Pennsylvania Neurological Associates

Charles S. Yanofsky, M.D. Jon L. Vickery, M.D.

Albert W. Heck, M.D. Francis J. Janton, III, M.D.

Liana Laza, M.D.

108 Lowther Street

Lemoyne, PA 17043

This is an outline version of a Lecture without graphics. If you have a fast Internet connection the complete lecture with graphics can be viewed at: The Death of Alzheimer’s

www.pneuro.com

The Death of Alzheimer’s Disease Lecture By Charles S. Yanofsky, M.D.

This Talk is About:

• Pipe dreams and practical matters

• The end of Alzheimer’s disease in time to be useful to “baby-boomers” (ME)

• Some useful new treatments

To get to

• Amyloid Hypothesis: The death of Alzheimer’s in our day

• Cholinergic Hypothesis and current treatments

Alzheimer Disease

• Dissolution of the Personality

• Inexorable Progression

Artistic Regression

• Distortion – comic-grotesque representation Condensation – filling to overflowing

• Transformation (neomorphism) – anatomic changes and strange facial features (physiognomy)

• Stereotype – ornamental stereotype and repetition of particular motives

• Woodenness – geometrical and diagrammatic design and pictures enclosed with a frame, lack of depth (lack of shading) and lack of movement (wooden rigidity)

• Disintegration – neglect of spacial relationships between objects and loosening of physiognomy of human beings and animals.

• Regression – relapse into primitive or child-like drawings and lack of perspective

– Maurer K, Frolich L, ALZHEIMER INSIGHTS Paintings of and Artist With Alzheimer Disease

Clock Drawing

Alzheimer’s Burden

• 4 Million Americans

• 14 Million Projected by 2050

• 1/10 over 65

• 85+ one of three has AD

• Life expect: 8 years

• in U.S .$110 B. in yr 2000

• Half of all NH patients

• $12500-70000/person year, avg lifetime cost=$174000

Life expectancy with Dementia

• 3.3 years, comparable to some malignancies

• In patients diagnosed with dementia

• Wolfson et al NEJM 2001;344:1111-1116

Alzheimer’s Burden (cont’d)

• Prevalence doubles every 5 years after 65

• 360,000 new cases/yr

• Higher in non-Caucasians whose numbers are growing in population

• 65+ now 13% but will reach 18% by 2025

• Sltly more than 50% receive care at home

Future Burden

• 2011: first baby boomers turn 65

• 18% of population by 2025

• 85+ now 4 million, 8.5 million by 2030

• 50% of Alz pts are at home, 50% in care

Neurological Disease
(Prevalence)

• Alzheimer Disease: 4 million

• Stroke: 3-4 Million

• Traumatic Brain Inj: 2.5-3.7 Million

• Epilepsy: 1.75 Million

• Parkinson’s: 1.5 Million

Risks

• Age

• ApoE4

• Down’s

• Head injury

• ?Low education

• ?Family History

Stanley Prusiner Nobel 1997

Thesis:

• Degenerative Disease is caused by the accumulation of toxic substances

• Deranged metabolism over long pds of time.

• Primarily diseases of elderly

• As in cholesterol and homocysteine in atherosclerosis

Neurologic Diseases attributed to Protein deposition

• Alzheimer disease: Aβ42

• Amyloid Angiopathy: Aβ42

• Huntington Disease: Huntingtin

• Prion Disease: PrP sc

• “Tauopathies: Pick’s, FT dementia, PSP

• Parkinson Disease, Lewy body Dementia (alpha synuclein)

• Spino-cerebellar Degenerations: Ataxins

• ALS: Neurofilament

• Macular Degeneration: A2E

Alzheimer prevalence

• Age 65+ = 1/10

• Age 85+ = 1/3

• Age related dementia

Macular Degeneration=“Age Related Maculopathy”

• 5% of 60 year olds, 20% of 80 year olds

• Disorder of Phagocytosing cells in Retinal Pigment epithelium

• Accumulation of drusen or lipofuscin in Retinal Pigment Epithelium

• Genetic forms: may be “A2E” accumulation

• Retinal Alzheimer’s Disease

Macular Degeneration: Alzheimer’s of the eye

Alzheimer Disease

• Cerebral Amyloidosis

The Amyloid Hypothesis

Pathogenesis

• Beta-Amyloid Accumulation

• Decrease in Acetylcholine, AchE

• Injury

• Free-Radical Formation

• Genetics

– Polygenic

– ApoE4

– Familial Alzheimer Disease

Characteristic Changes

• Pathology

– Tangles, plaques, Granulo-vacuolar degeneration, Atrophy,neuronal loss

• Biochemistry

– Decreased Ach, AchE

• Imaging

– Atrophy

– Decreased metab activity in post’r cerebral association Cortices

Senile Plaque

• A hallmark pathologic lesion specific for AD is senile plaque. Plaques are composed of amyloid-beta (A-beta), which is found in soluble form in the body fluids of patients with AD. Initially, A-beta aggregates into diffuse plaques that lack definite borders. Later, it matures into compact plaques formed of A-beta fibrils that may be toxic to surrounding neurons.

Amyloid Plaques

• Between Cells (extra-cellular)

• Appear before Tangles do

• Associated with Microglia (inflammation)

Amyloid Precursor Protein

• 695-770 Amino Acids

• Transmembrane protein

• Beta-Amyloid is snipped out precursor protein

• Beta-Amyloid- transmembrane component

Secretase Steps

• Alpha then Gamma – OK

• Beta then Gamma – yields Beta Amyloid

• 40 Amino Acid fragment is OK but minority cut into toxic 42 Amino acid fragment which constitutes plaque

Presenilins

• Early Onset Alzheimer's

• Trans-membrane Protein Cleavers

• PreI: Chr 14, PreII:Chr 1

• Knockout for these proteins: No Beta Amyloid

• Forms of Gamma-Secretase??

Amyloid Plaque

Amyloid

Pathogenesis of Senile Plaque

• Toxic Beta Amyloid fragments build up outside the cell

• E4 may be selectively removed from the extracellular space in place of beta-amyloid

• Beta-Amyloid is toxic and leads to other pathology

Cutting Beta-Amyloid Precursor Protein

• Alpha and Gamma Secretase give rise to harmless p3 protein

• Beta then Gamma secretase yield either:

– Harmless 40 amino acid residue of Beta-Amyloid OR

– Toxic 42 Amino Acid residue of Beta Amyloid

Gamma Secretase: a trans-membrane protease

Beta Amyloid Mediated Damage

• Ca++ Deregulation

• Creation of Free Radicals

• Immune Aggregation

New Strategies

• Beta-Amyloid Vaccine

• Beta and Gamma Secretase Blockers

• Zinc and Copper Chelators

Alzheimer Genes: Chromosome #s

• 21: Abn APP Gene

• 14: Presenilin 1

• 1 : Presenilin 2

• 19:APOE-epsilon 4: Incr risk in Caucasions

• 19:APOE-epsilon2 on Chr 19: decr risk

Apolipoprotein E4

• Variant alleles E2,E3

• Variants differ by only 1 amino acid

• E4 is present in 64% of late-onset Alz patients as 34% of unaffected controls

• 2 copies (homozygote) of E4 increases risk of Alz from 45% to 91%

Granulo-vacuolar Degeneration

Neurofibrillary Tangles

Strategies to Prevent and treat Alzheimer’s

• 1. Inhibition of the proteases (enzymes) that produce Aβ42 ;
2. Inhibition of Aβ42 aggregation that precedes A deposition;
3. Inhibition of Aβ42 -induced neurotoxicity

• Vaccine or antibody to Aβ42

Neurofibrillary Tangle

• Tau protein –Ass’d with microtubules

• Correlates more with degree of dementia

• Appear after than Senile plaque

• Not Specific for Alzheimer Disease

Mechanism of Amyloid destruction

• Liberating Calcium in Cells

• Damaging Mitochondria

• Enhancing inflammatory (Microglial) Response

Neurofibrillary Tangle

^• Abnormal intracellular structure caused by phosphorylation of the tau protein in the cytoskeleton of the neuron.

^• Microglial cell proliferation, especially in association with senile plaques, suggests inflammatory processes play a role in the disease process.

Beta Amyloid

• 4.2 kD fragment, 42-43

• Abnormal cleavage of Beta Amyloid precursor protein (APP)

– APP part of family of 70kD transmembrane proteins

• Beta-Secretase, APP cleaving Protein

• Injury, ischemia incr APP

• Amyloid is neurotoxic

Dennis Selkoe & Howard Weiner

Mouse Trials of Vaccine

• Nasal Administration

• Genetically affected mice make excessive Beta Amyloid

• Mice show evidence of Dementia

• 50% reduction in plaque formation

• Improvement on tests

• Human phase II trials begin this year

Elan Pharmaceutical trial

• In PDAPP mouse (a genetically engineered mouse model with Alzheimer’s-like pathology)

• AN-1792, both reduces pre-existing deposits of amyloid and inhibits accumulation

Gene linkage

• Long arm of Chromosome 10 in late onset Alzheimer

• ?Connected with degradation of Beta Amyloid?

• Insulin processing protein

• Rudy Tanzi Dec22,2000 Science

Lab Supports of Diagnosis

• Test for Aβ42 and Tau in CSF (ADmark©)

• APOE E4 allele

Fuel and Longevity

• Daf-2 gene in C. elegans

– When not functioning lifespan increases from 10 to 30 days

• An insulin receptor gene in humans

• Rat experiments with caloric reduction

• Monkey and human receptors

• Gary Ruvkun, Harvard Med’l School

Brain Activation f-MRI

• E4 dose effect on intensity of activation and number of areas activated

• NEJM Mazziota et al. 343:450, 8/17/2000

10 Warning Signs:

• Dysfunction on Job

• Problem with Language function

• Difficulty performing Familiar Tasks

• Disorientation

• Poor Judgment

• Altered Abstract thinking

• Misplacing Objects

• Personality Change

• Altered Mood and Behavior

• Loss of initiative

Diagnostic Criteria for Dementia

• Multiple Cognitive Deficits with Both

– Memory Impairment plus one or more of foll’g:

– Aphasia, Apraxia, Agnosia, Executive function

– Impaired abstraction, judgement

• Impaired Social or Occupational Function

– DSM IV (1994), 133-35

• Cognitive Deficits are not due to other processes incl

– Substances

– Systemic processes

– Delirium and acute conditions

– Not better accounted for by another Axis I disorder

Causes of Dementia

• Alzheimer –55%

• Vascular - 20%

• Lewy Body –15%

• Pick’s and lobar atrophy –5%

• Other 5%

– Small,GW et al JAMA 1997,278:1363-71, APA, Am J Psychiatry 1997,154 (suppl)1-39;

– Morris JC Clin GeriatrMed. 1994,10:257-76

Multi-infarct dementia

Hachinski Score for Dx of Vascular Dementia

• Abrupt onset

• Stepwise deterioration

• Fluctuating course: improvement between strokes

• Relative preservation of personality 

Nocturnal confusion   

• Depression

• Somatic complaints

• Emotional incontinence

• History of hypertension

• Evidence of atherosclerosis

– Pvd, MI

• Focal Neurological symptoms (TIA)
   Focal neurological signs

Vascular Dementia

• CT or MRI critical

• Either large volume of brain affected, preferably in both hemispheres or multi-infarcts in strategic locations

• Small Vessel

– Lacunar State, deep strokes

– Subcortical deficits

• Multiple Cortical Infarcts:aphasia, agnosia, apraxia

Treatment Cornerstones

• Cholinesterase Inhibitors

• Ancillary Symptoms

– Anxiety

– Agitation

– Disorientation and Wandering

– Sleep Disturbance

• Placement

• Caring for Caretaker

Cholinergic hypothesis

• Diffusely projecting area: Nucleus Basalis of Meynert

• Layers I and II major cholinergic cortical innervation

• Amygdala and hippocampus lgest innervation

AChE inhibitors

• Establish a diagnosis of probable AD. 

• Determine the stage of the patient (AChE-I are approved for mild to moderate AD).

• Discontinue agents with anticholinergic effects.

• Reduce dosage or discontinue if side effects are intolerable.

• Monitor efficacy by caregiver report, quantified mental status examination, effects on activities of daily living, or effects on behavior.

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