Alzheimer's disease

Question 1

Name the theories of alzheimer’s pathophysiology

Answer 1

Beta amyloid
Tau protein
Inflammation

Question 2

Recall the normal physiological metabolism of APP

Answer 2

1. APP cleavage –> sAPP-alpha fragment and C83 (alpha secretase)
2. C83 –> non-toxic products to be excreted (gamma secretase)

Question 3

Recall the theorised pathophysiological metabolism of APP

Answer 3

1. APP cleavage –> sAPP-beta fragment and C99 (beta-secretase)
2. C99 –> beta-amyloid protein (gamma secretase)
3. Beta amyloid forms fibrils and then plaques which can attach to blood vessels

Question 4

What is tau protein?

Answer 4

soluble protein present in axons, that is integrated in microtubules to promote neuron assembly and stability

Question 5

Recall the tau protein theory of alzheimers pathophysiology

Answer 5

Hyperphosphorylation of tau makes it insoluble

Tau proteins autoaggregate to form neurotoxic neurofibrillary tangles leading to cell death and microtubule instability

Question 6

Recall the inflammatory theory of alzheimers pathophysiology

Answer 6

Inappropriate activation of microglia increases inflammatory mediators, cytotoxic proteins and phagocytosis + decreases neuroprotective protein expression

Question 7

Recall 5 clinical symptoms of Alzheimers disease

Answer 7

Memory loss
Language loss
Personality changes
Poor judgement
Disorientation and confusion

Question 8

Recall three genetic associations with alzheimers disease and which of these associate to early-onset and late-onset disease

Answer 8

Mutations in:
APP (EOD)
PSEN (EOD)
ApoE (LOD)

Question 9

Recall the 2 classes of drugs currently approved for use in Alzheimer’s

Answer 9

Anticholinesterases

NMDA receptor antagonists

Question 10

Recall 3 examples of anti-cholinesterases

Answer 10

Donepezil
Rivastigmine
Galantamine

Question 11

Name an example of an NMDA receptor antagonist

Answer 11

Memantine

Question 12

Differnetiate the indications for anticholinesterase vs NMDAr antagonist use in Alzheimer’s

Answer 12

Anticholinesterase = mild-moderate disease

NMDAR antagonist = severe disease

Question 13

Which of the anti-cholinesterase drugs is the gold standard and why?

Answer 13

Donepezil

Long half life

Question 14

Recall the general MOA of donepezil

Answer 14

Reversible cholinesterase inhibitor

Question 15

How does rivastigmine’s MOA differ from donepezil, and what is the consequence of this?

Answer 15

1. Is pseudo-reversible

2. Also antagonises butyrylcholinesterases as well as AChesterases, so has additional side effects

Question 16

Recall the MOA of galantamine, how this differs from doneprezil and the consequences of this

Answer 16

1. Reversibly inhibits ACh esterase

2. Also agonises the alpha 7 subunit of nAChRs –> decreased symptoms of Alzheimer’s

Question 17

Describe why memantine is only indicated in severe disease

Answer 17

It is use-dependent as neurodegeneration causes increased activation of NMDA receptors

Question 18

Recall 3 classes of drug that were “treatment failures” for Alzheimer’s

Answer 18

Beta amyloid antibodies
Tau protein inhibitors
Gamma secretase inhibitors

Question 19

Recall the MOA of the gamma secretase inhibitor tarenflubil and why it is not licensed for use

Answer 19

1. Binds APP to inhibit gamma-S
2. NSAID to combat inflammation
   Unfortunately it is ineffective

Question 20

Recall the MOA of the gamma secretase inhibitor semagacestat and why it is not licensed for use

Answer 20

Small molecule gamma-S inhibitor

Inhibition of NOTCH pathway lead to skin cancer

Question 21

What are bapineuzumab and solanezumab examples of?

Answer 21

Beta-amyloid antibody drugs

Question 22

Recall an example of a tau-inhibiting drug

Answer 22

Methylene blue

Question 23

Why has methylene blue not been pursued as an Alzheimer’s treatment?

Answer 23

It was pretty effective but since it is already licensed for treatment of methaeglobinaemia drug companies would not make a profit from it. It also turns you blue.