Alzheimers Flashcards
What is Alzheimer’s disease
Alzheimer’s disease is a progressive neurodegenerative disorder and the most common cause of dementia, characterized by memory loss, cognitive decline, and behavioural changes due to the buildup of amyloid plaques and tau tangles in the brain
How is Alzheimer’s disease diagnosed
And what pathways are lost in AD
Cognitive testing
The cognitive domains that are affected indicate which regions of the brain ate affected which in turn indicates the type of dementia
In AD there is a loss of the cholinergic pathways
- Neurons that use Ach as their predominant neurotransmitter
Why do different tests have different scales and what is the downside of this
There are various congitive tests that can be used
○ Different scales are better at detecting different types/severities of cognitive impairments
○ Existence of different scales makes comparison across different studies difficult
What are some examples of cognitive tests and their clinical significance
Alzheimers Disease Assessment Scale - Cognitive Subscale (ADAS-Cog)
○ CS 4
Severe impairment battery test (SIB)
○ CS 7
Clinical Dementia Rating - Sum of Boxes (CDR-SB)
○ CS 1-2 over a year
Integrated Alzheimer’s disease rating scale
○ CS 5-point for mild cognitive impairment or CS 9-point diff. for mild dementia associated with AD
What is amyloid
Amyloid precursor protein (APP) exists in all of our brains
Single pass TM protein
What processes is amyloid precursor protein involved in (4)
cell growth
motility
neurite outgrowth
cell survival
what is APP fundamental for (2)
neuronal and synapse development and health
APP is the stick between the motor protein and the vesicle (which carries the growth factors and survival signals)
what are the 2 APP pathways called
Non-amyloidogenic
Amyloidogenic
Describe the non-amyloidogenic pathway
Alpha secretase cleaves APP -> soluble APP alpha
Gamma secretase cleavage -> P3 + ACID
Describe the amyloidogenic pathway and how does this lead to the formation of amyloid plaques
Beta secretase cleavage -> soluble APP beta
Gamma secretase cleavage -> same AICD + A beta (AB42)
AB42 monomers are released into the extracellular space and stick together to form small clusters (oligomers), which are toxic to neurons.
Over time, these oligomers aggregate further into fibrils and eventually form large, insoluble amyloid plaques that deposit in brain tissue, disrupting neural function
How are neurofibrillary tangles formed
Tau is a microtubule (MT) associated protein
Dynamically binds and stabilises the MT
Binding is dependent of phosphorylation status - dissociates when phosphorylated
This process becomes dysregulated so that Tau become hyperphosphorylated and forms neurofibrillary tangles (NFTs) and clumps together in AD
What is the amyloid cascade hypothesis
Accumulation of amyloid beta plaques (the causative agent in AD)
Accumulation of neurofibrillary tangles
Neuronal cell death
Cognitive impairment
What is the evidence against the amyloid cascade hypothesis (4)
Cognitively normal people develop amyloid plaques
The presence of amyloid plaques doesn’t correlate with cognitive decline over time much either (much better correlation with tau pathology)
Amyloid beta transgenic mice do not display neuronal death
○ Mice lifespan is 2 years so could just be the mouse doesn’t have the lifespan to see cell death
Amyloid and tau pathology spread through different parts of the brain
What are the new hypotheses other than the amyloid cascade hypothesis, explain how it works
Amyloid/tau/loss of synapses/loss of interneurons/the general chaos in the brain lead to an increase in glutamate concentration
Glutamate accumulates in AD -> binds NMDARs -> chronic Ca2+ leakage -> free radical production and cell death
What is the MoA of an NMDA receptor
At resting potential blocked by Mg2+
Voltage dependent release of Mg2+
Permeable to Ca2+
Need glutamate and glycine and depolarisation for the channel to open (unblock the Mg plug) and allow flow of ions
What are the potential drug targets in AD (4)
Amyloid
Tau
Loss of cholinergic neurons
Glutamate mediated excitotoxicity
What are the drugs that are used to treat the symptoms of Alzheimer’s disease (2)
Cholinesterase inhibitors
NMDAR inhibitor
What is the MoA of cholinesterase inhibitors and what are some examples
inhibits the enzymes that break down ACh (AChE) -> restores/boosts cholinergic signalling
Donepezil
Rivastigmine
Galantamine
What is the MoA of NMDAR inhibitors and what is an example
Dampen the effects of glutamate mediated excitotoxicity
Memantine
What is donepezil and how effective is it (clinical significance)
Reversible, long acting, selective inhibitor of AChE (neuronal)
Side effects due to increase Ach in the cholinergic neurons in the gut
Boosts cholinergic signalling in the brain
The mean difference (MD) between Donepezil and placebo is 2.33 (95% confidence interval: 1.77 to 2.88).
* Donepezil shows a statistically significant improvement in cognitive scores compared to placebo. However, for clinical significance, a 4-point change on the ADAS-cog scale is required
So therefore it is not deemed clinically significant
What is rivastigmine and how effective is it (clinical significance)
Pseudo-irreversible inhibitor for AChE and BChE
* Forms a covalent bond in the active site of the enzyme but it is very easily hydrolysed so will move off
Side effects due to increase Ach in the cholinergic neurons in the gut
The mean difference between rivastigmine and placebo is 2.23 (95% confidence interval: 0.15 to 4.30)
* Rivastigmine shows a statistically significant improvement in cognitive scores compared to placebo. However, for clinical significance, a 4-point change on the ADAS-cog scale is required
So therefore it is not deemed clinically significant
What is galantamine and how effective is it (clinical significance)
AChE inhibitor but it is also a positive allosteric modulator of the nicotinic receptor
* Boost signalling of the nicotinic receptor
* Binds to the nicotinic receptor and allows Ach to do its job better
The mean difference between galantamine and placebo is 2.17 (95% confidence interval: 1.33 to 3.00)
* Galantamine shows a statistically significant improvement in cognitive scores compared to placebo. However, for clinical significance, a 4-point change on the ADAS-cog scale is required
So therefore it is not deemed clinically significant
What is memantine (difference between a competitive, non-competitive and uncompetitive inhibitor) and how effective is it (clinical significance)
Weak uncompetitive NMDA receptor antagonist
Like “artificial magnesium” but doesn’t float away
Low affinity for the NMDA receptor
* Blocks tonic glutamate signalling
* Does not block the “phasic bursts associated with normal glutamate transmission
* Therefore, also does not block LTP
Competitive - would be competed out by glutamate therefore as [Glu] increases inhibition by drug decreases
Non-competitive - no change regardless of [Glu]
Uncompetitive - activity is contingent upon prior activation of the receptor. Increased [Glu] -> opening of channel -> drug can get in and inhibit
By itself and with an AChEI both were statistically significant but not clinically significant as it would need to be a 7 point increase on the SIB
What is the MoA of using monoclonal antibodies to remove plaques
Anti-amyloid antibodies target amyloid-beta plaques in Alzheimer’s disease.
They bind to amyloid-beta, helping the brain’s immune cells (microglia) clear plaques, prevent their formation, or break them down.
This reduces neurotoxicity and may slow cognitive decline
