Alzheimer's disease

Question 1

Describe the epidemiology of alzheimer’s?

Answer 1

Main risk factor – Age
Genetics: (hereditary ~ 8%)
- APP (amyloid precursor gene), PSEN (Mutation leads to early onset alzheimer’s disease)
- ApoE (increased risk of late stage alzheimer’s disease)

Huge economic cost in the UK BUT low research investment
Nov 2016 – ONS announces AD and dementia are leading cause of death in UK

Question 2

What are the clinical symptoms of Alzheimer’s?

Answer 2

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

Due to degeneration of the higher functions of the brain.

Question 3

What is the beta amyloid hypothesis?

Answer 3

4 proteins you need to know: APP, alpha secretase, beta secretase and gamma secretase

Physiological processing: What happens normally

1) Amyloid precursor protein (APP) cleaved by a-secretase
2) sAPPalpha released - C83 fragment remains
3) C83 –> digested by gamma-secretase
4) Products removed

Pathophysiological processing:

1) APP cleaved by beta-secretase
2) sAPPbeta released - C99 fragment remains
3) C99 –> digested by gamma-secretase releasing beta-amyloid (A beta) protein
4) A-beta forms toxic aggregates = neuronal cell death

beta-secretase –> beta-amyloid plaques

Question 4

What is the tau hypothesis?

Answer 4

Tau proteins are associated with microtubules.

Physiology:

• Soluble protein present in axons
• Important for assembly and stability of microtubules

Pathophysiology:

• Hyperphosphorylated tau is insoluble –> self-aggregates to form neurofibrillary tangles
• These are neurotoxic
• This also results in microtubule instability

Hyperphosphorylated tau –> neuronal instability

Question 5

What is the inflammation hypothesis?

Answer 5

Physiology - Microglia
- Specialised CNS immune cells - similar to macrophages

Pathophysiology - Microglia

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

Increased activity of microglial cells

• increases inflammatory mediators
• increased phagocytosis
• decreased neuroprotection

Question 6

List some anticholinesterases?

Answer 6

1) Donepezil
2) Rivastigmine
3) Galantamine

Question 7

Describe donepezil?

Answer 7

• Reversible cholinesterase inhibitor.
• Long plasma half-life (70 hours); you can give one oral tablet per day. By decreasing the breakdown of acetylcholine it improves the symptoms of AD.

Question 8

Describe rivastigmine?

Answer 8

• Pseudo-reversible AChE and BChE (butyrylcholinesterase) inhibitor (Inhibits both forms of aceytlcholinesterase)
• 8 hour half-life
• Reformulated as transdermal patch

Question 9

Describe galantamine?

Answer 9

• Reversible cholinesterase inhibitor
• 7-8 hour half-life
• alpha 7 nAChR agonist (partial agonist of neuronal ACh receptors)

Question 10

Describe a NMDA receptor blocker

Answer 10

NMDA receptor is activated by glutamate

Memantine:

• Use-dependent non-competitive NMDA receptor blocker with low channel affinity. The more the NMDA receptor is activated (excessive activity) the better the effect of memantine
• Only licensed for moderate-severe AD (late stage AZs); when there is excessive neurone degeneration, low GABA activity, high glutamate activity
• Long plasma half-life