Alzheimer's disease

Question 1

What is the main risk factor for Alzheimer’s?

Answer 1

Age

Question 2

What did ONS announce in Nov 2016?

Answer 2

AD and dementia are leading cause of death in UK

Question 3

What genetics are linked to Alzheimer’s?

Answer 3

APP, PSEN, ApoE

Question 4

What are the symptoms of Alzheimer’s?

Answer 4

Memory loss- especially recently acquired info
Disorientation/confusion- Forgetting where they are
Language problems- Stopping in the middle of a conversation
Personality changes- Becoming confused, fearful and anxious
Poor judgement- such as when dealing with money

Question 5

What is the physiological processing of the amyloid hypothesis?

Answer 5

Amyloid precursor protein (APP) cleaved by alpha-secretase
sAPPalpha released- C83 fragment remains
C83 -> digested by gamma secretase
Products removed

Question 6

What is the pathophysiological processing of amyloid hypothesis?

Answer 6

APP cleaved by beta-secretase
sAPPbeta released- C99 fragment remains
C99 -> digested by gamma-secretase releasing beta-amyloid protein
Abeta forms toxic aggregates

Question 7

What is the physiology of Tau hypothesis?

Answer 7

Soluble protein present in axons and it is important for assembly and stability of microtubules

Question 8

What is the pathophysiology of Tau hypothesis?

Answer 8

Hyperphosphorylated tau is insoluble -> self-aggregates to form neurofibrillary tangles. These are neurotoxic. This also results in microtubule instability

Question 9

What are microglia?

Answer 9

Specialised CNS immune cells- similar to macrophages

Question 10

What is the pathophysiology of the inflammation hypothesis involving microglia?

Answer 10

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

Question 11

What anticholinesterases are used to treat Alzheimer’s disease?

Answer 11

Donepezil
Rivastigmine
Galantamine

Question 12

What is donepezil?

Answer 12

Reversible cholinesterase inhibitor with a long plasma half-life

Question 13

What is rivastigmine?

Answer 13

Pseudo-reversible AChE and BChE inhibitor.

8 hour half life. Reformed as transdermal patch

Question 14

What is galantamine?

Answer 14

Reversible cholinesterase inhibitor
7-8 hour half life
Alpha7 nAchR agonist

Question 15

What NMDA receptor blocker is used to treat Alzheimer’s?

Answer 15

Memantine

Question 16

What is memantine?

Answer 16

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

Question 17

What treatment failures are there for Alzheimer’s disease?

Answer 17

Gamma secretase inhibitors
B-amyloid
Tau inhibitors

Question 18

How did gamma-secretase inhibitors fail?

Answer 18

Tarenflurbil and Semagacestat- Tarenflurbil binds to the amyloid precursor protein (APP) molecule whilst semagacestat is a small molecule gamma-secretase inhibitor

Question 19

How did B-amyloid fail?

Answer 19

Bapineuzumab and Solanezumab- Humanised monoclonal antibodies
Adacanumab
Vaccines also in early stages of development

Question 20

How did Tau inhibitors fail?

Answer 20

Methylene blue- licensed for treatment of methaemoglobinaemia