. This affects the hippocampus and other areas of the cerebral cortex.

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.

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

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.

AD and the Brain

Mild to Moderate AD• 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.

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.

AD and the Brain

Diagnosis

• Rating scale used to assess AD– MMSE– ADAS– SIB– NPI– GDS– CGL

Treatment: Alzheimer's Disease

• Desired Outcomes• Nonpharmacologic Therapy• Pharmacologic Therapy

– Pharmacotherapy for Cognitive Symptoms– Cholinesterase Inhibitors– Antiglutamatergic Therapy– Other Potential Treatment Approaches

Desired Outcomes

1. The primary goal of treatment in AD is to symptomatically treat cognitive difficulties and preserve patient function as long as possible.

2. 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.

Nonpharmacologic Therapy

Education, communication, and planning are the key nonpharmacologic components of caring for

an AD patient.

Basic Principles of Care for the Alzheimer's Patient

Consider vision, hearing, or other sensory impairments

Find optimal level of autonomy and adjust expectations for patient performance over time.

Bring sudden declines in function and the emergence of new symptoms to professional attention

Reduce choices, keep requests and demands of the patient simple, and avoid complex tasks that lead to frustration.

Provide frequent reminders, explanations, and orientation cues. Employ guiding, demonstration, and reinforcement.

Maintain a consistent, structured environment with stimulation level appropriate to the individual patient.

Avoid confrontation. Remain calm, firm, and supportive if the patient becomes upset.

Pharmacologic Therapy

• Pharmacotherapy for Cognitive Symptoms• Pharmacotherapy of Noncognitive Symptoms

Treatment Options for Cognitive Symptoms in Alzheimer's Disease

consider therapy with a cholinesterase inhibitorGalantamineDonepezil, or

   Rivastigmine, or

In mild-moderate disease

antiglutamatergic therapy Memantine

In moderate to severe disease

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

Cholinesterase Inhibitors

• Newer cholinesterase inhibitors 1. Donepezil2. Rivastigmine3. 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.

The mechanism of action

specifically and reversibly inhibits

acetylcholinesterase

•Donepezil

inhibits both butyrylcholinesterase and

acetylcholinesterase.

•Rivastigmin

e

is a selective, competitive, reversible

acetylcholinesterase inhibitor and also enhances the action of acetylcholine

on nicotinic receptors.

•Galantamin

e

Pharmacokinetics of Cholinesterase Inhibitors

Galantamine Rivastigmine Donepezil

7 hr 1.5 hr 70 hr Half life

20% kidney Kidney Liver Elimination

Yes 2D6,3A4

No Yes 2D6,3A4

Metabolism by CYP450

Dosing of Cholinesterase Inhibitors

Galantamine ER Rivastigmine Donepezil

8mg Qam 1.5mg BID 5mg/day Initial dose

4 week steps 2 week steps 4-6 weeks Dose Escalation

24 mg/day 12mg /day 10 mg /day Max. Dose

Yes Yes No Given with Food

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.

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.

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.

Antiglutamatergic Therapy

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

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

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.

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.

Other Potential Treatment Approaches

Estrogen• 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.

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.

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

Dietary Supplements

Vitamin E• 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.

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.