Chapter 14: Drugs for AD and Dementia

Question 1

What is Alzheimer’s Disease?

Answer 1

• A Neurodegenerative disorder of the elderly
• 1/12 of population 65-75 yrs of age
• 1/3 of population >85 Years of age
• Accounts for 60-80% of all dementias.
• Average Life expectancy following diagnosis is approximately 7-14 years.

Question 2

What are the Symptoms of Alzheimers?

Answer 2

Dementia

• Short term memory loss
• Impaired memory retrieval
• impaired ability to generate ideas and to manupulate concepts mentally
• impaired judgement and evaluation
  -** Labile** (Easily altered) and inappropriate emotions.

Motor function intact until late stages of the disease.

Question 3

What is the macroscopic neuropathology of AD?

Answer 3

• Neurodegeneration.
• Diffuse Cortical Atrophy
• High density of plaques and tangles in the frontal and temporal cortices.

Question 4

What is the Microscopic neuropathology of AD?

Answer 4

• Loss of Cholinergic Neurons in the Nucleus Basalis of Meynert that project ot the frontal cortex.
• Loss of Locus Coeruleus Neurons may even precede nBM loss.
• Neurodegeneration starts many years before the appearance of any symtpoms.

**Plaque Formation Mechanism -> **

Amyloid Precursor Protein (APP) found on cell membranes can be cleaved to form Beta-Amyloid. Beta-Amyloid can aggregate in the presence of inflammtion causing these plaques.

Question 5

What are the different proteins involved in APP processing?

Answer 5

A-Secretase - Creates Physiological functional proteins; stops from going down the amyloid beta pathway; also produced in response to 5HT.

B-Secretase - Generates Amyloid Beta; Is the rate limiting step of Amyloid Beta production.

Gamma-Secretase - This protein always cleaves its sites.

Question 6

What are the different function products of APP processing and what is their function?

Answer 6

sAPPa - Neuro-protective, promotes neurite outgrowth and synaptogenesis, enhances learning and memory.

sAPPB - stimulates axonal pruning and neuronal cell death.

AB - AB-40 neuroprotective against AB-42 (Toxic) ; Amyloid Beta can play phsiological role in lower amounts.

Question 7

What drug may delay the clincal decline of Alzheimers?

Answer 7

Aducanumab

Question 8

What is the mechanism behind Aducanumab?

Answer 8

Anti-Amyloid Antibody - Monoclonal Antibody directed against soluble and insoluble amyloids - *Promote clearance by Fc receptor-mediated phagocytosis. *

Delays clincal decline in early Alzheimers disease patients.

Question 9

Where is Aducanumab approved and not approved?

Answer 9

FDA - Approved
European Union - Rejected
Health Canada - In reviewing Process.

Question 10

What type of therapy was thought to work on AD but only showed limited success?

Answer 10

Acetyl-Choline replacement therapy. With AchE inhibitors.

Question 11

What are the different AchE inhibitors and what are their characteristics?

Answer 11

Question 11

What is the improved version of Memantine?

Answer 11

Nitromemantine

• Nitroglycerin added to memantine to enhance targeting/binding to extrasynaptic NMDA receptors.
• Nitrosylates the extrasynaptic chronically active NMDA receptor causing desensitivation.

Question 11

What is the mechanism of Memantine for treating Alzheimers?

Answer 11

Non-competitive low affinity antagonist at NMDARs.

Partial blockade of NMDARs ar therapeutic doses. -> Allows Synapses to still adapt.

Non-competitive antagonist at nAchRs (AB stimulates this to increae Glu release)

Recommended to manage moderat to severe AD in patients intolerant or contraindicated for AchE inhibitors.

No benefit in Mild AD.

Memantine combined with AchE inhibitors shows significant improvement.

Blocking NMDArs Reduce Ca toxicity.

Question 12

What are some alternatives treatments of Alzheimers?

Answer 12

• Vaccine dont work
• Valproic acid - Reduces/prevents formation of B-Amyloid deposits in tras-genic mouse models of Alzheimer’s Disease.
• Pioglitazone shown to stimulate amyloid clearance and reversal of cognitive deficits in mouse models of AD.

Question 13

How can Anti-oxidant therapy help treating AD?

Answer 13

In vitro, antioxidants block the neurotoxicity of ß-amyloid
* so far, only 1 clinical trial has been published
* 2000 IU vitamin E daily slowed progression of dementia in probable AD
patients

*Gingko biloba and vitamin E listed in Toronto Notes (2012) as other (not proven) treatment possibilities
* Existing anti-oxidant interventions include:
* vitamin E -tocopherol (synthetic or natural)
* vitamin C ascorbic acid (not megadose)
* blueberries wild or domestic
* strawberries local or imported
* ethanol your choice (2 to 3 drinks per day)