Alzheimer’s Disease and Related DementiasAlzheimer’s Disease and Related Dementias

Modified from a talk by :Andrea A. Chiba, UCSD

And KE Edwards, Amgen

Definition of DementiaDefinition of Dementia Memory loss and 1 or more cognitive

difficulties, such as– Disorientation (to time, place)– Disturbed executive functioning (planning, organizing,

abstraction, judgment)– Aphasia (impaired word use and comprehension)– Apraxia (impaired ability to carry out motor tasks)– Agnosia (cannot recognize objects or faces)– Impaired attention and concentration

Significant impairment of social/occupational function Change from baseline (prior) function

American Psychiatric Association. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. 1994.4th ed. 1994.

Diagnostic and Statistical Manual Diagnostic and Statistical Manual (DSM-IV) Criteria (DSM-IV) Criteria for Dementia of the Alzheimer Typefor Dementia of the Alzheimer Type Development of multiple cognitive deficits manifested by both

– Memory impairment (inability to learn new, or recall old, information)

– At least 1 of the following: aphasia, apraxia, agnosia, or disturbance in executive functioning

Cognitive deficits significantly impair social/occupational functioning; represent a significant decline from a previous level of functioning

Characterized by gradual onset and continuing cognitive decline Not because of other causes of progressive cognitive decline Deficits do not occur exclusively during the course of a delirium Disturbance not better accounted for by another medical

disorder

American Psychiatric Association. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. 1994 (C). 4th ed. 1994 (C).

Scope of AD Now and in the FutureScope of AD Now and in the Future

A Healthcare Crisis TodayA Healthcare Crisis Today

Approximately 1 of every 10 screened patients over the age of 65 years may have AD1

As many as 60% of individuals with AD may go undiagnosed in the primary care setting2

AD is ranked as the nation’s seventh leading cause of death among all persons3

1. Evans et al. 1. Evans et al. JAMAJAMA. 1989;262:2551-2556; 2. Knopman et al. . 1989;262:2551-2556; 2. Knopman et al. J Am Geriatr SocJ Am Geriatr Soc. 2000;48:300-. 2000;48:300-304; 3. Mini304; 3. Miniñño et al. o et al. Natl Vital Stat RepNatl Vital Stat Rep. 2006;54:1-50.. 2006;54:1-50.

ADAD

Can be divided into Early Onset (< 60) and Late Onset (>60).

Perhaps two different etiologies After age 65, the number of cases doubles every 5

years. 3% of people 65-74 have the disease Approx. 50% of people over 85 have the disease.

Prevalence Is Projected to Increase Prevalence Is Projected to Increase DramaticallyDramatically

0

2

4

6

8

10

12

14

2000 2030* 2050*

65-74 years

75-84 years

85+ years

4.5 Million4.5 Million

7.7 Million7.7 Million

13.2 Million13.2 Million

*Estimates.*Estimates.Hebert et al. Hebert et al. Arch Neurol. Arch Neurol. 2003;60:1119-1122.2003;60:1119-1122.

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Alzheimer’s Disease Education and Referral Center, National Cancer Institute, American Diabetes Association, Alzheimer’s Disease Education and Referral Center, National Cancer Institute, American Diabetes Association, Arthritis Association, National Center for Health Statistics.Arthritis Association, National Center for Health Statistics.

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$104 $104 $100$92

$65

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20

40

60

80

100

120

140

160

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Cardiovascular Cancer Drug-RelatedProblems

Alzheimer’sDisease

Diabetes Osteoarthritis

An Actual AD PlaqueAn Actual AD Plaque An Actual AD TangleAn Actual AD Tangle

AD and the BrainAD and the BrainPlaques and Tangles: The Hallmarks of ADPlaques and Tangles: The Hallmarks of AD

-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

The brains of people with AD have an abundance of 2 abnormal structures:

National Institute on Aging. Available at: http://www.nia.nih.gov/Alzheimers/Publications/UnravelingTheMystery/Part1/. National Institute on Aging. Available at: http://www.nia.nih.gov/Alzheimers/Publications/UnravelingTheMystery/Part1/. Accessed October 5, 2006.Accessed October 5, 2006.

1.1.

2.2.

3.3.

AD and the BrainAD and the Brain-Amyloid Plaques-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 -amyloid

3.-amyloid fragments come together in clumps to form plaques

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

PlaquesPlaques

Extracellular Contain A-beta (sequence cleaved from APP or

Amyloid Precursor Protein) Metals (aluminum, zinc) Immunoglobulin G Amyloid P apoE ETC….over 30 other proteins

Neurofibrillary Neurofibrillary TanglesTangles

AD and the BrainAD and the Brain

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

National Institute on Aging. Available at: http://www.nia.nih.gov/Alzheimers/Publications/UnravelingTheMystery/Part1/. National Institute on Aging. Available at: http://www.nia.nih.gov/Alzheimers/Publications/UnravelingTheMystery/Part1/. Accessed October 5, 2006.Accessed October 5, 2006.

TanglesTangles

Intracellular Bundles of long unbranched elements that form a

fibrous twisted pair of filaments Consist of tau protein (a protein that ordinarily

stabilizes cellular microtubules) Are somewhat correlated with degree of dementia

– post-mortem.

ApoE: One Hypothesis for Tangle FormationApoE: One Hypothesis for Tangle FormationDetails – only for those who care – not requisite knowledgeDetails – only for those who care – not requisite knowledge

What Causes AD?What Causes AD?

The “amyloid hypothesis” is the most widely accepted theory of AD etiology, but certainly not an answer at this time.

Several other potential causative or contributing factors under research – Tau– inflammation– cardiovascular risk factors– disruptions of neuronal signaling pathways.

Progression to DementiaProgression to DementiaNormal Normal

CognitionCognitionProdromal Prodromal DementiaDementia

Normal Normal brainbrainagingaging

Stable or Stable or reversible reversible

impairmentimpairment

Mild cognitive Mild cognitive impairment impairment

(MCI)(MCI)

Vascular Vascular dementiadementia

Alzheimer’s Alzheimer’s diseasedisease

Other Other dementiasdementias

DementiaDementia

Morris. Morris. GeriatricsGeriatrics. 2005;(suppl):9-14 (C).. 2005;(suppl):9-14 (C).

MixedMixed

MixedMixed

10% to 15% of individuals with amnestic MCI will be diagnosed with AD

Risk Factors for ADRisk Factors for ADDefinitive Increasing age Family history Genetics APOE 4 allele Down’s syndromeProbable Female sex Low level of education

Possible Head injury with loss of

consciousness Cerebrovascular disease Vascular brain lesions Cardiovascular disease Environmental toxins Depression* History of psychiatric

illness*

**May be premonitory manifestations of the disease process rather than risk factors.May be premonitory manifestations of the disease process rather than risk factors.Desai et al. Desai et al. Clin Geriatrics.Clin Geriatrics. 1999;7:43-52. 1999;7:43-52.

Normal AgingNormal Aging

Can have mild deficits– Slowed mental processing speed– Difficulty recalling names and other nouns

Changes should not materially affect ability to function

Subjective memory loss

Kawas. Kawas. N Engl J Med. N Engl J Med. 2003;349:1056-1063 (C). 2003;349:1056-1063 (C).

The increased significance of agingThe increased significance of aging

Increased life expectancy– Success of public health

Improved sanitation Antibiotics Vaccines

“Baby boom” generation– 1946-64: 75 million babies

By the year 2030 20% of the US > age 65

Live long and prosper?– Disease-free aging vs.

age-related disorders AD (5-10%), PD, ALS, HD Age-related memory deficits

Damage/dysfunction:– Anterograde amnesia for

new facts and events– Patient H.M. – Alzheimer’s Disease– Aging

Components:– Entorhinal Cortex – Hippocampus

Dentate Gyrus Ammon’s horn (CA1-CA3)

– Subiculum Unidirectional circuit

– EC DG HC Sub

HCF: The Hippocampal FormationHCF: The Hippocampal Formation

Aging vs. Alzheimer’sAging vs. Alzheimer’s

Normal “cognitive” aging – No neuronal loss– A few NFTs (neurofibrillary tangles) in

EC layer II, rarely in CA1 Very Mild AD

– Significant ~30% neuronal loss in entorhinal cortex layer II, CA1

– Increasing density of NFTs Severe AD

– ~90% loss in entorhinal cortex layer II– ~50% loss in other EC layers, CA1,

ITC– Extensive neurofibrillary tangles

(NFTs)– Cortical atrophy

Morrison and Hof, Science

Remember HM and his memory issues.Remember HM and his memory issues.Aspects of this circuit Aspects of this circuit MTLS: Medial temporal lobe systemMTLS: Medial temporal lobe system

Mayford et al., Current Biology 1997

MTLS: Medial temporal lobe systemMTLS: Medial temporal lobe system

Mayford et al., Current Biology 1997

Basis of age-related memory deficitsBasis of age-related memory deficits

Theories of brain aging:– Neuronal loss

Glucocorticoid stress Oxidative stress Inflammation- gliosis Neurogenesis

– Neuronal dysfunction Calcium homeostasis Synaptic dysfunction Neurotrophic factor loss Signal transduction deficits

– Environmental factors

Apoptosis

Mild Cognitive ImpairmentMild Cognitive Impairment

Memory complaint, preferably corroborated by an informant

Impaired memory function for age and education Normal general cognitive function Normal activities of daily living Not demented

Petersen et al. Petersen et al. Arch NeurolArch Neurol. 2001;58:1985-1992 (C).. 2001;58:1985-1992 (C).

Mild AD: Clinical CorrelatesMild AD: Clinical Correlates

Cognition Deficits in short-term memory, orientation, problem solving1

MMSE score in 20s2,3

Function Performance of complex tasks begins to deteriorate

(eg, shopping, managing money)2

Basic functions intactBehavior Agitation, apathy, disinhibition, and irritability most

frequent3

1. Hughes et al. 1. Hughes et al. Br J Psychiatry.Br J Psychiatry. 1982;140:566-572 (B); 2. Galasko. 1982;140:566-572 (B); 2. Galasko. Eur J Neurol.Eur J Neurol. 1998;5(suppl 4):S9-S17 (B); 3. Mega et al. 1998;5(suppl 4):S9-S17 (B); 3. Mega et al. NeurologyNeurology. 1996;46:130-135 (B).. 1996;46:130-135 (B).

Moderate AD: Clinical CorrelatesModerate AD: Clinical Correlates

Cognition Recent memory severely restricted1

Usually disoriented, social judgment impaired1

MMSE scores 10-202,3

Function Progressive loss of abilities to perform complex tasks

(eg, travel alone, use home appliances)2

Basic functions may require prompting (eg, dressing, grooming)2

Behavior Agitation, apathy, disinhibition, and irritability increase3

Anxiety, dysphoria, wandering/restlessness, delusions, hallucinations may also emerge3

1. Hughes et al. 1. Hughes et al. Br J Psychiatry.Br J Psychiatry. 1982;140:566-572 (B); 2. Galasko. 1982;140:566-572 (B); 2. Galasko. Eur J Neurol.Eur J Neurol. 1998;5(suppl 4):S9-S17 (B); 3. Mega et al. 1998;5(suppl 4):S9-S17 (B); 3. Mega et al. NeurologyNeurology. 1996;46:130-135 (B).. 1996;46:130-135 (B).

Severe AD: Clinical CorrelatesSevere AD: Clinical Correlates

Cognition Severe cognitive deficits observed1

For example, MMSE 11Function Deficits in complex functions observed (eg, using the

telephone, shopping)2

Deficits in basic functions observed (eg, toileting, dressing)2

Behavior Apathy, aberrant motor patterns, depression, anxiety, and

agitation were most prominent behavioral symptoms3

1. Feldman et al. 1. Feldman et al. NeurologyNeurology. 2001;57:613-620 (A); 2. Feldman et al. . 2001;57:613-620 (A); 2. Feldman et al. J Am Geriatr SocJ Am Geriatr Soc. . 2003;51:737-744 (A); 3. Gauthier et al. 2003;51:737-744 (A); 3. Gauthier et al. Int PsychogeriatrInt Psychogeriatr. 2002;14:389-404 (A).. 2002;14:389-404 (A).

Differential DiagnosesDifferential DiagnosesFeatures that favor the diagnosis of …Features that favor the diagnosis of …

Vascular Dementia1 Lewy Body Dementia2 Frontotemporal Dementia3

Abrupt onsetFocal neurological signs and symptomsStepwise deteriorationAtherosclerosis/TIAs (transient ischemic attacks)transient ischemic attacks) History of strokesHistory of hypertension

Visual hallucinationsExtrapyramidal symptoms

–Shuffling gait–Masked facies–Rigidity–Gait instability

Waxing/waning alertnessNeuroleptic supersensitivity

Behavioral disinhibitionApathy/social withdrawal“Personality change”Socially inappropriate behaviorEuphoria/irritabilityNonfluent aphasia

1. Román et al.1. Román et al. Neurology Neurology. 1993;43:250-260 (C); 2. McKeith et al. . 1993;43:250-260 (C); 2. McKeith et al. Lancet NeurolLancet Neurol. 2004;3:19-28 (C); 3. Neary et al. . 2004;3:19-28 (C); 3. Neary et al. NeurologyNeurology. 1998;51:1546-1554 (C); Liu et al. . 1998;51:1546-1554 (C); Liu et al. Neurology.Neurology. 2004;62:742-748 (B) 2004;62:742-748 (B)

GRADING SYSTEM

Grade 1 (top row of 4 images) corresponds to mild cerebral atrophy and ventricular dilatation. Note this degree of change may be assessed as compatible with normal

aging. Thus, grade 1 accomodates scoring of brains from nondemented control subjects with minimal or no gross neuropathology.

Grade 2 (middle row of 4 images) corresponds to moderately severe cerebral atrophy and ventricular dilatation. Note widening of sulci, rounding of frontal horns, and

expansion of the area of the body and 3rd ventricle.

Grade 3 (bottom row of 4 images) corresponds to severe cerebral atrophy and ventricular dilatation. Dramatic shrinkage of gyri, gaping of some sulci, and extreme

ventricular dilatation is obvious. Note also the white matter area is markedly diminished from the amount noted in grade 1 brains.

Pharmacologic Approaches Pharmacologic Approaches

FDA-Approved Medications for ADFDA-Approved Medications for AD

Cholinesterase inhibitors– Tacrine (Cognex)* - rarely prescribed– Galantamine (Razadyne)*– Rivastigmine (Exelon)*– Donepezil (Aricept)†

N-methyl-D-aspartate receptor antagonist– Memantine (Namenda)†

*Approved for use in mild-to-moderate AD; *Approved for use in mild-to-moderate AD; ††mild through severe AD.mild through severe AD.Aricept (donepezil hydrochloride) [package insert]. New York, NY: Pfizer Inc; 2005; Exelon Aricept (donepezil hydrochloride) [package insert]. New York, NY: Pfizer Inc; 2005; Exelon (rivastigmine tartrate) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; (rivastigmine tartrate) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2004 (A); Razadyne ER (galantamine hydrobromide) [package insert]. Titusville, NJ: Ortho-2004 (A); Razadyne ER (galantamine hydrobromide) [package insert]. Titusville, NJ: Ortho-McNeil Neurologics, Inc.; 2005 (A); Namenda (memantine) [package insert]. St Louis, Mo: McNeil Neurologics, Inc.; 2005 (A); Namenda (memantine) [package insert]. St Louis, Mo: Forest Pharmaceuticals, Inc.; 2005Forest Pharmaceuticals, Inc.; 2005 (A).(A).

Dosing Comparison of Dosing Comparison of Cholinesterase InhibitorsCholinesterase Inhibitors

Characteristic Donepezil Rivastigmine GalantamineGalantamine

ERDoses per day 1 2 2 1

Initial dose (mg/d) 5 3 8 8

Dose escalation 4-6 weeks 2 weeks 4 weeks 4 weeks

Clinically effectivedose range (mg/d)

5-10 6-12 16-24 16-24

Given with food With/without Yes Recommended Recommended

Aricept (donepezil hydrochloride) [package insert]. New York, NY: Pfizer Inc; 2005; Exelon Aricept (donepezil hydrochloride) [package insert]. New York, NY: Pfizer Inc; 2005; Exelon (rivastigmine tartrate) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2004 (rivastigmine tartrate) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2004 (A); Razadyne ER (galantamine hydrobromide) [package insert]. Titusville, NJ: Ortho-McNeil (A); Razadyne ER (galantamine hydrobromide) [package insert]. Titusville, NJ: Ortho-McNeil Neurologics, Inc.; 2005 (A).Neurologics, Inc.; 2005 (A).

Bentué-Ferrer et al. Bentué-Ferrer et al. CNS Drugs.CNS Drugs. 2003;17:947-963. 2003;17:947-963.

Side-Effect Profile for Cholinesterase InhibitorsSide-Effect Profile for Cholinesterase Inhibitors

Gastrointestinal side effects include nausea, vomiting, diarrhea, and abdominal pain – Resulting in anorexia and weight loss

Cardiovascular side effects include bradycardia, tremor, and dizziness – Resulting in asthenia and fatigue

Neuromuscular side effects include muscle cramps and weakness

CNS effects include insomnia, nightmares, agitation, and a panic-like state

New Formulations of Cholinesterase InhibitorsNew Formulations of Cholinesterase Inhibitors Donepezil oral disintegrating tablets (ODT) Rivastigmine oral solution Rivastigmine transdermal patch evaluated in the

IDEAL trial– 1195 patients randomized to 1 of 2 doses of a transdermal patch

(equivalent to 9.4 mg/24 h or 17.4 mg/24 h), 6-mg oral capsules of rivastigmine bid or placebo

– Lower dose patch as effective as oral therapy and associated with one third of the gastrointestinal side effects

– No difference in side-effect profile between higher dose patch and oral treatment

– Not available yet

Galantamine extended-release (ER) capsules

IDEAL=Investigation of Transdermal Exelon in Alzheimer’s Disease.IDEAL=Investigation of Transdermal Exelon in Alzheimer’s Disease.Aricept (donepezil hydrochloride) [package insert]. New York, NY: Pfizer Inc; 2005 (A); Aricept (donepezil hydrochloride) [package insert]. New York, NY: Pfizer Inc; 2005 (A); Exelon (rivastigmine tartrate) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2004 (A). Exelon (rivastigmine tartrate) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2004 (A).

Rationale for MemantineRationale for Memantine

The normal activity of the neurotransmitter glutamate plays an integral role in neural pathways associated with learning and memory1

Voltage-dependent, low-moderate affinity, uncompetitive NMDA-receptor antagonist with fast on/off kinetics2

Blocks the effects of abnormal glutamate activity (excitotoxicity) that may lead to neuronal cell death and cognitive dysfunction2

Preserves physiological activation of NMDA receptor, which is required for learning and memory2

1. Ghosh. 1. Ghosh. Science. Science. 2002;295:449-451; 2. Parsons et al. 2002;295:449-451; 2. Parsons et al. Neuropharmacology. Neuropharmacology. 1999;38:735-767; Alzheimer’s Association. Available at: http://www.alz.org/Resources/1999;38:735-767; Alzheimer’s Association. Available at: http://www.alz.org/Resources/FactSheets/FSmemantine.pdf. Accessed December 1, 2006.FactSheets/FSmemantine.pdf. Accessed December 1, 2006.

Memantine: PharmacokineticsMemantine: Pharmacokinetics

Bioavailability: 100% Protein binding: 45% T1/2: 60 to 80 hours Can be administered with or without food Limited metabolism—eliminated mostly in urine as parent

drug, metabolites inactive No or minimal effects on CYP450 isoenzymes No PK/PD interactions with ChEIs Possible PD interaction with high-affinity NMDA receptor

antagonists?

PK=pharmacokinetic; PD=pharmacodynamic.PK=pharmacokinetic; PD=pharmacodynamic.Namenda (memantine) [package insert]. St. Louis, Mo: Forest Pharmaceuticals, Inc.; 2005Namenda (memantine) [package insert]. St. Louis, Mo: Forest Pharmaceuticals, Inc.; 2005 (A).(A).

Namenda (memantine) [package insert]. St. Louis, Mo: Forest Pharmaceuticals, Inc.; 2005Namenda (memantine) [package insert]. St. Louis, Mo: Forest Pharmaceuticals, Inc.; 2005 (A).(A).

Memantine: Suggested DosingMemantine: Suggested Dosing

Start with 5 mg qd (5101520 mg) Titrate memantine to 20 mg/d over 4 week period

Decrease dose (to 5 mg bid) in patients with severe renal impairment (CrCl: 5-29 mL/min)

Memantine Adverse EventsMemantine Adverse EventsPercentage of Adverse Events Reported in Controlled Clinical Percentage of Adverse Events Reported in Controlled Clinical Trials in Trials in ≥4% of Patients Receiving Memantine and at a Higher≥4% of Patients Receiving Memantine and at a HigherFrequency Than Placebo-Treated PatientsFrequency Than Placebo-Treated Patients11

Adverse EventPlacebo (n=922)

%Memantine (n=940)

%Hypertension 2 4

Dizziness 5 7

Headache 3 6

Constipation 3 5

Confusion 5 6

Coughing 3 4

1. Namenda (memantine) [package insert]. St. Louis, Mo: Forest Pharmaceuticals, Inc; 2005; 1. Namenda (memantine) [package insert]. St. Louis, Mo: Forest Pharmaceuticals, Inc; 2005; 2. Reisberg et al. 2. Reisberg et al. Arch Neurol.Arch Neurol. 2006;63:49-54. 2006;63:49-54.

Memantine 1-year safety data available (28-week, randomized, double-blind, placebo-controlled period, plus 24-week, open-label extension phase2)