24. Alzheimer's disease

Question 1

What is the main risk factor for AD?

Answer 1

Age - increases exponentially above 65yrs

Question 2

Outline the genetic component to AD

Answer 2

APP - mutations in the amyloid precursor protein gene (increases early onset)
PSEN - mutations in presenilin gene (increases early onset)
ApoE - Apo Lipoprotein E mutation (increases late onset)

Question 3

What are the clinical symptoms of AD?

Answer 3

• Memory loss - especially recently acquired information
• Disorientation
• Language problems
• Personality changes - confused, anxious
• Poor judgement
• Higher function problems (frontal lobe degeneration)

Question 4

What is the beta amyloid hypothesis of AD?

Answer 4

• Incorrect APP (amyloid precursor protein) processing
• Suggests accumulation of beta amyloid plaques in the CNS
• Alpha-secretase, gamma-secretase and APP seen on neuronal cell membranes

Question 5

Describe the physiological processing of APP

Answer 5

• APP cleaved by α-secretase
• secreted APPα (sAPPα) released, but the C83 fragment remains
• C83 is digested by γ-secretase and the products are removed

Question 6

Describe the pathophysiological processing of APP

Answer 6

• APP cleaved by β-secretase
• sAPPα released, but C99 fragment remains, because it has been cut at a different point
• C99 digested by γ-secretase, releasing Aβ peptides
• Aβ forms toxic aggregates (polymers) => formation of beta-amyloid plaques
• Increase likelihood of neuronal cell death

Question 7

What is the Tau hypothesis of AD?

Answer 7

Physiology
• Tau protein - soluble protein present in neuronal axons
• Forms the internal skeleton of neuronal cells
• Allows transport of substances along the axon
• Important for assembly + stability of microtubules

Pathophysiology
• Hyper-phosphorylated Tau is insoluble
• Self-aggregates to form neurofibrillary tangles
• These are neurotoxic => microtubule instability => axon degeneration

Question 8

What types of AD treatments are used?

Answer 8

Anticholinesterases and NMDA receptor blockers

Question 9

Describe the different types of Anticholinesterases for the treatment of AD and their half-lives

Answer 9

Donepezil - Gold Standard
• Reversible cholinesterase inhibitor
• Long half life

Ribastigmine
• Pseudo-reversible Acetylcholinesterase and Butyrylcholinesterase inhibitor
• Relatively short half life
• Transdermal patch formulation

Galantamine
• Reversible cholinesterase inhibitor
• Agonist of specific isoforms of the nicotinic ACh receptor
• Relatively short half-life

Question 10

Where is Butyrylcholesterase (BChE) found?

Answer 10

In the liver

Question 11

How do Anticholinesterases help AD?

Answer 11

• Increase synpatic ACh
• Helps improve symptoms e.g. retrieve memories
• Improves quickly but only lasts around a year - early stage treatment

Question 12

Describe an example of an NMDA receptor blocker used in treating AD?

Answer 12

Memantine
• Moderate to severe AD
• Use-dependent non-competitive NMDA receptor blocker with low channel affinity
• More NMDAr activated => more likely that memantine will have an inhibitory effect
• Long plasma half-lie

Question 13

Which neurotransmitter activates the NMDA receptor and how is the relevant in AD?

Answer 13

• Glutamate (major excitatory NT in the CNS)

* Excessive NMDA receptor activation during neurodegeneration => reduced inhibition by GABA => more glutamate released

Question 14

Why are there not that many treatment options for AD?

Answer 14

Many treatment failures