Alzheimer's Flashcards
What are the genetic components to Alzheimer’s?
APP: Mutations in the amyloid precursor protein results in early onset of Alzheimer’s disease.
PSEN: Mutations in presenilin gene increases likelihood of early onset Alzheimer’s disease.
ApoE (8%): Apolipoprotein E mutation increases likelihood of late onset Alzheimer’s.
What are the clinical symptoms of Alzheimer’s?
MEMORY LOSS: Especially recently acquired information, this is the most prominent symptom.
DISORIENTATION/CONFUSION: Forgetting where they are.
LANGUAGE PROBLEMS: Stopping in the middle of a conversation.
PERSONALITY CHANGES: Becoming confused, fearful, anxious.
POOR JUDGEMENT: Such as when dealing with money.
What is the normal physiology of the beta amyloid pathway hypothesis?
Amyloid precursor protein (APP) is cleaved by α-secretase. sAPPα is released, but the C83 fragment remains. C83 is then digested by γ-secretase, and the products removed.
What is the pathophysiology of the beta amyloid pathway hypothesis?
APP cleaved by β-secretase. sAPPβ released, but the C99 fragment remains. C99 is then digested by γ-secretase, releasing β-amyloid (Ab) protein. Ab forms toxic aggregates which leads to formation of β-amyloid plaques.
What is the normal physiology of the tau hypothesis?
TAU PROTEIN: Soluble protein present in neuronal axons – form the internal skeleton of neuronal cells. Tau protein is important for assembly and stability of microtubules.
What is the pathophysiology of the tau hypothesis?
Hyper-phosphorylated tau is insoluble self-aggregates to form neurofibrillary tangles. These are neurotoxic results in microtubule instability.
What is the normal physiology of the inflammation pathway hypothesis?
Microglia are specialised CNS immune cells - similar to macrophages.
What is the pathophysiology of the inflammation pathway hypothesis?
There is an inappropriate activation of microglial cells, increased release of inflammatory mediators and cytotoxic proteins and increased phagocytosis. There are decreased levels of neuroprotective proteins.
It is unknown what triggers this process. In Alzheimer’s, we see increased inflammation in the CNS, so maybe this is what is driving the neurodegeneration. People who take NSAIDs are less likely to develop Alzheimer’s.
Name the drugs used to treat Alzheimer’s
ANTICHOLINESTERASE
Donezepril
Rivastigmine
Galantamine
NMDA RECEPTOR BLOCKER
Memantine
What are the pharmacokinetics and pharmacodynamics of donezepril?
This is a reversible cholinesterase inhibitor. It has a long plasma half-life and so only needs to be administered once a day.
What are the pharmacokinetics and pharmacodynamics of rivastigmine?
This is a pseudo-reversible AChE/BChE inhibitor (inhibits acetylcholinesterase and butyrylcholinesterase). Inhibition of butyrylcholinesterase enzyme leads to liver problems.
It has a relatively short (8 hour) half-life and so needs to be administered 2-3 times a day. It has been reformulated as transdermal patch formulation.
What are the pharmacokinetics and pharmacodynamics of galantamine?
This is a reversible cholinesterase inhibitor. It has a half life of 7-8 hours. It is an α7 nAChR agonist (specific isoforms of the nicotinic ACh receptor (in the CNS)).
What are the pharmacokinetics and pharmacodynamics of memantine?
This is only licensed for moderate to severe Alzheimer’s disease. It is use-dependent non-competitive NMDA receptor blocker with low channel affinity. The more the NMDAr is activated, the more likely memantine is to have an inhibitory effect. It has a long plasma half-life.
Name classes and drug names of treatment failures
γ-secretase inhibitors – Tarenflurbil and Semagacestat
β-amyloid antibodies – Bapineuzumab and Solanezumab
Tau inhibitors – Methylene blue
What are the pharmacokinetics and pharmacodynamics of γ-secretase inhibitors?
Tarenflurbil (NSAID) binds to the amyloid precursor protein (APP) molecule.
Semagacestat is a small molecule γ-secretase inhibitor – however it increases morbidity. Semagacestat also causes skin cancer as it inhibits the NOTCH pathway.
Both of these failed clinical trials.
