Alzheimer's Disease

Question 1

Main RF for Alzheimer’s?

Answer 1

Age

Question 2

How much does genetics contribute to A.D?

Answer 2

8% of risk to developing A.D

• genes include - APEN, APP, ApoE

Question 3

Clinical symptoms associated with A.D?

Answer 3

Memory loss
• short-term

Disorientation/confusion

Language problems
• stop mid-conversation

Personality changes
• becoming confused, fearful, anxious

Poor judgement
• e.g. w. money

Question 4

What are the 3 hypotheses associated with A.D pathophysiology?

Answer 4

(1) Amyloid Hypothesis
(2) Tau Hypothesis
(3) Inflammation Hypothesis

Question 5

Explain the (1) Hypothesis of pathophysiology

Answer 5

(1) Amyloid Hypothesis

NORMAL:
1. Amyloid precursor protein (APP) cleaved by a-secretase

2. sAPPalpha released and the C83 fragment remains
3. C83 is then digested by gamma-secretase
4. Products are then removed

PATHOPHYSIOLOGY:
1. APP cleaved by BETA-secretase

2. sAPPBETA released leaving the C99 fragment
3. C99 is digested by gamma-secretase releasing BETA-amyloid (Abeta) protein
4. Abeta protein forms the toxic aggregates

Question 6

Explain the (2) Hypothesis regarding A.D pathophysiology

Answer 6

(2) Tau Hypothesis

 Tau protein is a soluble protein present in axons
 Tau is important for assembly and stability of microtubules

PATHOPHYSIOLOGY:
1. Hyperphosphorylated tau is insoluble –> self-aggregates

2. The self-aggregates form neurofibrillary tangles
   • These are neurotoxic
3. The tangles result ultimately in microtubule instability and neurotoxic damage to neurones

Question 7

Explain the (3) Hypothesis regarding A.D pathophysiology

Answer 7

(3) Inflammation Hypothesis

 Microglial cells are specialised CNS immune cells (like macrophages)

PATHOPHYSIOLOGY:
1. Increased release of inflammatory mediators & cytotoxic proteins

2. Increased phagocytosis
3. Decreased levels of neuroprotective proteins

Question 8

Outline the A.D treatments available

Answer 8

Anticholinesterases:

(1) Donepezil
(2) Rivastigmine
(3) Galantamine

NMDA receptor blocker:
(4) Memantine

Question 9

Explain how the ANTICHOLINESTERASES can be used to treat A.D

Answer 9

o Donepezil:
 Reversible cholinesterase inhibitor
 Long plasma T1/2

o Rivastigmine:
 Pseudo-reversible anti-cholinesterase (AChE) & butyl-cholinesterase (BChE) inhibitor
 T1/2 = 8 hours.
 Can be given as a transdermal patch

o Galantamine:
 Reversible cholinesterase inhibitor
 T1/2 = 7-8 hours
 alpha7 nAChR agonist

Question 10

Explain how NMDA RECEPTOR BLOCKERS can be used to treat A.D

Answer 10

NMDA (glutamate) R.blockers

o Memantine:
 Use-dependant non-competitive NMDA receptor blocker with low channel affinity
 Treats moderate-severe AD
 Long plasma T1/2

Question 11

Explain some FAILED or NON-CURRENT DRUG treatment for AD

Answer 11

1. gamma-secretase inhibitors – both failed clinical trials

• Tarenflurbil – binds to APP molecule
• Semagacestat – SMI of the gamma-secretase molecule

2. BETA-amyloid:

a. Passive drugs:
i. Bapineuzumab – antibody against Abeta-protein
ii. Solanezumab – antibody against Abeta-protein

b. Active drugs – in development:
i. Vaccines

3. Tau inhibitors – in clinical trials
   a. Methylene blue – currently treats methaemoglinanaemia.

(onenote!!)