Alzheimer's Disease

Question 1

what is the main risk factor of AD?

Answer 1

age

Question 2

what genetic contribution is there to AD?

Answer 2

APEN, APP, ApoE

8% contribution to risk in early onset

Question 3

what are the symptoms of AD?

Answer 3

o Memory loss – short-term.
o Disorientation/confusion.
o Language problems 
– stops mid-conversation.
o Personality changes
 – becoming confused, fearful, anxious.
o Poor judgement 
– e.g. with money.

Question 4

what are the 3 main hypotheses for explaining the pathophysiology for AD?

Answer 4

1) amyloid hypothesis
2) Tau hypothesis
3) inflammation hypothesis

Question 5

what occurs normally with amyloid?

Answer 5

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

Question 6

what are the main enzymes involved in normally physiological removal of amyloid precursor protein?

Answer 6

alpha and gamma secretase

Question 7

what is the pathophysiological process that occurs according to the amyloid hypothesis?

Answer 7

1. APP is cleaved by beta-secretase instead of alpha-secretase
2. sAPP-beta released instead of sAPP-alpha leaving the C99 fragment
3. C99 is digested by gamma-secretase releasing beta-amyloid protein.
4. beta-amyloid forms toxic aggregates in and around neurones

normally:
APP —> alpha secretase–> sAPPalpha released, C83 remains–> C83 digested by gamma secretase–> products removed

Question 8

what are the enzymes involved in pathophysiology in amyloid H0?

Answer 8

BETA-secretase and gamma- secretase

Question 9

what is Tau protein? what is its function normally?

Answer 9

Tau protein is a soluble protein present in axons.

Tau is important for assembly and stability of microtubules.

Question 10

how is Tau protein involved in the pathophysiology of AD according to the tau hypothesis?

Answer 10

1. Hyperphosphorylated tau is insoluble and therefore 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 11

what are the cells involved in the inflammatory hypothesis?

Answer 11

microglial cells (immune cells of the CNS like macrophages)

Question 12

what are microglial cells?

Answer 12

specialised CNS immune cells (like macrophages)

Question 13

how do microglial cells get involved in the pathophysiology of AD according to the inflammatory hypothesis?

Answer 13

1. Increased release of inflammatory mediators & cytotoxic proteins.
2. Increased phagocytosis.
3. Decreased levels of neuroprotective proteins.

Question 14

what system can be targeted in the treatment of AD? therefore which drugs are used?

Answer 14

NMDAs and cholinergic system

therefore use NDMA receptor blocker and anticholinesterases

Question 15

what are the anticholinesterases used in AD treatment?

why use anticholinesterases?

Answer 15

o Donepezil
o Galantamine
o Rivastigmine

enhanced ACh effect means communication between neurones is increased

Question 16

what is donepezil?

Answer 16

Reversible cholinesterase inhibitor.

Long plasma T1/2 therefore one dose daily

Question 17

what is rivastigmine?

Answer 17

Pseudo-reversible anti-cholinesterase (AChE)
& butyl-cholinesterase (BChE) inhibitor (not good–> accounts for the side effects)

T1/2 = 8 hours.
- Side effects can be counteracted by administration as a transdermal patch.

Question 18

what is galantamine?

Answer 18

Reversible cholinesterase inhibitor.
alpha 7 nAChR agonist also

T1/2 = 7-8 hours.

Question 19

why is galantamine also an agonist of nAChR?

Answer 19

AChR differ in different systems i.e. outside CNS due to different expression of receptor subunits therefore the drug can have an agonist effect on a different structured receptor

Question 20

what NMDA (glutamate) receptor blocker is used in the treatment of AD?

Answer 20

Memantine

used in moderate to severe AD

Question 21

what is memantine?

Answer 21

Use-dependant non-competitive NMDA receptor blocker with low channel affinity.

Long plasma T1/2.

Question 22

what is the effect of using anticholinesterases and NMDA receptor blockers?

Answer 22

there is a build up ACh (more available) which reduces the symptoms of AD

Question 23

what is the significance of using donezepil?

Answer 23

it has immediate effects on AD symptoms but does not treat the underlying disease

effects do not last long

Question 24

why is memantine use-dependent? how does this affect the disease level is can be used for?

Answer 24

memantine is most effective when there is high NMDA receptor activity which only occur in more severe neurodegeneration, hence its use in moderate to severe AD

Question 25

what are the failed/non-drugs in the attempted treatment of AD?

Answer 25

1. gamma-secretase inhibitors 
– failed clinical trials.
2. beta-amyloid humanised antibodies 
3.Tau inhibitors
 – in clinical trials.

Question 26

examples of gamma-secretase inhibitors

Answer 26

e. g. Tarenflurbil – binds to APP molecule.

e. g Semagacestat – SMI of the gamma-secretase molecule.

Question 27

what is the problem with using gamma-secretase inhibitors?

Answer 27

gamma-secretase is used in the normal physiologically removal of amyloid precursor protein

Semagacestat made people worse (Notch receptor–> skin cancer)

Question 28

examples of beta amyloid antibody drugs

Answer 28

1) Passive drugs:
- Bapineuzumab – antibody against beta amyloid protein.
- Solanezumab – antibody against beta amyloid protein.

2) Active drugs – in development:
- Vaccines

Question 29

example of tau inhibitor

Answer 29

Methylene blue (in phase 3) 
– currently treats methaemoglinanaemia