L4 Alzheimer's Disease Flashcards
Hallmarks of AD pathology
- early loss of cholinergic neurons
- amyloid plaques (extracellular)
- neurofibrillary tangles (intracellular)
All Alzheimer’s cases display signs of __
dementia
Early-onset inherited cases of AD are caused by incredibly rare mutations in which 3 genes?
PSEN1, PSEN2, APP
Having 2 copies of the __ gene makes you >8 times more likely to develop AD
APOE4
Risk variant in __ makes a person 3 times more likely to develop AD
TREM2
APOE4 gene carriers should consider…
dietary modifications to reduce lipid levels
Biggest risk factor for AD
Advanced age
What brain region does AD usually begin in?
Temporal lobe
Main neural networks that degenerate in AD
- Cholinergic basal forebrain neurons
- Glutamatergic neurons (medial temporal lobe)
Additional neural networks that degenerate in late-stage AD
- Noradrenergic neurons
- Serotonergic neurons
- Dopaminergic neurons
Major component of amyloid plaques
An aggregated form of amyloid-β protein (Aβ)
What is the Amyloid Cascade Hypothesis?
Aβ accumulation is a starting point in disease pathogenesis
Evidence against the Amyloid Cascade Hypothesis
- 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
What are neurofibrillary tangles?
Paired helical filaments (PHFs) of hyperphosphorylated tau protein
What does the presence of neurofibrillary tangles lead to?
- Destabilisation of microtubules
- Loss of dendritic & axonal transport ability
- Damage to neuronal cytoskeleton → neurodegeneration
Approved clinical therapies for AD
- AChE inhibitors: Donepezil (Aricept), Rivastigmine (Exelon), Galantamine (Razadyne)
- NMDA receptor antagonist Memantine (Namenda)
- Amyloid vaccine: Aducanumab (Aduhelm)
Disease-modifying therapy for AD
Aducanumab
The first cholinesterase inhibitor (now rarely prescribed)
Tacrine (Cognex)
Plasma half-life of Donepezil
70h
Administration of Rivastigmine
Transdermal patch
Rivastigmine MOA
Inhibits both AChE and butrylcholinesterase
Plasma half-life of Rivastigmine
2h
Galantamine MOA
- Competitive and reversible inhibitor of AChE
- Positive allosteric modulator of pre- and post-synaptic nACh receptors
Memantine MOA
- Weak NMDA receptor antagonist
- Interacts with Mg²⁺ binding site
- Spares normal NMDA receptor function
- Used in combination with AChE inhibitors
- Reduces excitotoxicity
Plasma half-life of Memantine
60-80h
Mild to severe side effects of cholinergic drugs (uncommon)
- Cardiac: bradycardia, dysrhythmias, hypotension
- GI: increased output of gastric acid, nausea, vomiting, abd cramps, diarrhoea
- Excessive salivation
- Bronchoconstriction
Experimental drugs in AD treatment
- 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
Example of a 𝛾-secretase inhibitor
Semagacestat (Eli Lilly)
How do high cholesterol diets affect Aβ pathology in animals?
They increase Aβ pathology. Cholesterol has a direct effect on APP processing.
What metal ions is Aβ aggregation partly dependent on?
Cu²⁺ and Zn²⁺
What is Clioquinol?
An anti-fungal/protozoan/viral agent that chelates Cu²⁺/Zn²⁺ → anti-amyloidogenic
Therapies that address __ may be most effective in treating AD
cellular aging
