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PT4024 > L4 Alzheimer's Disease > Flashcards

L4 Alzheimer's Disease Flashcards

1
Q

Hallmarks of AD pathology

A
  • early loss of cholinergic neurons
  • amyloid plaques (extracellular)
  • neurofibrillary tangles (intracellular)
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2
Q

All Alzheimer’s cases display signs of __

A

dementia

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3
Q

Early-onset inherited cases of AD are caused by incredibly rare mutations in which 3 genes?

A

PSEN1, PSEN2, APP

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4
Q

Having 2 copies of the __ gene makes you >8 times more likely to develop AD

A

APOE4

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5
Q

Risk variant in __ makes a person 3 times more likely to develop AD

A

TREM2

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6
Q

APOE4 gene carriers should consider…

A

dietary modifications to reduce lipid levels

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7
Q

Biggest risk factor for AD

A

Advanced age

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8
Q

What brain region does AD usually begin in?

A

Temporal lobe

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9
Q

Main neural networks that degenerate in AD

A
  • Cholinergic basal forebrain neurons
  • Glutamatergic neurons (medial temporal lobe)
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10
Q

Additional neural networks that degenerate in late-stage AD

A
  • Noradrenergic neurons
  • Serotonergic neurons
  • Dopaminergic neurons
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11
Q

Major component of amyloid plaques

A

An aggregated form of amyloid-β protein (Aβ)

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12
Q

What is the Amyloid Cascade Hypothesis?

A

Aβ accumulation is a starting point in disease pathogenesis

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13
Q

Evidence against the Amyloid Cascade Hypothesis

A
  • Cognitively normal elderly people with extensive amounts of amyloid plaques
  • Aβ vaccines that remove plaques from brain do not slow or halt cognitive decline in AD
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14
Q

What are neurofibrillary tangles?

A

Paired helical filaments (PHFs) of hyperphosphorylated tau protein

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15
Q

What does the presence of neurofibrillary tangles lead to?

A
  • Destabilisation of microtubules
  • Loss of dendritic & axonal transport ability
  • Damage to neuronal cytoskeleton → neurodegeneration
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16
Q

Approved clinical therapies for AD

A
  1. AChE inhibitors: Donepezil (Aricept), Rivastigmine (Exelon), Galantamine (Razadyne)
  2. NMDA receptor antagonist Memantine (Namenda)
  3. Amyloid vaccine: Aducanumab (Aduhelm)
17
Q

Disease-modifying therapy for AD

A

Aducanumab

18
Q

The first cholinesterase inhibitor (now rarely prescribed)

A

Tacrine (Cognex)

19
Q

Plasma half-life of Donepezil

A

70h

20
Q

Administration of Rivastigmine

A

Transdermal patch

21
Q

Rivastigmine MOA

A

Inhibits both AChE and butrylcholinesterase

22
Q

Plasma half-life of Rivastigmine

A

2h

23
Q

Galantamine MOA

A
  • Competitive and reversible inhibitor of AChE
  • Positive allosteric modulator of pre- and post-synaptic nACh receptors
24
Q

Memantine MOA

A
  • Weak NMDA receptor antagonist
  • Interacts with Mg²⁺ binding site
  • Spares normal NMDA receptor function
  • Used in combination with AChE inhibitors
  • Reduces excitotoxicity
25
Q

Plasma half-life of Memantine

A

60-80h

26
Q

Mild to severe side effects of cholinergic drugs (uncommon)

A
  • Cardiac: bradycardia, dysrhythmias, hypotension
  • GI: increased output of gastric acid, nausea, vomiting, abd cramps, diarrhoea
  • Excessive salivation
  • Bronchoconstriction
27
Q

Experimental drugs in AD treatment

A
  • Amyloid reducing therapies e.g. vaccine, B or 𝛾 secretase inhibitors
  • Tau reducing therapies e.g. kinase inhibitors, vaccine
  • Antioxidants (Vit E, melatonin)
  • Nicotinic receptor agonist
  • PPAR𝛾 agonist
28
Q

Example of a 𝛾-secretase inhibitor

A

Semagacestat (Eli Lilly)

29
Q

How do high cholesterol diets affect Aβ pathology in animals?

A

They increase Aβ pathology. Cholesterol has a direct effect on APP processing.

30
Q

What metal ions is Aβ aggregation partly dependent on?

A

Cu²⁺ and Zn²⁺

31
Q

What is Clioquinol?

A

An anti-fungal/protozoan/viral agent that chelates Cu²⁺/Zn²⁺ → anti-amyloidogenic

32
Q

Therapies that address __ may be most effective in treating AD

A

cellular aging

PT4024 (12 decks)

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