Alzheimer's disease

Question 1

What factors contribute to the development of AD?

Answer 1

Environmental factors (90% of cases)
Mutations in genes increase risk

Question 2

What are 5 clinical symptoms of Alzheimer’s disease?

Answer 2

Memory loss: esp. recently acquired info
Language problems: stopping mid-sentence
Personality changes: confusion, fear, anxiety
Poor judgement: e.g. when dealing with money
Disorientation/confusion

Question 3

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

Answer 3

Advancing age

Question 4

What classes of 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

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 = forms toxic aggregates on neurons + microvasculature

Question 7

What is the tau hypothesis?

Answer 7

Hyperphosphorylated tau is insoluble+ self-aggregates to form neurotoxic intracellular neurofibrillary tangles
Also results in dissociation of tau from microtubules + microtubule instability

Question 8

What is the inflammation hypothesis?

Answer 8

Microglia (specialised CNS immune cells) become activated in AD resulting in:
increased release of inflammatory mediators + cytotoxic proteins
increased phagocytosis
decreased levels of neuroprotective proteins

Question 9

Compare the anticholinesterases used to treat AD

Answer 9

Donepezil: reversible cholinesterase inhibitor, long plasma half-life
Rivastigmine: pseudo-reversible AChE + BChE inhibitor, 8 hour half-life, reformulated as transdermal patch to counteract BChE inhibition side effects
Galantamine: reversible cholinesterase inhibitor, 7-8 hour half-life, α7 nAChR agonist (increases ACh available)

Question 10

What type of drug is memantine? When is memantine used in AD?

Answer 10

NMDA receptor antagonist

Only in moderate to severe AD

Question 11

Describe memantine

Answer 11

Use-dependent non-competitive NMDA receptor blocker
Low channel affinity
Long plasma half-life

Question 12

What does normal physiological processing of the amyloid precursor protein involve?

Answer 12

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 + removed

Question 13

Describe the normal physiology of Tau

Answer 13

Tau = soluble protein associated w/microtubules in neurons

Involved in stabilisation + assembly

Question 14

What molecules/ processes have been unsuccessful targets in AD?

Answer 14

Gamma secretase inhibitors (target both pathophysiological + physiological)
Antibodies against B-amyloid plaques
Tau inhibitors (reduce aggregation)