Alzheimer's Disease Flashcards

1
Q

What is the epidemiology of Alzheimer’s disease?

A

The main risk factor for Alzheimer’s disease (AD) is advancing age with prevalance increasing from around 2% for people below 75 to around 20% for people above 75.

Due to people living increasing long lives the prevalance of AD is increasing and it is a huge economic cost in the UK BUT low research investment.

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2
Q

What are the causes of Alzheimer’s disease?

A

The vast majority of AD cases are due to environmental factors (~90%) but individuals with mutations in certain genes (e.g. APP, PSEN, ApoE) are known to have an increased risk of developing AD.

APP - Amyloid Precursor protein (Affects Early onset)
PSEN - Presenilin (Affects Early onset)
ApoE - Apolipoprotein E (Affects Late onset)

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3
Q

What is the amyloid hypothesis of Alzheimer’s disease?

A

Normal physiological processing of amyloid precursor:
-Amyloid precursor protein (APP) cleaved by α-secretase
-sAPPα released – C83 fragment remains
-C83 digested by γ-secretase
(end-products non-toxic and removed)

Pathophysiological processing:
-APP cleaved by β-secretase
-sAPPβ released – C99 fragment remains
-C99 digested by γ-secretase releasing β-amyloid (Aβ) protein
Aβ major constituent of amyloid plaques, form toxic aggregates on neurons and the microvasculature.

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4
Q

What is the Tau hypothesis of Alzheimer’s disease?

A

In normal physiology, tau is a protein that is associated with microtubules in neurons and is involved in their stabilisation and assembly.

Under pathophysiological circumstances hyperphosphorylated tau is insoluble and self-aggregates to form intracellular neurofibrillary tangles which are neurotoxic.

Dissociation of of tau from microtubules also results in microtubule instability.

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5
Q

What is the inflammatory hypothesis of Alzheimer’s disease?

A

Inappropriate activation of inflammatory pathways in brain known to be involved in pathogenesis of AD. No consensus about how pathways contribute to neurodegeneration.

Microglia are specialised CNS immune cells and astrocytes are also facultative macrophages. There is eveidence that these cells become activated in AD resulting in:

increased release of inflammatory mediators and cytotoxic proteins
increased phagocytosis
reduced levels of neuroprotective proteins

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6
Q

What are the four licesenced drugs to treat AD in the UK? What do they treat?

A

Just treat the symptoms not the underlying pathology.
The main drug category act to increase levels of acetylcholine in the CNS.

Donepezil
Rivastigmine
Galantamine
Memantine

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7
Q

Describe the MOA of donepezil

A

Reversible cholinesterase inhibitor.
Long plasma half-life
Used in mild-moderate AD

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8
Q

Describe the MOA of Rivastigmine

A

Pseudo-reversible AChE and BChE inhibitor
8 hour half-life

Reformulated as transdermal patch -This is because oral administration has high side effects due to BChE inhibition (Majority of BChE in liver not CNS)

Used in mild-moderate AD

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9
Q

Describe the MOA of Galantamine

A

Reversible cholinesterase inhibitor
7-8 hour half-life
α7 nAChR agonist (No effect on muscle nAChR)
Used in mild-moderate AD

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10
Q

Describe the MOA of Memantine

A

NMDA receptor blocker - ONLY ONE OF THESE LISCENCED

Use-dependent non-competitive NMDA receptor blocker with low channel affinity

Only licensed for moderate-severe AD (NMDA receptor activity higher after neurodegeneration - Only effective late in disease)

Long plasma half-life

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11
Q

What were two significant treatment failures in AD drug production?

A

γ-secretase inhibitors
Tarenflurbil and Semagacestat are both γ-secretase inhibitors.
Tarenflurbil binds to the amyloid precursor protein (APP) molecule whilst semagacestat is a small molecule γ-secretase inhibitor.
Both failed in phase III clinical trials
(Semagacestat also caused Melanoma due to alterations to NOTCH signalling)

β-amyloid antibodies
Bapineuzumab and Solanezumab are humanised monoclonal antibodies

Tau Inhbitors
Methylene blue - Some success but companies don’t care because no money involved. Past Tau inhibitors have failed

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