Alzheimer's Disease

Question 1

Describe the epidemiology of Alzheimer’s

Answer 1

Main risk factor – Age
Huge economic cost in the UK but low research investment
Nov 2016 – ONS announces AD and dementia are leading cause of death in UK
Genetics

Question 2

What is the genetic epidemiology of Alzheimer’s

Answer 2

APP, PSEN, ApoE (hereditary ~ 8%)

Question 3

What are the clinical symptoms of Alzheimer’s

Answer 3

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 4

Describe the physiological processing of amyloid

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

Question 5

Describe the pathophysiological processing of amyloid in alzheimer’s

Answer 5

1. APP cleaved by beta-secretase
2. sAPP-beta released - C99 fragment remains
3. C99 digested by gamma-secretase releasing beta-amyloid (A-beta) protein
4. A-beta forms toxic aggregates

Question 6

Describe the physiology of Tau

Answer 6

Soluble protein present in axons

Important for assembly and stability of microtubules

Question 7

Describe the pathophysiology of Tau in Alzheimer’s

Answer 7

Hyperphosphorylated tau is insoluble so it self-aggregates to form neurofibrillary tangles
These are neurotoxic (intracellular)
This also results in microtubule instability

Question 8

Describe the physiology of microglia

Answer 8

Specialised CNS immune cells

Question 9

Describe the pathophysiology of microglia in Alzheimers

Answer 9

Increased release of inflammatory mediators + cytotoxic proteins and phagocytosis
Decreased levels of neuroprotective proteins

Question 10

What are the 3 hypotheses for Alzheimer’s disease

Answer 10

Amyloid
Tau
Inflammatory (microglia)

Question 11

What are the current drugs used to treat Alzheimers

Answer 11

Anticholinesterases (donepezil, rivastigmine, galantamine)

NMDA receptor blockers (memantine)

Question 12

What drug class is Donepezil and describe its pharmacokinetics

Answer 12

Reversible cholinesterase inhibitor.

Long plasma half-life (administered once daily)

Question 13

What drug class is Rivastigmine and describe its pharmacokinetics

Answer 13

Pseudo-reversible AChE and BChE inhibitor
8 hour half-life
Reformulated as transdermal patch

Question 14

What drug class is Galantamine and describe its pharmacokinetics

Answer 14

Reversible cholinesterase inhibitor
7-8 hour half-life
alpha7 nAChR agonist

Question 15

What drug class is Memantine and describe its pharmacokinetics

Answer 15

Use-dependent non-competitive NMDA receptor blocker with low channel affinity
Only licensed for moderate-severe AD
Long plasma half-life

Question 16

Which potential treatments for alzheimers have failed in the past

Answer 16

gamma-secretase inhibitors
Beta-amyloid
Tau inhibitors

Question 17

What is Tarenflurbil + Semagacestat

Answer 17

gamma-secretase inhibitors
Failed Alzheimers treatment
Tarenflurbil binds to amyloid precursor protein (APP) molecule
Semagacestat is a small molecule gamma-secretase inhibitor

Question 18

What is beta-amyloid as an Alzheimers treatment

Answer 18

Bapineuzumab and Solanezumab
Humanised monoclonal antibodies
Aducanumab?
Vaccines also in early stages of development

Question 19

Give an example of a Tau inhibitor and state what it is licensed for

Answer 19

Methylene Blue

Licensed for the treatment of methaemoglobinaemia