Alzheimer's

Question 1

Prevalence of Alzheimer’s

Answer 1

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.

Question 2

Symptoms of Alzheimer’s

Answer 2

• memory deficits
• Initiation deficits
• Visuo-spatial deficits
• Language deficits - word finding - comprehension - paraphasia
• Impaired judgment and executive functions - risk assessment
• Psychotic episodes

Question 3

Descent of Alzheimer’s

Answer 3

• Initially presents with loss of memory
• Depersonalization
• Textural blunting
• Loss of self

Question 4

Pathology of Alzheimer’s

Answer 4

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

Question 5

Effects of damage to the entorhinal cortex

Answer 5

Memory and speech defects

Question 6

Diagnostic hallmarks of Alzheimer’s cells

Answer 6

Neuritic plaques (NP) - extracellular - amyloid-β-protein
Neurofribrillary tangles (NFT) - intracellular - abnormal cytoskeletal protein Tau

Question 7

Cellular pathology of Alzheimer’s

Answer 7

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

Question 8

Amyloid Precursor Protein (APP)

Answer 8

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.

Question 9

Amyloid cascade hypothesis

Answer 9

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

Question 10

Beta amyloid plaques

Answer 10

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

Question 11

Abnormal APP processing

Answer 11

• 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

Question 12

Aβ40/42

Answer 12

Not normally produced
Excess γ-secretase makes more
May block LTP, which can impair memory mechanisms.

Question 13

Plaques and neuronal death

Answer 13

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.

Question 14

Metal Hypothesis

Answer 14

• 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).

Question 15

Cholinesterase inhibitors

Answer 15

Cholinergic neurons damaged early in AD
These enhance ACh at nicotinic and muscarinic receptors
Cause small improvements in cognition, not on progression

Question 16

Memantine

Answer 16

Non-competitive NMDA receptor blocker
Neuroprotective?
Slight improvements in cognition

Question 17

Drugs targeting the Alzheimer’s disease progression

Answer 17

• Secretase inhibitors - in trials
• Anti-amyloid-beta vaccine / monoclonal antibodies – in trials
• Anti-tau vaccine / monoclonal antibodies – in trials
• Copper and zinc chelators - metal ions promote plaque formation – toxic
• Growth factors - not feasible for routine therapy
• Antioxidants – limited evidence – eg. Vitamin C, flavinoids
• Statins – some epidemiological evidence

Question 18

How to diagnose early?

Answer 18

Biomarkers

Question 19

Gamma secretase inhibitors as Alzheimer’s treatment

Answer 19

Inhibitors of gamma secretase should have blocked Aβ aggregations
Clinical trials showed worsening of disease in AD patients
Failure

Question 20

Antibodies to Aβ as Alzheimer’s treatment

Answer 20

• Antibodies against Aβ reduce plaque load and cognitive decline by 20-40%
• Delivered through cannuala infusion
• “Believed” to act through recruitment of microglia
• Side-effects quite severe (brain hemoraging)
• Overall effects of these considered “minimal”