Presented by

Bondre Rameshwar B.

M.Pharm

(Pharmacology),Nanded1

Introduction

Risk factor for AD

symptoms of AD

Pathogenesis of AD

Therapeutic targets of AD

Treatment of AD

Conclusion

References

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Alzheimer’s Disease (AD) is an irreversible, progressive brain disease

that slowly destroys memory, cognition, and abilities to function

In most cases, symptoms appear after Age 60

Alzheimer’s Disease is named after Dr. Alois Alzheimer.

In 1906, he noticed changes in the brain tissue of a woman who had died

of an unusual mental illness with symptoms of memory loss, language

problems, and unpredictable behavior.

He examined her brain and found many abnormal clumps and tangled

bundles of fibers (neurofibrillary tangles)..

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Risk Factors for AD:

1. advancing age

2. family history

3. head trauma

4. lack of mental stimulation = “use it or lose it”

5. Down’s syndrome

6. environmental toxins: aluminum, mercury

7. oxidative stress due to accumulation of free radicals

and/or low antioxidant levels

8. abnormal protein processing

9. neurotransmitter deficit

10. genetic polymorphism

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Repetitive questions or conversations.

Misplacing personal belongings.

Getting lost on a familiar route.

Poor understanding of safety risks.

Poor decision-making ability.

Inability to plan complex or sequential activities.

Speech, spelling, and writing errors.

Early: mild forgetfulness and short-term memory loss

Middle: problems speaking, understanding, reading, or writing

anxiety and aggression

Late: need complete care

complete memory loss, including inability to remember family

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Alzheimer’s Disease

Neurofibrillary Tangles

Cortical Atrophy

Β-Amyloid Plaques

Diseased Neuron

Non-Diseased Neuron

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Pathogenesis of AD

“The physiology of AD is “characterized by marked atrophy of the

cerebral cortex and loss of cortical and sub-cortical neurons.”

Amyloid Plaques in the spaces between the brain’s nerve cells.

“The senile plaques are extra cellular proteinaceous deposits of

amyloid-beta (Abeta) peptides.”

amyloid + dead brain cell = amyloid plaque

Neurofibrillary Tangles in the brain’s nerve cells.

“Neurofibrillary tangles consist of paired helical filaments which

are composed of hyperphosphorylated microtubule associated

protein tau.”

tau + dead brain cell = neurofibrillary tangle

1. Abnormalities in APP mutation leads

to its cleavage by β- and γ-secretase

enzymes

3. Deposits as Amyloid Plaques and

impairs synaptic function

2. Neurotoxic Aβ42 peptides released and

aggregate into Oligomers and Amyloid Fibrils

APP: Amyloid Precursor Protein

Aβ42: Toxic Aβ fragments

TARGETS

MK-8931

Solanezumab

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The toxicity of oligomers and amyloid fibrils cause Tau-Hyperphosphorylation leading to

Neurofibrillary Tangles and eventually Neuronal Death.

Apoliopoprotein E gene ε4 allele has

been shown to be a genetic risk

Targets

Aβ pathology begins years before the

onset of Alzheimer’s

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Neurofibrillary tangles

are due to the accumulation of Tau in the brain.

Tau is a microtubule-associated protein.

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Acetylcholine (Ach) is a CNS messenger

important for learning and memory

Targets:

Ach is degraded by acetylcholinesterase

(AchE)

In AD, Ach level is low due to excessive

degradation by AchE.

Cholinesterase Inhibitors correct the

deficit of Ach by blocking the action of

AchE and thereby increasing the amount

of Ach that remains in the synaptic cleft.

Cholinesterase Inhibitor

1.

1.

2.

2.

3.

3.

Ach: Acetylcholine

AchE: Acetylcholinesterase

ChEIs: Cholinesterase Inhibitors

As disease progress, the brain gradually

produces less acetylcholine and ChEIs

may lost their effect.

4.

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1. Glutamate is an excitatory

neurotransmitter involved in cognition

and higher mental function.

2. In AD, abnormalities in NMDA

receptors and excess glutamate in the

synapse due to failure of reuptake

3. Excess glutamate causes release of

excess excitatory ions leading to

excitotoxicity and neuronal death.

4. NMDA Antagonists modulates the

NMDA receptor during the excessive

glutamate stimulation

NMDA: N-Methyl D-Aspartate

NMDA-R: NMDA Receptors

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Alzheimer’s Disease

PREVENT TANGLES BY DELAYING PLAQUE FORMATION

About 10-15 years after plaque formation, Neurofibrillary Tangles form and cause Neuronal

Death

TARGETED THERAPIES

Aβ Inhibitors

Immunotherapy

Diabetes Medications

EARLY PREVENTION OF DISEASE PROGRESSION

Delaying disease onset by targeting the underlying mechanism

Previous Prevention Treatments without Significant Results

Immunotherapy Bapineuzumab, AN-1792

Aβ Inhibitors Tramiprostate, Latrepirdine, Semagacestat

DM Medications Rosiglitazone

Others Hormone Replacement Therapy, NSAIDs, Gingko Biloba

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Mechanism of action :

MK-8931 is a potent BACE 1 (β site APP Cleaving Enzyme 1)

Inhibitor

Reduces neurotoxic Aβ peptide production by inhibiting the β-

secretase from cleaving APP

Therefore reducing Amyloid Plaque formation and delaying

Tangle formation, neuronal degeneration and progression of

Alzheimer’s-aaCLI

NICAL DATA

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Mechanism of Action:

Humanized anti-Aβ peptide immunoglobulin G-1 monoclonal

antibody

Binds with high affinity to the deposited soluble Aβ42 peptides

and mobilizes them

Thereby decreasing amyloid plaque formation and slowing the

progression to Alzheimer’s

Solanezumab

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1. Glucose enters the brain via Glucose

Transporters (GLUT) at the BBB

2. Brain glucose is converted to ATP energy to

maintain normal neuronal functions such as

cognition and learning.

4. Cerebral energy depletion causing oxidative

stress and inflammation

3. In AD, significant reduction in brain glucose

metabolism and transport

5. Initiates neurodegeneration by amyloid

deposition and abnormal tau phosphorylation

6. Synaptic injury and dysfunction leading to

cognitive impairments

ATP: Adenosine Triphosphate

NFT: Neurofibrillary Tangles

BBB: Blood Brain Barrier

Blood Brain Barrier

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2. Insulin mitigates hippocampal synapse

vulnerability to β-amyloid and protects against

the detrimental effects of Aβ peptides on

synapses

3. In AD, insulin resistance in the brain and

decreased CSF levels of insulin due to impaired

transport of insulin at the BBB

4. Glucose metabolism and Insulin sensitivity is

decreased by 50% in AD and continues to

decrease throughout disease progression

1. Neurons highly express Insulin receptors with

an important role in brain glucose metabolism

including the regulation of neuronal

development, memory and learning processes

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MECHANISM OF ACTION Potent agonist of PPAR-y (peroxisome proliferator-activated receptor

gamma), which is found in tissues sensitive to insulin action. Crosses the BBB and regulates glucose and lipid metabolism in

neuronal cells and prevents glucose deprivation-induced neuronaldeath.

MECHANISM OF ACTION

Brain insulin receptors are densely localized in the hippocampusand modulates the levels of Aβ and protects against thedetrimental effects of Aβ oligomers on synapses.

Peripheral administration of insulin is not viable due to the risk ofhypoglycemia.

INI provides rapid delivery of insulin to the CNS withoutadversely affecting blood insulin or glucose levels. (Expected toincrease insulin levels in CSF within 60 mins)

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Normal Brain Alzheimer’s Brain

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1. Symptomatic Treatments:

- Acetylcholinesterase Inhibitors

- NMDA-receptor Antagonists

- Nicotinic-receptor Agonists

2. Disease-modifying Treatments:

- Inhibition of amyloid formation: beta and gamma-secretase inhibitors

- Inhibition of abeta aggregation

- Tau phosphorylation inhibitors

3. Other Therapies:

- Cholesterol-lowering therapies

- Anti-inflammatory therapies

- Therapies involving antioxidants: vitamin E and gingko biloba

- Therapies involving neurotrophic factors: nerve growth factor (NGF) and estrogen

4. The “Do-It-Yourself” Approach:

- Diet control

- Use of exercise

- Stress control

- Herbal remedies

- Use it or Lose it!

5. Psychotic Treatments:

- Antidepressants [depression]

- Anxiolytics [anxiety]

- Antipsychotics [severe confusion, paranoia, and hallucinations]

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1. Symptomatic Treatments:

Treatment of mild to moderate dementia of the Alzheimer's type

- Acetylcholinesterase Inhibitors

- tacrine [Cognex®]

- donepezil [Aricept®]

- rivastigmine [Exelon®]

- galantamine [Razadyne®, formerly Reminyl®]

- NMDA-receptor Antagonists

- memantine [Namenda®]

- Nicotinic-receptor Agonists

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2. Disease-modifying Treatments:

Treatment of moderate to severe dementia of the Alzheimer's type

- Inhibition of amyloid formation

1. gamma-secretase inhibitors

-Semagacestat,avagacestat(ongoing)

2.Beta-secretase inhibitors

-GRL-834,TAK-070

- Inhibition of abeta aggregation

1.solanezumab 2.ponezumab,Curcumin(ongoing)

- Tau phosphorylation inhibitors

1.Methylene blue,NAP,

2.Lithium salts,valproate

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3. Other Therapies:

- Cholesterol-lowering therapies

- Anti-inflammatory therapies

- aspirin

- ibuprofen

- COX-2 inhibitors: Celebrex

- naproxen sodium

- Rx drugs used for arthritis

- Therapies involving antioxidants

- vitamin E

- gingko biloba

- Therapies involving neurotrophic factors

- nerve growth factor (NGF)

- estrogen25

5. Psychotic Treatments:

- Antidepressants [depression]

- bupropion [Wellbutrin]

- desipramine [Norpramin or Pertofrane]

- fluvoxamine [Luvox]

- Anxiolytics [anxiety]

- Antipsychotics [severe confusion, paranoia, hallucinations]

- carbamazepine [Tegretol]- olanzapine [Zyprexa]

- divalproex [Depakote] - risperidone [Risperdal]

- Haloperidol [Haldol]

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The pathogenesis of AD is a complex process

involving both genetic and environmental factors;

therefore development of effective disease-modifying

drugs is proving to be a difficult task. Current therapies

for patients with AD may ease symptoms by providing

temporary improvement and reducing the rate of

cognitive decline. The concurrent treatment & drug

agent for AD are under research.

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1. Alzheimer’s Disease. Alzheimer’s Disease Education & Referral Center. National Institute on Aging. National

Institutes of Health. NIH Publication. 11-6423.

2. Alzheimer’s Disease Medications. Alzheimer’s Disease Education & Referral Center. National Institute on

Aging. National Institutes of Health. NIH Publication. 08-3431

3. Tomohiro C. Emerging Therapeutic Strategies in Alzheimer’s Disease. InTech.

4. Christensen D. Alzheimer‘s Disease: Progress in the Development of Anti-amyloid Disease-Modifying

Therapies

5. Francis P, Parsons C, Jones R. Rationale for Combining Glutamatergic and Cholinergic Approaches in the

Symptomatic Treatment of Alzheimer’s Disease. Neurotherapeutics. 2012;12(11):1351-1365

6. Alzheimer’s Disease Trials. ClinicalTrials.gov

7. Kaushik S, DeSilva S, Abbruscato T. The Role of Glucose Transporters in Brain Disease: Diabetes and

Alzheimer’s Disease. International Journal of Molecular Sciences. 2012;13(10):12629-12655

8. Craft S, Baker L, Montine T, et al. Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild

Cognitive Impairment. JAMA Neurology. 2012;69(1):29-38

9. Ivan Aprahamian*, Florindo Stella*+ & Orestes V. Forlenza*. New treatment strategies for Alzheimer’s disease .

Indian J Med Res 138 October 2013, pp 449-460

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Alzheimer’s Disease

THANK YOU!

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