25 - Alzheimer's Disease Flashcards
Outline the main risk factor for Alzheimer’s Disease
MAIN RISK FACTOR = AGE
Above the age of 65, the risk of Alzheimer’s increases almost exponentially
65-85 causes a quadrupling of risk of being diagnosed
What do these graphs show?
Alzheimer’s (Dementia) causes huge economic cost in the UK
- not due to the drugs
- more to do with carers and maintenance of Alzheimer’s patients
But, there is low research investment into the disease
What did ONS announce about AD and dementia in 2016?
In 2016, ONS announced that AD and dementia are the leading cause of death in the UK
What genetics are thought to be contributing factors to Alzheimer’s Disease development?
GENETICS
- APP - Amyloid Precursor Protein
- PSEN - Presenilin
More likely to lead to early onset Alzheimer’s Disease
- ApoE (hereditary - 8%)
More likely to lead to late stage Alzheimer’s Disease
But main risk factor for Alzheimer’s Disease is still age
What are the clinical symptoms of Alzheimer’s Disease?
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
Outline the Amyloid Hypothesis
PHYSIOLOGICAL PROCESSING - in normal brain
- Amyloid precursor protein (APP) cleaved by α-secretase
- sAPPα released
- C83 fragment remains
- C83 is digested by γ-secretase
- Products removed
PATHOPHYSIOLOGICAL PROCESSING
- Amyloid precursor protein (APP) cleaved by β-secretase
- C99 fragment remains
- C99 is digested by γ-secretase, releasing β-amyloid (Aβ) protein
- Aβ forms toxic aggregates
- These plaques form on the neuronal cells
- Lead to increased likelihood of neuronal cell death
Outline the Tau Hypothesis
PHYSIOLOGY - in healthy brain
- Tau protein is a soluble protein present in axons
- Important for assembly and stability of microtubules
PATHOPHYSIOLOGY
- Tau protein is hyperphosphorylated
- Hyperphosphorylated tau protein is insoluble
- Therefore, it self-aggregates to form neurofibrillary tangles
- The aggregates tend to be intracellular
- These are neurotoxic because they lead to microtubule instability and degeneration
- Leads to neuronal cell death
List the different hypotheses regarding Alzhemier’s Disease development
Amyloid Hypothesis
Tau Hypothesis
Inflammation Hypothesis
Outline the Inflammation Hypothesis
PHYSIOLOGY - MICROGLIA
- Specialised CNS immune cells - similar to macrophages
PATHOPHYSIOLOGY - MICROGLIA
- Change in phenotype of microglial cells due to alzheimer’s progression
- Increased release of inflammatory mediators and cytotoxic proteins
- Increased phagocytosis
- Decreased levels of neuroprotective proteins
State the two forms of drugs used in Alzheimer’s Disease treatment
Anticholinesterases
NMDA Receptor Blockers
How can anticholinesterases be used as therapy for Alzheimer’s?
DONEPEZIL - gold standard for AD
- Reversible cholinesterase inhibitor
- Long plasma half-life (one tablet per day)
RIVASTIGMINE
- Pseudo-reversible AChE and BChE inhibitor
- 8 hour half-life
- Reformulated as transdermal patch
- Inhibits both isoforms of the cholinesterase enzyme (acetylcholinesterase - CNS, butylcholinesterase - CNS but mainly in liver)
- Inhibiting butylcholinesterase causes more side effects
GALANTAMINE
- Reversible cholinesterase inhibitor
- 7-8 hour half-life
- Only available orally
- α7 nAChR agonist
- Doesn’t only prevent ACh breakdown, but also partially agonises the nAChR
INCREASING THE AMOUNT OF SYNAPTIC ACh HAS BEEN SHOWN TO BE EFFECTIVE IN TREATMENT OF AD SYMPTOMS.
BENEFITS ONLY LAST FOR ABOUT A YEAR.
ACTS ON NEURONAL ACh RECEPTORS
USED FOR EARLY STAGE AD MAINLY
NOT DISEASE-MODIFYING, JUST SYMPTOMATIC TREATMENT
How can NMDA Receptor Blockers be used as therapy for Alzheimer’s?
MEMANTINE
- Use-dependent, non-competitive NMDA receptor blocker with low channel affinity
- More often the NMDA is being activated, the more effective this drug is
- Get excessive NMDA activity during neurodegeneration, less GABA activity and more glutamate activity
- Only licensed for moderate-severe Alzheimer’s (late-stage) as there is a lot of neurodegeneration at this point
- Long plasma half-life
NOT DISEASE-MODIFYING, JUST SYMPTOMATIC TREATMENT
What drugs have been treatment failures for Alzheimer’s Disease?
1. γ-SECRETASE INHIBITORS
Tarenflurbil & Semangacestat
- Tarenflurbil binds to amyloid precursor protein (APP) molecule
- Semagacestat is a small molecule γ-secretase inhibitor
- Lead to increased risk of skin cancer by activating the notch pathway
2. β-AMYLOID
Bapineuzumab & Solanezumab
- Humanised monoclonal antibodies
- Aducanumab? - phase 1 clinical trials currently
- Vaccines against B-amyloid also in early stages of development
3. TAU INHIBITORS
Methylene Blue
- Licensed for the treatment of methaemoglobinaemia
- Might be effective in AD but not interesting for big pharma currently
AS MOST DRUG TRIALS FOR AD HAVE BEEN UNSUCCESSFUL, THERE IS LESS ECONOMIC INVESTMENT IN AD
Analyse the effects of drugs A and B compared to placebo
DRUG A - Solanezumab (beta-amyloid antibody but no effect on AD symptoms)
DRUG B - Methoprizil
Asterisks denote a significant difference compared to placebo
What is confusing about the treatments used for Alzheimer’s Disease?
The pharmacology is not based on or related to the pathophysiology of the disease
