Alzheimer's Flashcards
Prevalence of Alzheimer’s
The most common neurodegenerative disease and the most common cause of dementia.
Likelihood increases with age. Those over 85 have a 47% chance to develop the disease.
Symptoms of Alzheimer’s
- memory deficits
- Initiation deficits
- Visuo-spatial deficits
- Language deficits - word finding - comprehension - paraphasia
- Impaired judgment and executive functions - risk assessment
- Psychotic episodes
Descent of Alzheimer’s
- Initially presents with loss of memory
- Depersonalization
- Textural blunting
- Loss of self
Pathology of Alzheimer’s
Early shrinkage in the temporal poles and the frontal cortex
Early damage to the entorhinal cortex
Progressive spread to the whole cortex and subcortical structures
Effects of damage to the entorhinal cortex
Memory and speech defects
Diagnostic hallmarks of Alzheimer’s cells
Neuritic plaques (NP) - extracellular - amyloid-β-protein
Neurofribrillary tangles (NFT) - intracellular - abnormal cytoskeletal protein Tau
Cellular pathology of Alzheimer’s
Primarily affect glutamate and acetylcholine neurones and terminals
Aberrant function - synapse loss - neuronal death - brain shrinkage
Deposition of phosphorylated tau in the form of paired helical filaments or tangles.
Metal hypothesis
Amyloid Precursor Protein (APP)
Concentrated in the synapses of neurons and has trophic (positive) effects.
Alpha or beta secretases cut the amyloid and break it down.
Alpha secretases cut the protein down in the typical way.
Amyloid cascade hypothesis
Beta secretase cuts APP at a different point and gamma secretase cuts that to for beta amyloid.
This can aggregate to form beta amyloid plaques which are usually taken away
Beta amyloid plaques
Mutations in gamma secretase increase the rate of formation of plaques.
These plaques are thought to drive the hyperphosphorylation of Tau which is thought to drive the neurodegeneration
Abnormal APP processing
- More beta secretase than alpha causes plaques, may be enhanced by environmental, disease, inflammation
- Genetic mutations identified in early onset AD (<65 years)
- In presenilin genes - excess β-secretase activity – make more Aβ42 which is MOST likely to form plaques
- Genetic risk factor in late onset
- ApoE4 mutations lead to increased aggregation
Aβ40/42
Not normally produced
Excess γ-secretase makes more
May block LTP, which can impair memory mechanisms.
Plaques and neuronal death
Peroxidation compromises the function of receptors and channels, which can cause the accumulation of Ca2+ and therefore cell death.
A cycle is created as excess Ca also increases Tau phosphorylation which is also increased by the plaques.
Metal Hypothesis
- AD is linked to a protein that occurs normally in the brain
- In each case the protein binds copper.
- In each case there is a suggestion that metals play some role in the cause (either iron or copper).
Cholinesterase inhibitors
Cholinergic neurons damaged early in AD
These enhance ACh at nicotinic and muscarinic receptors
Cause small improvements in cognition, not on progression
