Alzheimer's disease

Question 1

What is dementia?

Answer 1

• An irreversible, progressive brain disease that slowly destroys memory and cognitive skills
• Affects comprehension, calculation, learning, language, personality, mood and behaviour
• Does not affect consciousness

Question 2

What is the mean life expectancy following AD diagnosis?

Answer 2

7 years

Question 3

Why is the temporal lobe an important region in AD?

Answer 3

• It is involved in auditory perception and is home to the primary auditory cortex.
• It is also important in both speech and vision.
• The temporal lobe contains the hippocampus which plays a key role in the formation of long-term memory.

Question 4

What are some of the features of mild dementia/AD?

Answer 4

Memory loss, language problems, mood swings, personality changes

Question 5

What are some of the features of moderate dementia/AD?

Answer 5

Unable to learn/recall new info, long-term memory affected, wandering, agitation, aggression, require assistance with activities of daily living

Question 6

What are some of the features of severe dementia/AD?

Answer 6

Gait, incontinence, motor disturbances, bed ridden, unable to perform ADL, placement in long-term care needed

Question 7

How is AD diagnosed?

Answer 7

• Confident diagnosis can only be made by autopsy
• Diagnostic criteria designed to detect short term memory loss, difficulties with ADL and changes in personality
  
  • collateral history taking
  • physical exam
  • MSE
• Supported by neuroimaging

Question 8

What are some newer diagnostic techniques used to detect AD?

Answer 8

• PET - detects metabolically active cells/brain regions or cerebral blood flow
• CSF biomarkers - total Tau increases to about 300%, amyloid beta decreases to about 50% (increased plaque deposition)

Question 9

How can PET distinguish between AD and frontotemporal dementia (FTP)?

Answer 9

AD shows rear brain inactivity, FTD shows inactivity in the frontal part of the brain

Question 10

What are amyloid beta plaques?

Answer 10

Insoluble aggregates of amyloid beta proteins that form outside neurons

Question 11

What are neurofibrillary tangles?

Answer 11

Insoluble aggregates of hyper-phosphorylated Tau protein that form inside neurons

Question 12

What variant of the amyloid beta peptide is found more in cerebral plaques? AB42 or AB40?

Answer 12

AB42 - more hydrophobic, more prone to fibril formation and is the predominant isoform found in cerebral plaques

Question 13

What is the toxic form of AB peptide - soluble or insoluble aggregates?

Answer 13

• Fibrillar/aggregated forms of AB peptide but not soluble monomeric AB peptide are toxic to cells in culture and brain of rhesus monkeys
• Neurodegeneration appears prior to the appearance of plaques in mouse models of AD
• Plaques are found in people without dementia or brain injury

Question 14

Are the majority of AD cases sporadic or familial?

Answer 14

• Majority of cases are sporadic
• Hereditary forms of AD generally induce earlier onset of neurodegeneration

Question 15

What do most AD-related mutations cause?

Answer 15

Increased formation of amyloid plaques

Question 16

Why do people with Down’s syndrome have an increased likelihood of developing AD?

Answer 16

• The APP gene is located on chromosome 21
• There are three chromosome 21s and therefore 3 APP genes which leads to increased plaque formation

Question 17

What evidence is there to support AB as a cause for AD?

Answer 17

• Increased number of plaques in brains of AD patients
• Mutations in familial AD cause increased production of AB peptides
• AB plaques appear in Down Syndrome patients that carry an extra copy of the APP gene
• APOE4 allele increases the risk of sporadic AD
• Transgenic mice expressing mutant human APP genes develop plaques and neurodegeneration

Question 18

What makes amyloid beta toxic to cells?

Answer 18

• Induce production of reactive oxygen species (ROS), leading to cell damage and apoptosis
• May directly insert into cellular membranes and disrupt cellular integrity, act as a non-selective ion channel, or allow release of ROS
• May promote aggregation of tau to form neurofibrillary tangles

Question 19

What are the 2 major hypotheses for AD?

Answer 19

• BAPtists - Beta Amyloid Protein - accumulation of a fragment of APP (AB42) leads to the formation of plaques that sometimes kill neurons
• TAUists - abnormal phosphorylation of tau proteins makes them sticky, leading to the break up of microtubules. The resulting loss of axonal transport causes cell death

Question 20

How does tau cause neuronal death?

Answer 20

Disintegrates microtubules

Question 21

What makes tau toxic in AD?

Answer 21

Tau is normally found in axons but in AD aggregates and is redistributed to cell bodies and dendrites

Question 22

What happens to tau in AD?

Answer 22

It is hyperphosphorylated early in AD which impairs its ability to bind microtubules and promotes it’s aggregation, forming neurofibrillary tangles

Question 23

Describe the importance of tau pathology in AD

Answer 23

• NFTs show higher correlation with AD progression than plaques
• Familial AD is due to mutations in APP processing molecules and result in high levels of plaques and tangles, FTD has NFT but never plaques

Question 24

What is the current theory for the pathogenesis of AD?

Answer 24

• Multifactorial - involving several pathways
• Protein accumulation -> plaques and tangles
• Inflammation - unregulated activation of glia
• Lipid distribution - lipid membrane site of APP cleavage

Question 25

Describe the multifactorial threshold model

Answer 25

* Many common alleles with low penetrance, most people will have several risk alleles * Risk alleles are additive, plus there are many additive environmental factors * Genes + environment -\> liability * Once liability reaches a certain value i.e. a threshold, a disease process begins

Question 26

What is apolipoprotein E and where is it produced?

Answer 26

* An amino acid glycoprotein * Produced in high levels in the liver and brain * Synthesised by glia in the brain (mainly astrocytes)

Question 27

What does apolipolipoprotein E bind to?

Answer 27

Binds to soluble and aggregated amyloid beta

Question 28

What is the main function of ApoE?

Answer 28

Body's primary cholesterol transport protein

Question 29

Which ApoE allele triples the risk of developing AD?

Answer 29

Presence of ApoE4 allele triples the risk of developing AD and decreases onset by a decade

Question 30

What are some of the influences ApoE has on AD progression?

Answer 30

* Regulation of membrane cholesterol levels by ApoE influences amyloid beta production * ApoE influences AB clearance i.e. ApoE and low density lipoprotein related receptor (LRP) tranpsport AB peptide across the BBB

Question 31

What receptor mediates influx of amyloid beta across the BBB?

Answer 31

RAGE - receptor for advanced glycation end products

Question 32

What are the 2 main proteases involved in amyloid beta degradation?

Answer 32

* IDE and NEP * Presence of IDE or NEP decreases AB accumulation * Inactivating mutations of IDE and NEP have been detected in AD patients

Question 33

What happens to acetylcholinesterase activity in AD?

Answer 33

* One of the earliest changes in AD progression is loss of acetylcholinesterase activity in the cortex and hippocampus * This contributes substantially to the characteristic cognitive and non-cognitive symptoms

Question 34

How do acetylcholinesterase inhibitors work in treating AD?

Answer 34

They are designed to combat impairment of cholinergic neurons by slowing degradation of acetylcholine after its release at synapses

Question 35

How effective are AChE inhibitors in treating AD and what are some examples?

Answer 35

* Donepezil, rivastigmine, galantamine * All 3 drugs improve memory and thinking in around 50% of patients * AChE inhibitors delay neurodegeneration by ~6 months

Question 36

What is the role of glutamate in AD?

Answer 36

* Glutamate is the major excitatory neurotransmitter in the CNS. * Glutamate signalling is important for information storage, processing and retrieval in the cortex/hippocampus but high levels are neurotoxic

Question 37

How does excitotoxicity via glutamate occur?

Answer 37

* Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate. * This occurs when glutamate receptors e.g. NMDA receptor and AMPA receptor are overactivated. * Excitotoxins like NMDA and kainic acid which bind to these receptors, as well as pathologically high levels of glutamate can cause excitotoxicity by allowing high levels of Ca ions to enter the cell. * Ca inflex activates a number of enzymes which go on to damage cellular structures

Question 38

How does memantine work in treating AD?

Answer 38

Memantine is an NMDA receptor antagonist, therefore it blocks the excitotoxic effects of pathologically high levels of glutamate

Question 39

What are the 3 main opportunities for the treatment of AD?

Answer 39

1. Reducing amyloid beta production 2. Plaque build-up 3. Clearance

Question 40

What are some proposed methods for reducing amyloid beta production?

Answer 40

* Gamma-secretase - certain NSAIDs allosterically modulate gamma-secretase to favour production of AB40 over AB42 * Beta secretase - lacks other substrates and is therefore a safer target * Alpha-secretase - stimulating its activity could decrease AB since it cleaves within the peptide

Question 41

What drug has been shown to prevent amyloid beta aggregation?

Answer 41

Clioquinol, an antibiotic and Cu/Zn chelator

Question 42

What are some potential methods of increasing clearance amyloid beta?

Answer 42

* Immunotherapy for removal of amyloid beta plaques * The antibody aducanumab has been shown to reduce AB plaques in AD