Alzheimer's disease

Question 1

What factors contribute to the development of AD?

Answer 1

• Environmental factors (90% of cases)

- Mutations in genes (APP, PSEN, APoE) increase risk

Question 2

What are the clinical symptoms of Alzheimer’s disease?

Answer 2

• Memory loss***
• Language problems
• Personality changes
• Poor judgement
• Disorientation/confusion

Question 3

What is the main risk factor of Alzheimer’s disease?

Answer 3

Advancing age

Question 4

What drugs are used to treat Alzheimer’s disease?

Answer 4

1. Anticholinesterases

2. NMDA receptor antagonists

Question 5

What are the 3 main theories regarding the underlying pathophysiology of AD?

Answer 5

1. Amyloid hypothesis
2. Tau hypothesis
3. Inflammation hypothesis

Question 6

What is the amyloid hypothesis?

Answer 6

Normal physiological processing of the amyloid precursor protein involves:
1. Amyloid precursor protein (APP) cleaved by α-secretase
2. Soluble APPα released – C83 fragment remains
3. C83 digested by γ-secretase
End-products of this pathways are non-toxic and are removed

Pathophysiological processing:

1. APP cleaved by β-secretase
2. Soluble APPβ released – C99 fragment remains
3. C99 digested by γ-secretase releasing β-amyloid (Aβ) protein
   - Aβ = major constituent of amyloid plaques, which form toxic aggregates on neurons and microvasculature

Question 7

What is the tau hypothesis?

Answer 7

Normal physiology:

• Tau = protein associated w/microtubules in neurons
• Involved in stabilisation and assembly

Pathophysiological circumstances:

• Hyperphosphorylated tau is insoluble
• Tau self-aggregates to form neurotoxic intracellular neurofibrillary tangles
• Dissociation of tau from microtubules –> microtubule instability

Question 8

What is the inflammation hypothesis?

Answer 8

Inappropriate activation of inflammatory pathways in the brain is known to be involved in AD pathogenesis, but there is no consensus about exactly how inflamm pathways contribute to neurodegeneration

Microglia (specialised CNS immune cells) and astrocytes (facultative macrophages) become activated in AD resulting in:

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

Question 9

Compare the anticholinesterases used to treat AD

Answer 9

1. Donepezil - reversible cholinesterase inhibitor, long plasma half-life
2. Rivastigmine - pseudo-reversible AChE & BChE inhibitor, 8 hour half-life, reformulated as transdermal patch
3. Galantamine - reversible cholinesterase inhibitor, 7-8 hour half-life, α7 nAChR agonist

Question 10

When is memantine (NMDA receptor antagonist) used in AD?

Answer 10

Only in moderate to severe AD

Question 11

Discuss memantine (NMDA receptor blocker)

Answer 11

Use-dependent
Non-competitive
Low channel affinity
Long plasma half-life