Alzheimer's disease

Question 1

…

Answer 1

• The main risk factor for Alzheimer’s disease is age
• Huge economic cost in the UK BUT low research investment
• The ONS announced that Alzheimer’s disease and dementia are leading cause of death in UK

Question 2

What is Alzheimer’s?

Answer 2

The brain degenrates to the extent where you can no longer function, due to neurogeneration

Question 3

What are some genetic components involved in Alzheimer’s?

Answer 3

APP – mutations in the amyloid precursor protein -> early onset of Alzheimer’s disease

PSEN – mutations in presenilin gene -> increase likelihood of early onset Alzheimer’s disease

ApoE (8%) – Apo Lipoprotein E mutation -> increased likelihood of late onset Alzheimer’s

Question 4

What are the clinical symptoms of Alzheimer’s?

Answer 4

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

Question 5

What is the beta amyloid hypothesis of Alzheimer’s?

Answer 5

• This theory suggests that there is an accumulation of beta amyloid plaques within the brain/CNS

Question 6

What is the physiological process that normally occurs (amyloid precursor)?

Answer 6

1. Amyloid precursor protein (APP) is cleaved by a-secretase
2. sAPPa released, but the C83 fragment remains
3. C83 is then digested by g-secretase, and the products removed

Question 7

What is the pathological process that occurs in Alzheimer’s (amyloid precursor)?

Answer 7

1. APP cleaved by b-secretase
2. sAPPb released, but the C99 fragment remains
3. C99 is then digested by g-secretase, releasing b-amyloid (Ab) protein
4. Ab forms toxic aggregates -> formation of beta-amyloid plaques

Question 8

What is the Tau hypothesis for Alzheimer’s - what happens physiologically and what is pathological?

Answer 8

Physiology

• Tau protein: soluble protein present in neuronal axons -> form the internal skeleton of neuronal cells
• Tau protein is important for assembly & stability of microtubules

Pathophysiology

• Hyper-phosphorylated tau is insoluble -> self-aggregates to form neurofibrillary tangles
• These are neurotoxic -> results in microtubule instability

Question 9

What is the inflammation hypothesis for Alzheimer’s?

• Physiological and pathological

Answer 9

Physiology – Microglia
- Microglia are specialised CNS immune cells - similar to macrophages

Pathophysiology – Microglia

• Inappropriate activation of microglial cells
• Increased release of inflammatory mediators & cytotoxic proteins
• Increased phagocytosis
• Decreased levels of neuro-protective proteins

It is unknown what triggers this process. In Alzheimer’s, we see increased inflammation in the CNS, so maybe this is what is driving the neurodegeneration. People who take NSAIDs are less likely to develop Alzheimer’s.

Question 10

What are the 4 drugs licensed in the UK to treat Alzheimer’s?

Answer 10

• Anitcholinesterases: donepezil, rivastigmine and galantamine
• NMDA receptor blocker: memantine

Question 11

How does Donepezil work?

How often is it given and why?

Answer 11

Reversible cholinesterase inhibitor

Long plasma half-life – only needs to be administered once a day

Question 12

How does Rivastigmine work?
How often is it given and why?
How is it administered?

Answer 12

• Pseudo-reversible AChE/BChE inhibitor (inhibits acetylcholinesterase and butyrylcholinesterase)
• Inhibition of butyrylcholinesterase enzyme -> side effects (liver problems)
• 8 hour half-life (relatively short) – needs to be administered 2-3 times a day
• Reformulated as transdermal patch formulation

Question 13

How does Galantamine work?
Half life?
What is it an agonist of?

Answer 13

• Reversible cholinesterase inhibitor
• 7-8 hour half-life
• a7 nAChR agonist – agonist of specific isoforms of the nicotinic ACh receptor (in the CNS)

Question 14

How does Memantine work?
Half life?
When is the drug chosen?

Answer 14

• Only licensed for moderate to severe Alzheimer’s disease
• Use-dependent non-competitive NMDA receptor blocker with low channel affinity
• The more the NMDAr is activated, the more likely memantine is to have an inhibitory effect
• Long plasma half-life

Question 15

Give examples of drug treatments for Alzheimer’s that failed?

Answer 15

Beta amyloid antibodies: Bapineuzumab & Solanezumab

g-secretase inhibitors – Tarenflurbil & Semagacestat

Tau inhibitors – Methylene blue

Question 16

How were g-secretase inhibitors – Tarenflurbil & Semagacestat meant to work?

Why wasn’t semagacestat passed? (both failed though)

Answer 16

• Tarenflurbil (NSAID) binds to the amyloid precursor protein (APP) molecule
• Semagacestat is a small molecule g-secretase inhibitor – however it increases morbidity
• Caused skin cancer – inhibits the NOTCH pathway

Question 17

How did Bapineuzumab & Solanezumab work?

Answer 17

• These are humanised monoclonal antibodies – antibody for beta-amyloid proteins
• Bapineuzumab targets the oligomers of beta-amyloid
• Solanezumab: shown to have some effect, but even then, it has been shown to be ineffective
• Aducanumab – still in clinical trials and has shown some very positive effects (PASSIVE)
• Vaccines are also in early stages of development (ACTIVE)

Question 18

Tau inhibtors - methylene blue?

Answer 18

• Licensed for the treatment of methaemoglobinaemia

- It is in phase III clinical trials

Question 19

3 underlying pathological causes? of Alzheimer’s

Answer 19

b-Amyloid plaques due to incorrect processing of APP

Tau hyper-phosphorylation leading to the formation of neurofibrillary tangles

Inappropriate activation of microglia