Alzheimer's disease

Question 1

what is the main risk factor for Alzheimer’s?

Answer 1

age

Question 2

is there a genetic link to Alzheimer’s?

Answer 2

• genes include: APEN, APP –> genetic link to getting early onset Alzheimer’s (8%)
• ApoE –> genetic link to late onset Alzheimer’s (most common)

Question 3

what are the symptoms of Alzheimer’s?

Answer 3

• memory loss (short term)
• disorientation/confusion
• language problems
• personality changes
• poor judgement

Question 4

in the amyloid hypothesis, what is the normal physiology?

Answer 4

1. Amyloid precursor protein (APP) cleaved by alpha-secretase
2. sAPP alpha released and C83 fragment remains
3. C83 then digested by gamma-secretase
4. products then removed

Question 5

in the amyloid hypothesis, what is the pathophysiology?

Answer 5

1. APP cleaved by beta-secretase
2. sAPP beta released, leaving C99 fragment
3. C99 is digested by gamma-secretase releasing beta-amyloid protein
4. beta-amyloid protein forms toxic aggregates
5. toxic aggregated cause neurodegeneration

Question 6

what are tau proteins? what are they important for physiologically?

Answer 6

• tau protein is a soluble protein present in axons

- important for assembly and stability of microtubules

Question 7

what happens in pathophysiology?

Answer 7

• tau gets hyperphosphorylated
• hyperphosphorylated tau is insoluble –> self aggregates
• self aggregates from neurofibrillary tangles = neurotoxic
• tangles result ultimately in microtubule instability and neurotoxic damage to neurones

Question 8

what are microglia cells used for?

Answer 8

• specialised CNS immune cells

- like macrophages

Question 9

what is the pathophysiology in inflammation hypothesis?

Answer 9

1. inc release of inflammatory mediators and cytotoxic proteins
2. inc. phagocytosis
3. dec. levels of neuroproteins

Question 10

what are the main treatment drugs for AD?

Answer 10

4 drugs

• 3 acetylcholinesterases (Donepezil, Rivastigmine, Galantamine)
• NMDA (glutamate) receptor blocker (Memantine)

Question 11

what is important to remember with these drugs?

Answer 11

none of these drugs affect disease progession, just symptoms

Question 12

describe donepezil

Answer 12

• reversible cholinesterase inhibitor
• long plasma half life
• inc. levels of Ach
• effective in treating symptoms
• effects only last for around a year

Question 13

describe rivastigmine

Answer 13

• inhibits both isoforms
• pseudo-reversible AChE and BChE inhibitor
• 8hr half life
• transdermal patch

Question 14

describe galantamine

Answer 14

• reversible cholinesterase inhibitor
• half life = 7/8 hours
• can also activate neuronal nicotininc AChR (agonist effects)
  = alpha 7 nAChR agonist

Question 15

what is memantine?

Answer 15

• non competitive NMDA receptor blockade
• NMDA-R activated by glutamine
• only for late stage

Question 16

when is memantine most effective?

Answer 16

• more often this receptor is activated, more effective memantine is
• used best when excessive NMDA-R activity
• get this when there is excessive neurodegeneration

Question 17

what are the 3 treatment failures?

Answer 17

• gamma-secretase inhibitors
• beta-amyloid
• tau inhibitors