Alzheimer's disease Flashcards
What is important to remember about the pathophysiology of Alzheimer’s
No absolute law- but many theories.
Summarise the epidemiology of Alzheimer’s disease
Main risk factor – Age
Huge economic cost in the UK BUT low research investment
Nov 2016 – ONS announces AD & dementia are leading cause of death in UK
Genetics - APP, PSEN, ApoE (hereditary ~ 8%)
Describe how age is a risk factor for Alzheimer’s disease
The main risk factor for Alzheimer’s disease (AD) is advancing age with prevalance increasing from around 2% for people below 75 to around 20% for people above 75.
Describe the economic effects of Alzheimer’s disease
Due to people living increasing long lives the prevalance of AD is increasing and it is a huge economic cost in the UK BUT low research investment.
High costs- due to burden of treatment and carers who take time off work
Low research investment- risky as many drugs have failed.
Describe the genetics associated with Alzheimer’s disease
The vast majority of AD cases are due to environmental factors (~90%) but individuals with mutations in certain genes (e.g. APP, PSEN, ApoE are known to have an increased risk of developing AD
APP= Amyloid precursor protein
PSEN- encodes for Presenillin protein
ApoE- Apolipoprotein E
Increase risk of early onset Alzheimer’s- different subset to that of elderly dementia.
Describe the clinical symptoms of Alzheimer’s
Memory loss – especially recently acquired information
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
Memory loss- most important- cardinal symptom
The other symptoms tend to vary between individuals.
Outline the physiological processing of amyloid precursor protein
Amyloid Precursor protein is membrane bound
Alpha-secretase and gamma-secretase are membrane bound enzymes.
Amyloid precursor protein (APP) cleaved by -secretase
sAPP released - C83 fragment remains
C83 digested by -secretase
Products removed
The end products of this pathway are non-toxic.
Outline the pathophysiological processing of APP thought to be involved in Alzheimer’s disease
APP cleaved by -secretase (at a different site to alpha-secretase)
sAPP released - C99 fragment remains (longer than CD83)
C99 digested by -secretase releasing -amyloid (A) protein
A forms toxic aggregates- monomer aggregates
Aβ is the major constituent of amyloid plaques, which form toxic aggregates on neurons and the microvasculature
Why is beta-amyloid thought to be involved in the pathophysiology of Alzheimer’s disease
Beta amyloid plaques are found in the autopsy of brains of patients who have died from Alzheimer’s disease
Beta amyloid plaques build up isnide the neurones or outside the neurones (mostly) and cause neuronal cell death (neurodegeneration) either by:
Triggering an immune response- inflammation kills neurones
Releasing toxins which kill the neurones directly.
What is the Tau protein
Soluble protein present in axons
Important for assembly & stability of microtubules
Microtubules needed in neurones for:
Stability, shape and integrity
Transport of proteins along the axon to pre-synpatic terminal.
Describe the role of Tau proteins in the pathophysiology of Alzheimer’s disease
Hyperphosphorylated tau is insoluble self-aggregates to form neurofibrillary tangles
These are neurotoxic
This also results in microtubule instability (less Tau available for microtubules) - tau dissociated from the microtubules.
Both of these are responsible for the neuronal cell death seen in Alzheimer’s
Are the Tau hypothesis and Amyloid hypothesis mutually exclusive
No, both can occur in the same patient
Often, tau precedes amyloid plaque build up
What are microglial cells
Specialised CNS immune cells - similar to macrophages
Involved in release of inflammatory mediators, neuroprotection and phaocytosis.
Summarise the inflammation hypothesis for the pathophysiology of Alzheimer’s disease
Inappropriate activation of inflammatory pathways in the brain is known to be involved in the pathogenesis of AD but there is no consensus about exactly how the inflammatory pathways contribute to neurodegeneration.
Microglia are specialised CNS immune cells and astrocytes are also facultative macrophages. There is eveidence that these cells become activated in AD resulting in:
increased release of inflammatory mediators & cytotoxic proteins
increased phagocytosis
reduced levels of neuroprotective proteins
In the inflammation hypothesis, what may activated the microglia
The Tau proteins and beta amyloid plaques
Or the individual just may be predisposed to having aberrantly activated microglia.
The inflammation process became relevant as retrospective studies have shown a reduced incidence of Alzheimer’s in patients who reguarly took NSAIDs- however NSAIDs can’t be given as treatment for patients once they get Alzheimer’s.
What is important to remember about the treatments available for Alzheimer’s disease
The drugs are not related to the pathophysiology seen.
Therefore, they treat the symptoms but not the underlying condition
Hence they tend to be beneficial for around 2 years, but soon will be overcome by the ongoing neurodegeneration.
Why may anticholinesterases be useful in treating alzheimer’s disease
Although changes in many transmitter systems have been observed, mainly from measurements on postmortem AD brain tissue, a relatively selective loss of cholinergic neurons in the basal forebrain nuclei (Ch. 40) is characteristic. This discovery, made in 1976, implied that pharmacological approaches to restoring cholinergic function might be feasible, leading to the use of cholinesterase inhibitors to treat AD (see later).
Choline acetyl transferase activity, acetylcholine content and acetylcholinesterase and choline transport in the cortex and hippocampus are all reduced considerably in AD but not in other disorders, such as depression or schizophrenia
What are the three anticholinesterases used in A.D
Donepezil (first line therapy)
Rivastigmine
Galantamine
These are used for mild-moderate A.D
Describe donepezil
Reversible cholinesterase inhibitor.
Long plasma half-life- important for A.D- only needs to be given orally once a day
Describe Rivastigmine
Pseudo-reversible AChE & BChE inhibitor
8 hour half-life
Reformulated as transdermal patch
transdermal patch- makes it selective for AChE found in the CNS- minimising side effects in the Liver.
Differentiate between AChE and BChE
AChE = acetylcholinesterase BChE= Butyrylcholinesterase
AChE- found primarily in CNS
BChE-found in liver (but small amount also found in the CNS)
Describe Galantamine
Reversible cholinesterase inhibitor 7-8 hour half-life alpha7 nAChR agonist - nicotinic receptors found in the CNS- beneficial- increase ACh available- reverses symptoms of A.D nAChR in CNS ( 5 alpha 7 subunits) nAChR in NMJ (3 Alpha, beta, gamma)
Where are Nicotinic receptors expressed
NMJ and CNS
What severity of A.D are NMDA receptor blockers used to treat
Moderate- Severe
Describe Memantine (NMDA receptor blocker)
Use-dependent non-competitive NMDA receptor blocker with low channel affinity
Only licensed for moderate-severe AD
Long plasma half-life
Use-dependent- more access to channel with greater activity of channel. Why only used in moderate-severe- more neurodegeneration hence more loss of inhibitory GABA neurones- greater excitotxicity of NMDA receptors
Non-competitive- binds to the NMDA receptor at a different site to glutamate.
its adverse effects include headache, dizziness, drowsiness, constipation, shortness of breath and hypertension as well as a raft of less common problems.
List some cholinergic side effects
Increased salivation and sweating, lacrimation, increased urinary incontinence, G.,I cramps, diahhroea, blurred vision
Describe how gamma-secretase failed
Targets both physiological and pathophysiological processing of APP
Tarenflurbil binds to amyloid precursor protein (APP) molecule - enantiomer of ibuprofen- failed in trials- not an NSAID but inhibits gamma secretase
Semagacestat is a small molecule -secretase inhibitor- inhibited the enzyme called notch, increasing the risk of skin cancer
Describe how drugs that targeted B-amyloid failed
Bapineuzumab & Solanezumab
Humanised monoclonal antibodies
Aducanumab?- targets B-amyloid plaques- but targets of fibrils and monomers slightly differently- may be licences in U.S soon
Vaccines also in early stages of development
Can get drugs which target B-secretase but they failed- not even named
Beta-amyloid a better target.
Describe how Tau inhibitors failed
Methylene blue
Licensed for the treatment of methaemoglobinaemia
Evidence of being effective at reducing Tau
But can make you blue, and no money in trialling it (already licenced).
Methylene blue is in phase III clinical trials
What is a consequence of these drugs not working
Questions whether our understanding of the pathophysiology (Amyloid hypothesis) is correct.
What may be more effective in terms of preventing and treating A.D than drugs
Diet and exercise.
