Alzheimer's disease Flashcards
What is the main risk factor for Alzheimer’s disease?
Age.
What is the leading cause of death in the UK?
Alzheimer’s disease and dementia (neurodegenerative).
Discuss the genetics of Alzheimer’s disease.
Amyloid precursor protein (APP)- mutations lead to early onset of Alzheimer’s disease.
Presenilin (PSEN) gene mutation increases likelihood of early onset Alzheimer’s disease.
Apolipoprotein E (ApoE) gene mutation increases the likelihood of late onset Alzheimer’s disease.
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.
According to the amyloid hypothesis, what happens in normal physiological processing?
On the cell membrane of a normal neuronal cell, there is gamma-secretase, amyloid precursor protein and alpha-secretase.
Amyloid precursor protein (APP) cleaved by alpha-secretase.
sAPP-alpha released- C83 fragment remains.
C83 → cleaved by gamma-secretase.
Products removed.
According to the amyloid hypothesis, what happens in pathophysiological processing to lead to Alzheimer’s disease?
Amyloid precursor protein (APP) cleaved by beta-secretase instead of alpha-secretase.
Smaller cut of APP, leaving smaller fragment within membrane.
sAPP-beta released- C99 fragment remains.
C99 → digested by gamma-secretase releasing beta-amyloid (A-beta) protein.
A-beta forms toxic aggregates- originally cleaved as a monomer but can subsequently form oligomers and fibrils, which accumulate into plaques.
Accumulation of beta-amyloid plaques within the brain- attached to neuronal cells and blood vessels.
Causes Alzheimer’s disease or vascular dementia due to incorrect processing of APP, plaque formation and neurodegeneration.
What is the tau protein in normal physiology?
Soluble protein present in axons, supported by microtubules.
Important for assembly and stability of microtubules.
What is the significance of the tau protein in the pathophysiology of Alzheimer’s disease?
Hyperphosphorylated tau is insoluble → self-aggregates to form neurofibrillary tangles and move away from the microtubule.
These are neurotoxic.
This also results in microtubule instability and degeneration, cell death as axons cannot support themselves.
Neurodegeneration.
What are microglia?
Specialised CNS immune cells, similar to macrophages.
According to the inflammation hypothesis, how are microglia involved in the pathophysiology of Alzheimer’s disease?
Increased release of inflammatory mediators and cytotoxic proteins from microglia.
Increased phagocytosis by microglia.
Decreased levels of neuroprotective proteins released from microglia.
What are the 4 drugs currently licensed in the UK for treatment of Alzheimer’s disease?
Anticholinesterases: donepezil, rivastigmine, galantamine.
NMDA receptor blocker: memantine- moderate/severe AD.
What is donepezil?
Reversible cholinesterase inhibitor used in the treatment of Alzheimer’s disease.
Long plasma half-life.
What is rivastigmine?
Pseudo-reversible AChE and BChE inhibitor used in the treatment of Alzheimer’s disease.
8 hour half-life.
Reformulated as transdermal patch.
What is galantamine?
Reversible cholinesterase inhibitor used in the treatment of Alzheimer’s disease.
7-8 hour half-life.
Alpha-7 nAChR agonist.
What is memantine?
Use-dependent non-competitive NMDA receptor blocker with low channel affinity.
Only licensed for moderate-severe AD.
Long plasma half-life.
