Alzheimer's disease (04.03.2020)

Question 1

Epidemiology of AD (incl. RFs)

Answer 1

• Main risk factor – Age
• Huge economic cost in the UK BUT low research investment
• Nov 2016 – ONS announces AD & dementia are leading cause of death in UK
• Genetics - APP, PSEN, ApoE (hereditary ~ 8%) -> these increase the risk of getting early onset AD, not seen in the majority of patients so this is not the age related AD. (2 different types of AD - we are not sure what causes the late onset one)

Question 2

What are the symptoms of AD?

Answer 2

• Memory loss – especially recently acquired information

The following ones are may be present at different levels:

• 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 3

Name the theories that are established to explain the pathophysiology of AD

Answer 3

• Amyloid Hypothesis
• Tau Hypothesis
• Inflammation Hypothesis

=> there are 2 main hypotheses and many smaller ones.

Question 4

Physiological processing of APP

Answer 4

1. Amyloid precursor protein (APP) cleaved by alpha-secretase
2. sAPP alpha released - C83 fragment remains
3. C83 -> digested by gamma-secretase
4. Products removed

The three components (APP, alpha and gamma-sec) are found on the cell membrane in normal conditions (primarily in the CNS).

Question 5

Pathophysiological processing of APP

Answer 5

1. APP cleaved by beta-secretase (cleaves at a slightly different site)
2. sAPPbeta released - C99 fragment remains
3. C99 -> digested by gamma-secretase releasing beta-amyloid (A-beta) protein
4. A-beta forms toxic aggregates

-> not removed (congregate within or outside neurones and form clumps) primarily form outside the neurones

Question 6

Why would the beta-amyloid plaques cause AD?

Answer 6

Not known but the thought is that they cause neurodegeneraation in some way.

Ideas:

a) immune reaction -> inflammation which causes neuronal destruction -> neurodegenerative disorder
b) the plaques release toxic compounds themselves that are destroying the neurones.

Question 7

Physiology and pathophysiology of Tau proteins

Answer 7

Phys:

• Soluble protein present in axons
• Important for assembly, integrity & stability of microtubules

Pathophysiology:

• Hyperphosphorylated tau is insoluble -> self-aggregates to form neurofibrillary tangles (intracellular)
• These are neurotoxic
• This also results in microtubule instability (because of redistribution of tau from the microtubules to aggregates)

Question 8

Do the beta-amyloid and tau hypotheses exclude one another?

Answer 8

No, they could be occurring simultaneously.

Generally Tau first and then beta-amyloid.

Question 9

Inflammation hypothesis

Answer 9

Not mutually exclusive to amyloid or tau

Physiology - Microglia
- Specialised CNS immune cells - similar to macrophages

Pathophysiology - Microglia

• increase release of inflammatory mediators & cytotoxic proteins
• increase phagocytosis
• decreased levels of neuroprotective proteins

Why this theory?
people taking NSAIDs (e.g. Ibuprofen) for years have less incidence 0f AD; however giving people with AD ibuprofen does not help.

Question 10

Why do pharmaceutical companies not want to put too much money into AD drug research?

Answer 10

• there have been numerous fails.
• therefore high risk
• however AD is a big financial burden, both of the patients themselves as well as because of people having to stay eat home and help them.

Question 11

Pharmacology of AD

Answer 11

-> not relaxed to pathophysiology

• Anticholinesterases
• NMDA receptor blockers

Question 12

Anticholinesterases in AD

Answer 12

-> for mild and moderate AD

1. Donepezil
   - Reversible cholinesterase inhibitor.
   - Long plasma half-life (admin 1x/d)
2. Rivastigmine
   - Pseudo-reversible AChE & BChE inhibitor (the BChEi is bad and there are some SE; lessened as a td patch)
   - 8 hour half-life
   - Reformulated as transdermal patch
3. Galantamine
   - Reversible cholinesterase inhibitor
   - 7-8 hour half-life
   - alpha7 nAChR agonist (also acts as an agonist which has a beneficial effect)

=> the effects are almost immediate and these drugs are really good at reversing memory; however these effects only last for about 2 years.

Question 13

NMDA receptor

Answer 13

• N-methyl-D-aspartate receptor
• activated by ACh
• found at NMJ and in the brain (slightly different subtypes)
• prevents Glu binding to NMDA R

Question 14

What are the names of the 3 anticholinesterases used in AD?

Answer 14

Donepezil
Rivastigmine
Galantamine

Question 15

First line treatment for AD

Answer 15

Donepezil

also for severe AD

Question 16

NMDA receptor blockage in AD

Answer 16

Drug: Memantine

• Use-dependent non-competitive NMDA receptor blocker with low channel affinity (only works if there is excessive activity of the NMDAR which is quite common in neurodegeneration)
• Only licensed for moderate-severe AD
• Long plasma half-life

Question 17

Treatment failures in AD

Answer 17

1. gamma-secretase inhibitors
   - Tarenflurbil & Semagacestat
   - Tarenflurbil binds to amyloid precursor protein (APP) molecule (it is an enantiomer of flurbiprofen; it is not a NSAID; did not work in praactice)
   - Semagacestat is a small molecule gamma-secretase inhibitor (made people worse and increased the risk of skin cancer)
2. beta-amyloid
   - Bapineuzumab & Solanezumab
   - Humanised monoclonal antibodies
   - Aducanumab? (currently phase 3)
   - Vaccines also in early stages of development
3. Tau inhibitors
   - Methylene blue
   - Licensed for the treatment of methaemoglobinaemia
   - there is evidence that it is effective at reducing Tau
   - not running clinical trials because not much money in it
   - also: makes the skin blue

Question 18

LO1: Alzheimer’s disease: identify the underlying pathology, the clinical symptoms and risk factors

Answer 18

• beta- amyloid plaques due to incorrect processing of APP
• Tau hyperphophorylation leading to the formation of neurofibrillary tangles
• Inappropriate activation of microglia
• Main risk factor – Age
• Memory loss, disorientation/ confusion, language problems, personality changes, poor judgement

Question 19

LO2: Alzheimer’s medication: summarise and compare the mechanisms of action of drugs used to treat Alzheimer’s disease

Answer 19

• Donepezil is a cholinesterase inhibitor with a long duration of action
• Rivastigmine also inhibits BChE and is available in patch formulation Galantamine has additional nAChR agonist properties
• Memantine is a NMDA receptor antagonist licensed for moderate-severe AD

Question 20

Different cholinesterases

Answer 20

Acetylcholinesterase found primarily in the CNS

Butyrylcholinesterase is found e.g. in the liver, some in the CNS bit lower levels

Question 21

Targets in AAD treatment

Answer 21

• anticholinesterases
• NMDA R blockers
• gamma-secretase
• tau
• beta-amyloid