28. ALZHEIMER'S

Question 1

identify the underlying pathology

Answer 1

Incorrect processing of APP = APP is normally cleaved by alpha-secretase but in Alzheimer’s it is cleaved by beta-secretase => forms sAPPb instead of sAPPa

this means a C99 fragment remains (rather than C83)

C99 is digested by gamma-secretase

Releasing beta-amyloid plaques

beta-amyloid forms toxic aggregates

ALSO

Tau hyperphosphorylation –> insoluble –> self aggregates –> neurofibrillary tangles + neurotoxic + –> neuronal instability

Tau proteins are normally soluble proteins in axons which are important in assembly and stability of microtubules

ALSO

Inappropriate activation of microglia (inflammation)
–> ^release of inflammatory mediators + cytotoxic proteins + phagocytosis + lower levels of neuroprotective proteins

Question 2

clinical symptoms

Answer 2

Memory loss
(esp. recently acquired info)

Disorientation/ confusion

Language problems
(stop mid convo)

Personality changes
(confused, fearful, anxious)

Poor judgement
(e.g. when dealing with £)

Question 3

risk factors

Answer 3

AGE

GENETICS
APP, PSEN, ApoE

Question 4

treatments

Answer 4

ANTICHOLINESTERASES 
- Donepezil
- Rivastigmine 
- Galantamine
NMDA RECEPTOR BLOCKER
- Memantine (moderate/ severe AD)

Question 5

Treatment Failures

Answer 5

gamma-secretase inhibitors

tau inhibitors