Alzheimer's disease

Question 1

What factors contribute to the development of AD?

Answer 1

• Environmental factors (90% of cases) - Mutations in genes (APP, PSEN, APoE) increase risk

Question 2

What are the clinical symptoms of Alzheimer’s disease?

Answer 2

• Memory loss*** - Language problems - Personality changes - Poor judgement - Disorientation/confusion

Question 3

What is the main risk factor of Alzheimer’s disease?

Answer 3

Advancing age

Question 4

What drugs are used to treat Alzheimer’s disease?

Answer 4

1. Anticholinesterases 2. NMDA receptor antagonists

Question 5

What are the 3 main theories regarding the underlying pathophysiology of AD?

Answer 5

1. Amyloid hypothesis 2. Tau hypothesis 3. Inflammation hypothesis

Question 6

What is the amyloid hypothesis?

Answer 6

Normal physiological processing of the amyloid precursor protein involves: 1. Amyloid precursor protein (APP) cleaved by α-secretase 2. Soluble APPα released – C83 fragment remains 3. C83 digested by γ-secretase End-products of this pathways are non-toxic and are removed Pathophysiological processing: 1. APP cleaved by β-secretase 2. Soluble APPβ released – C99 fragment remains 3.C99 digested by γ-secretase releasing β-amyloid (Aβ) protein - Aβ = major constituent of amyloid plaques, which form toxic aggregates on neurons(axons) and microvasculature

enzymes and APP= present on membrane of cell body

Question 7

What is the tau hypothesis?

Answer 7

Normal physiology: - Tau =

• Soluble protein present in axons
• Important for assembly & stability of microtubules

Pathophysiological circumstances: - Hyperphosphorylated tau is insoluble - Tau self-aggregates to form neurotoxic intracellular neurofibrillary tangles

•This also results in microtubule instability

Question 8

What is the inflammation hypothesis?

Answer 8

Inappropriate activation of inflammatory pathways in the brain is known to be involved in AD pathogenesis, but there is no consensus about exactly how inflamm pathways contribute to neurodegeneration Microglia (specialised CNS immune cells) and astrocytes (facultative macrophages) become activated in AD resulting in:

• increased release of inflammatory mediators &cytotoxic proteins
• increased phagocytosis
• reduced levels of neuroprotective proteins

Question 9

Compare the anticholinesterases used to treat AD

Answer 9

1. Donepezil - reversible cholinesterase inhibitor, long plasma half-life 2. Rivastigmine - pseudo-reversible AChE & BChE(present in the liver therefore leading to more side effects than donepezil) inhibitor, 8 hour half-life, reformulated as transdermal patch 3. Galantamine - reversible cholinesterase inhibitor, 7-8 hour half-life, α7 nAChR agonist

Question 10

When is memantine (NMDA receptor antagonist) used in AD?

Answer 10

Only in moderate to severe AD

Question 11

Discuss memantine (NMDA receptor blocker)

Answer 11

Use-dependent Non-competitive Low channel affinity Long plasma half-life

Question 12

Are there any cures to alzheimers

Answer 12

No, the current treatment involve dealing with symptoms

Question 13

Discuss the treatment failures for alzheimers disease

Answer 13

1.g-secretase inhibitors

Tarenflurbil & Semagacestat

• Tarenflurbil binds to amyloid precursor protein (APP) molecule
• Semagacestat is a small molecule g-secretase inhibitor

2.b-amyloid

Bapineuzumab & Solanezumab

• Humanised monoclonal antibodies
• Aducanumab?

Vaccines also in early stages of development

•

3.Tau inhibitors

Methylene blue

•Licensed for the treatment of methaemoglobinaemia