PATHOPHYSIOLOGY and PHARMACOLOGY Alzheimer's Disease (AD)

Familiar AD or FAD

Also known as early onset AD Often second decade of life Due to genetic mutation: APP, Presenilin 1 and 2 genes

Sporadic AD

Also known as late onset AD or LOAD Usually after 65 yrs ApoE polymorphism in many cases

Progressive dementing disorder resulting from widespread degeneration of neurons in the cerebral cortex and hippocampus (first described by Alois Alzheimer in 1907)

Alzheimer's Disease (AD)

APP

Amyloid precursor protein

Donepezil*

Aricept® 1/2 70h

Alzheimer's Disease (AD) Drug Therapy - Acetylcholinesterase Inhibitors Mechanism of action

Block catabolism of acetylcholine (Ach) and therefore increase the amount of Ach in presynaptic terminals available for the release Inhibit acetylcholinesterase - enzyme responsible for the catabolism of Ach Small improvements in memory and thinking and delay or slow worsening of symptoms for years Effectiveness varies from person to person

Acetylcholinesterase (AchE) inhibitors

Donepezil (Aricept ®) Galantamine (Reminyl ®) Rivastigmine (Exelon ®) Tacrine (Cognex ®)

Rivastigmine

Exelon® 1.5h

Alzheimer's Disease (AD) Pathology

Extracellular amyloid plaques Intracellular neurofibrillary tangles (NFTs) Synaptic deterioration and neuronal death in cerebral cortex and hippocampus

Alzheimer's Disease (AD) Drug Therapy - Acetylcholinesterase Inhibitors Common side effects

Generally well tolerated Nausea, vomiting, loss of appetite, bradycardia, increased frequency of bowel movements, tremors, muscle cramps Tacrine - produce hepatotoxicity (liver damage), therefore now rarely prescribed

Alzheimer's Disease (AD) Drug Therapy - Acetylcholinesterase Inhibitors Pharmacokinetics -

Good oral bioavailability Variable PK and half-life: donepezil-70hr, galantamine - 7hr, rivastigmine - 1.5hr Donepezil, galantamine are metabolizes by P450 liver enzymes (CYP3A4 and CYP2D6), rivastigmine is metabolized by the plasma cholinesterase

- Apolipoprotein E (ApoE) polymorphism

Human ApoE has three isoforms: apoE2, apoE3, and apoE4 Three major alleles: ε2, ε3, and ε4 Six common APOE genotypes, ε22, ε32, ε42, ε33, ε43 and ε44 Six ApoE phenotypes: apoE22, apoE32, apoE42, apoE33, apoE43 and apoE44 In AD - Mutant Apo E4 causes ineffective at proteolytic break-down of the beta-amyloid peptide and clearance Apo E4 mutation = gain of toxic function and loss of neuroprotective function

10 WARNING SIGNS OF ALZHEIMER'S DISEASE

MEMORY LOSS, DISRUPTS DAILY LIFE CHALLENGES IN PLANNING OR SOLVING PROBLEMS DIFFICULTY COMPLETING FAMILIAR TASKS AT HOME, WORK/LEISURE CONFUSION WITH TIME OR PLACE TROUBLE UNDERSTANDING VISUAL IMAGES AND SPACE PROBLEMS WITH SPEAKING OR WRITING MISPLACING THINGS AND NOT RETRACING DECREASED OR POOR JUDGMENT WITHDRAWAL FROM WORK OR SOCIAL ACTIVITIES CHANGES IN MOOD AND PERSONALITY

Alzheimer's Disease (AD) IS A DISEASE OF THE BRAIN THAT CAUSES PROBLEMS WITH

MEMORY, THINKING AND BEHAVIOR IT IS NOT A NORMAL PART OF AGING FORGETFULNESS, CONFUSION, LANGUAGE AND LIFESTYLE are HALLMARKS

Typical age-related changes

Making a bad decision once in a while Missing a monthly payment Forgetting which day it is and remembering later. Sometimes forgetting which word to use. Losing things from time to time.

NMDA receptor inhibitor

Memantine (Namenda ®)

Alzheimer's Disease (AD) Drug Therapy - NMDA receptor antagonist Memantine HCL (Namenda®) PK -

Metabolized into 1-hydroxy-tacrine (active) t ½ = 57-95 hrs. pH dependent tubular reabsorption; renal clearance reduces by approx., 80-87% with alkaline urine

In AD

Mutant Apo E4 causes ineffective at proteolytic break-down of the beta-amyloid peptide and clearance

Alzheimer's Disease (AD) Drug Therapy - NMDA receptor antagonist Memantine HCL (Namenda)

NMDA receptor antagonist (low affinity), derivative of amantadine Blockade of NMDA receptors, memantine protects neurons from Ca2+ overload that can lead to neuronal death (excitotoxicity) Improves daily activities and cognitive functions, benefits are additive when given with donezepil

Alzheimer's Disease (AD) Drug Therapy - FDA approved

No cure and no way to slow the progression of the disease Symptoms can be improved with drugs Acetylcholinesterase (AchE) inhibitors NMDA receptor inhibitor

Sign's of Alzheimer's/dementia

Poor judgment & decision making. Inability to manage a budget Losing track of the date or season Difficulty having a conversation Misplacing things and being unable to retrace steps to find them.

Galantamine

Razadyne® 1/2 6/7h

Loss of axon stability and cellular integrity, thus reduced

Viability

Beta-amyloid

a protein fragment snipped from an amyloid precursor protein (APP)

Human ApoE has three isoforms

apoE2, apoE3, and apoE4

Six ApoE phenotypes

apoE22, apoE32, apoE42, apoE33, apoE43 and apoE44

Pathology - Cholinergic failure (hypothesis) Dysfunction of Ach containing neurons in the brain contributes

cognitive decline (forebrain) Ach involved in memory, judgment etc.

Plaques

deposits of protein fragment called beta-amyloid that builds up in the spaces between neurons

Alzheimer's Disease (AD) Pathology - Apolipoprotein E (ApoE)

found in the chylomicron Produced by the liver, macrophages, microglia & astrocytes Function - transport cholesterol to neurons via Apo E receptors Important in CV diseases due to increased plasma cholesterol and impaired chylomicron clearance (e.g. type III hyperlipoproteinemia (HLP III)

Apo E4 mutation

gain of toxic function and loss of neuroprotective function

Newer - (phase 3 trials) Gantenerumab

human IgG that binds A-beta fibrils. Elicits phagocytosis of human A0beta deposits. Example of immunotherapy.

Neurofibrillary Tangles (NFTs)

insoluble twisted fibers found inside neurons of the brain.

Hyperphosphorylated tau protein aggregates

into helical filamentous NFT that are deposited preferentially within the neurons (hippocampus and cortex)

NFT causes

microtubule structures to collapse

Tau is involved in

microtubules assemble and is essential for axonal growth and neuronal development.

Secretases

proteases that cause proteolytic cleavage of target protein

Tangles consist of a protein called

tau

Cholinergic failure (hypothesis) Therapeutic approach

treat cognitive loss associated with AD with: Cholinergic replacement therapy Muscarinic and nicotinic-cholinergic ligands Acetylcholinesterase inhibitors (tacrine, donepezil, rivastigmine and galantamine)

APP mutation increases

β-secretase activity Presenilin 1 and 2 mutations increases γ-secretase activity

Apolipoprotein E (ApoE) polymorphism Three major alleles

ε2, ε3, and ε4

Six common APOE genotypes

ε22, ε32, ε42, ε33, ε43 and ε44