AD II Flashcards
Discuss current and future treatments of AD
current treatment for AD (symptomatic)
Cholinesterase inhibitors (donepezil/rivastigmine/galantamine)
memantine
cognitive stimulation therapy/cognitive behavioural therapy
aromatherapy
dance/music
antidepressants
antipsychotics
pain relief
cholinesterase inhibitors
for mild AD
promote cholinergic neurotransmission(loss of cholinergic neurons in AD)
reduces ACh breakdown/cholinergic transmission/increases glutamatergic transmission/increase cognition
memantine
for moderate to severe AD
promotes glutamatergic neurotransmission since there is reduced glutamate uptake by glial cells causing excitotoxicity
reduces NMDAR activation and reduces glutamate excititoxicity
limitation of current treatments
do not slow or alter AD progression
only modest improvements in cognition ~50% individuals
3 therapeutic targets for AD pathology
1) AB - clearest initial causative pathway (19%)
2) Tau - correlates better with cognitive dysfunction than plaques (behind in development) (6%)
3) neuroinflammation (AB/tau plateau (behind in development/broad target) (6%)
amyloid therapies
immunotherapies (increase clearance) - rely on antibodies to treat disease (not neuroinflammation)
vaccine (active immunisation) - introduce peptides to stimulate antibody production to target protein by host immune system
direct antibodies (passive immunisation)
immunotherapy mode of action
1) neutralises target (prevents further binding) by forming antigen-antibody complex which reduces aggregation
2) bind/attract immune cells to degrade target - cause fc-mediated phagocytosis, target freely diffusing AB plaques for clearance by microglia
3) form antigen-antibody complex in blood that acts as a peripheral sink (prevent accumulation in the brain)
AB vaccine
AN1792
synthetic full length AB peptide
phase II stopped in 2002 due to 6% cases have brain inflammation
targetting AB production
y-secretase inhibition (semagacestat) - phase I/II reduced AB phase III worsens cognition/increase in skin cancer via Notch signalling
B-secretase inhibition (Verubecestat) phase II (90% AB reduction) phase II/III worsens anxiety/depression/sleep 2020- rapid atrophy in amyloid rich regions, impored verbal fluency only
Bapineuzumab (pfizer)
recognises the N-terminal AB peptide (not the full length)
Phase I - safe/well tolerated but new microhaemorrhages amyloid-related imaging abnormalities (ARIA) asymptomatic/mild confusion/headaches
phase II/III - halted after no effect in cogntion/function
Solanezumab (Eli Lilly)
recognises soluble monomeric AB peptide
phase I - reduced AB, no improvement in cognition
phase II - small improvement in cognition in mild AD
phase III - non significant trend in mild AD
2020 - increased CSF AB42 (clearance), no change in tau biomarkers
gantenerumab (Roche)
high affinity binding to a conformational epitope on AB fibrils, reduces AB42 to control by PET imaging
FDA - breakthrough therapy designation (failed to show improvements in cognitive decline) - insignificant results
though reduced tau biomarkers/synaptic loss/slowed increase in cognition compared to placebo
why do trials not work
timing of treatment - drugs given when AB already plateaued (overcome with early intervention/prevention trials/DIAN-TU)
poor design of trials and outcome measures are too strict (use more sensitive assessment 3 variations/adaptive trials designs)
Aducanumab (Aduhelm) (biogen)
monoclonal antibody to aggregated AB (oligomeric/fibrillary structures) derived from healthy aged donors
phase Ib/III - major reduction in AB in PET imaging and reduced cognitive decline
phase III (2019) - terminated, no sig improvement in cognition 33% ARIA and cerebral oedema, increase in APOE4 carriers
improved cognitive score and reduced tau pathology
first case of accelerated approval of disease modifying treatment for AD (2021) substantial evidence for effect on intermediate marker (AB removal)
limitation of aducanumab
ICER review claimed inadequate health benefit
rejected by european medicines agency/japan’s healthcare ministry
not covered by medical insurance in the US
phase III showed 33% ARIA (3% death)
biogen withdrew application for full market approval, undergoing phase IV trials (finish ~2026)
