Alzheimer's Disease

Question 1

Alzheimer’s epidemiology

Answer 1

• main risk factor=age
• high economic burden in UK but low research investment
• Alzheimer’s and dementia=leading causes of death in UK
• Hereditary contribution to risk of developing Alzheimer’s disease (early onset)=8% (APP, PSEN, ApoE)

Question 2

Alzheimer’s clinical symptoms

Answer 2

• memory loss (eg: especially recently acquired information)
• disorientation/ confusion (eg: forgetting where they are)
• language problems (eg: stops mid-conversation)
• personality changes (eg: confused, fearful, anxious)
• poor judgement (eg: dealing with money)

Question 3

Amyloid hypothesis physiological processing

Answer 3

• amyloid precursor protein (APP) cleaved by alpha-secretase
• sAPPalpha released and the C83 fragment remains
• C83 digested by gamma-secretase
• products removed

Question 4

Amyloid hypothesis pathophysiological processing

Answer 4

• APP cleaved by beta-secretase
• sAPPbeta released and C99 fragment remains
• C99 digested by gamma-secretase releasing beta-amyloid protein
• beta-amyloid protein forms toxic aggregates (beta-amyloid plaques)

Question 5

Tau hypothesis physiology

Answer 5

• soluble protein present in axons

- important for assembly and stability of microtubules

Question 6

Tau hypothesis pathophysiology

Answer 6

-hyperphosphorylated tau is insoluble=self-aggregates to form neurofibrillary tangles (neurotoxic)=tangles result in microtubule instability and neurotoxic damage to neurones

Question 7

Inflammation hypothesis physiology

Answer 7

-microglia are specialised CNS immune cells (macrophage similarity)

Question 8

Inflammation hypothesis pathophysiology

Answer 8

• increased release of inflammatory mediators and cytotoxic proteins (increased microglial activity due to inappropriate activation)
• increased phagocytosis
• decreased neuroprotective protein levels

Question 9

Anticholinesterases (Alzheimer’s treatment)

Answer 9

1) Donepezil
- reversible cholinesterase inhibitor
- long plasma half-life
2) Rivastigmine
- pseudo-reversible anti-cholinesterase and butyl-cholinesterase inhibitor
- 8 hour half life
- reformulated as transdermal patch
3) Galantamine
- reversible cholinesterase inhibitor
- 7-8 hour half life
- additional alpha7 nAChR agonist properties

Question 10

NMDA receptor blocker (Alzheimer’s treatment)

Answer 10

1) Memantine
- use-dependent non-competitive NMDA receptor blocker with low channel affinity
- only licensed for moderate to severe Alzheimer’s disease
- long plasma half life

Question 11

Gamma-secretase inhibitors (failed clinical trials)

Answer 11

• Tarenflurbil=binds to amyloid precursor protein molecule

- Semagacestat=small molecule gamma-secretase inhibitor

Question 12

Beta-amyloid inhibitors (treatment failures)

Answer 12

• Bapineuzumab and solanezumab (passive)=humanised monoclonal antibodies
• vaccines (active)=early stages of development

Question 13

Tau inhibitors

Answer 13

-Methylene blue=methaemoglobinaemia treatment (in phase III clinical trials)