Alzheimers

Question 1

What are the main risk factors for alzheimers?

Answer 1

• Main risk = age

Question 2

What are the genetic risk factors for alzheimers?

Answer 2

Genetic risks

1. Early onset Alzheimers

• APP gene (amyloid precursor protein)
• PSEN gene (Presenilin) - part of the gamma-secretase complex

1. Late-onset Alzheimers
   * ApoE (apo lipoprotein E)

Question 3

What are the clinical symptoms of Alzheimer’s?

Answer 3

Deterioration of the higher functions

• Memory loss – especially recently acquired information
• Disorientation/ confusion – forgetting where they are
• Language problems – stopping in the middle of a conversation
• Personality changes – becoming confused, fearful, anxious
• Poor judgement – such as when dealing with money

Question 4

How does amyloid processing occur in normal physiology?

Answer 4

• APP (amyloid precursor protein) found in neuronal membranes in the CNS
• APP is cleaved by alpha-secretase
• sAPPalpha (secreted APP alpha) released leaving C83 fragment in the membrane
• C83 is then digested by gamma-secretase
• Products are then removed

Question 5

What are the hypotheses for Alzheimer’s?

Answer 5

1. Amyloid hypothesis
2. Tau hypothesis
3. Inflammatory hypothesis

Question 6

How does amyloid processing happen in Alzheimer’s pathology?

Answer 6

1. APP cleaved by ß-secretase
2. sAPPß (secreted APP ß) released leaving the C99 fragment in the membrane
3. C99 is digested by gamma-secretase
4. Releases ß-amyloid protein (Aß)
5. Aß is a monomer that can form multimers
6. Multimers associate with other elements to form toxic ß-amyloid plaques

Question 7

What is the tau hypothesis in Alzheimer’s?

Answer 7

• Tau becomes hyper-phosphorylated
• Phosphorylated tau is insoluble and dissociates from microtubules
• This causes microtubule instability
• Phosphorylated Tau forms self-aggregates called neurofibrillary tangles
• These are neurotoxic

Question 8

What is tau protein in normal physiology?

Answer 8

• Soluble protein present in axons
• Very important for assembly and stability of microtubules
• Microtubules are very important for stability of axon and axonal transport

Question 9

What is the inflammatory hypothesis for Alzheimer’s?

Answer 9

1. Microglia are macrophage-like cells of the CNS
2. In Alzheimer’s they become dysfunctional:

• increased release of inflammatory mediators & cytotoxic proteins
• increased phagocytosis
• decreased levels of neuroprotective proteins

Question 10

What effect does taking ibuprofen have on Alzheimer’s?

Answer 10

Decreases likelihood of developing Alzheimer’s as the NSAI effect reduced the neurotoxic effects of microglial cells in Alzheimer’s

Question 11

What are the classes and names of drugs effective at treating Alzheimer’s?

Answer 11

1. Anticholinesterases

• Donepezil
• Rivastigmine
• Galantamine

1. NMDA receptor blockers
   * Memantine

Question 13

What are the feature of Donepezil treatment?

Answer 13

1. Gold standard for Alzheimer’s treatment
2. Only needs 1 tablet per day - long plasma half life
3. Treatment benefits only last for 1 year
4. Inhibitor of AChE

Question 15

What kind of drug is Rivastigmine?

Answer 15

‘Pseudo-reversible’ AChE and BChE inhibitor

Pseudo because it can’t be agreed whether it is reversible or not

Question 16

Why does rivastigmine have more side effects than donepezil?

Answer 16

Rivastigmine inhibits both isoforms of the cholinesterase enzyme

BChE is found primarily in the liver

Inhibiting this causes many nasty side effects

Question 17

What are the half lives of the Anticholinesterases used to treat Alzheimer’s?

Answer 17

1. Donepezil = 70 hours
2. Rivastigmine = 8 hours
3. Galantamine = 7-8 hours

Question 18

What is significant about the action of galantamine?

Answer 18

• Directly activates NEURONAL nicotinic ACh receptors (alpha 7 nAChR agonist)
• Doesn’t activate muscle type ACh receptors

Question 19

How is the NMDA receptor linked to Alzheimer’s?

Answer 19

• NMDA receptor is activated by glutamate
• It is activated excessively in neurodegenerative disorders like Alzheimer’s
• There is less GABA inhibition in neurodegeneration so more glutamate activity
• This, in turn, leads to more neurodegeneration because of increased NMDA activity - vicious cycle

Question 20

What is memantine?

Answer 20

• Use-dependent non-competitive NMDA receptor blocker with low channel affinity
• Only licensed for moderate-severe AD
• Long plasma half-life