Alzheimer's Disease Flashcards
Hallmarks of AD pathology
- early loss of cholinergic neurons
- amyloid plaques (extracellular)
- neurofibrillary tangles (intracellular)
Early-onset inherited cases of AD are caused by incredibly rare mutations in which 3 genes?
PSEN1, PSEN2, APP
AD is the leading form of…
Dementias
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
“The Nun study”
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, abdominal 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
