Alzheimers

Question 1

what are the 3 hypotheses for the pathophysiology of Alzheimer’s

Answer 1

Tau hypothesis
Beta-amyloid hypothesis
inflammation hypothesis

Question 2

explain the tau hypothesis of Alzheimer’s

Answer 2

in normal people tau is soluble and required for assembly and stability of microtubules

if Tau is HYPERPHOSPHORYLATED–> it becomes insoluble and SELF AGGREGATES

These self aggregates form NEUROFIBRILLARY TANGLES

These are neurotoxic–> microtubule instability–> damage to neurones

Question 3

explain the Beta amyloid hypothesis of Alzheimer’s

Answer 3

in normal brains:

Amyloid precursor protein is broken down by ALPHA SECRETASE into sAPPalpha and C83 fragment

this C83 fragment is then digested by GAMMA SECRETASE to ALPHA AMYLOID which is removed

In pathophysiology APP is broken down by BETA SECRETASE and this gives C99 fragment instead

when the C99 fragment is digested by GAMMA SECRETASE it produces BETA AMYLOID–> toxic aggregates

Question 4

explain the inflammation hypothesis of Alzheimer’s

Answer 4

MICROGLIAL CELLS ARE OVERACTIVE (they are like CNS macrophages)—>

• Release of inflammatory mediators and cytotoxic proteins
• increased phagocytosis
• LESS neuroprotective proteins produced

Question 5

what are the 4 drugs given to treat Alzheimer’s + their MoAs

Answer 5

Cholinesterase inhibitors:

• Donepezil- reversible
• Rivastigmine- pseudo-reversible (+ BchE inhibitor–> liver effects) - given as transdermal patch
• Galantamine- reversible (+ nAChR agonist)

NMDR antagonist/blocker:

Memantine - USE DEPENDANT non comp inhibitor
this treats moderate to severe disease

Question 6

what are the possible treatments of Alzheimer’s (either failed approval or not finished yet)

Answer 6

GAMMA- SECRETASE INHIBITORS:
-failed clinical trials

BETA-AMYLOID:

• passive: anti Beta- Amyloid antibodies (eg Solazenumab)
• Active: vaccines- in development

TAU INHIBITORS:
-in clinical trials

Question 7

what are the main risk factors for Alzheimer’s

Answer 7

AGE

(genes contibute about 8%- APP, APEN, ApoE

Question 8

what are the symptoms of Alzheimers

Answer 8

short term memory loss 
disorientation/ confusion 
language problems- stops mid convo 
personality changes 
poor judgement eg with money