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Ek slides for aa webinar 230911pdf


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Ek slides for aa webinar 230911pdf

  1. 1. The amyloid cascade hypothesis• This has influenced much of AD research over the past twenty years• The hypothesis has led to several compounds being tested in phase 3 clinical trials.
  2. 2. APP PS1/PS2 FAD + + APP FAD mutations mutations Trisomy 21 Ab42 aggregation ?Soluble forms ? Amyloidof oligomeric Ab plaque AGGREGATE STRESS Tau dysfunction PHF formation Neuronal dysfunction and death DEMENTIA
  3. 3. Phase 3 Clinical trial failures for AD disease-modifying therapeutics• Tramiprosate – m.o.a. anti-aggregation inhibitor• Tarenflurbil – m.o.a. g-secretase modulator• Semagecestat – m.o.a. g-secretase ‘inhibitor’
  4. 4. Two key questions1. By how much should Ab production be lowered, or Ab clearance facilitated, to mediate a therapeutic disease-modifying effect (that can be detected in a phase 3 trial given current clinical assessment tools)?2. At what stage in the disease process would an amyloid-directed therapeutic approach be likely to show clinical efficacy?
  5. 5. More specifically….1. What is the minimum threshold reduction in Ab load required … and why?2. What patient population, at which stage in the disease process, would this minimum reduction show clinical efficacy?
  6. 6. But the questions became1. When and how does Ab play a role in AD?2. When and how might an Ab-directed therapeutic be shown to be efficacious?3. What constitutes a test of the amyloid cascade hypothesis?
  7. 7. APP N GF CuBD KPI Ab C g-secretase b-secretase GSM g g z e BI GSI EISEVKMDAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIATVIVITLVMLKKKQYTSFAD mutations NL R GK N TI AT L P Q VAMVI G F Ab37/38 Benign Effect of GSM - shift to smaller Ab39/40 Ab species Pathogenic Ab42/43 Effect of GSI – Effect of BI – Ab species reduced All Ab species but Ablonger/smaller reduced uniformly Cleavage point GSI = g-secretase inhibitor ratio increased GSM = g-secretase modulator BI = BACE inhibitor
  8. 8. Anti-Ab antibodies• Bapineuzumab – Binds to the N-terminus of Ab – Primary m.o.a. is binding to deposited Ab and mediating clearance• Solaneuzumab – Binds to the mid-domain of Ab – does not recognize deposited Ab – Primary m.o.a. is peripheral sink
  9. 9. A summary consensus of the literature• In Alzheimer’s disease, the regional distribution and amount of deposited Ab does not correlate well with the extent of tangle pathology, cell loss or dementia.• In preclinical experiments:- – genetic and pharmacological reduction in Ab production or facilitation of clearance does not reduce deposited Ab to below the t=0 point, but can prevent additional deposition. – Reduction in Ab production can markedly delay onset of Ab deposition
  10. 10. Effect of FAD mutations and ApoE genotype• Often commented that FAD mutations result in a more ‘aggressive’ disease process• Substantial and compelling data that the age of onset can be brought forward very significantly, but very little data that the duration of the disease is shortened thereafter• Effect seems to be in triggering, rather than driving the disease process
  11. 11. Age of onset versus duration of disease Effect of FAD mutations/ApoE4 genotypeDemented Familial Sporadic AD AD A=B C<D A B Normal 20 C 40 Age/Years 60 D 80 Age of Age of Death Death onset onset
  12. 12. Testing the amyloid cascade hypothesis – which scenario is ‘right’?Tau pathology Ab pathology Ab Ab Ab L3 trigger threshold driver O O P L3* L2 Arbitrary Ab trigger /threshold level O P P L2* L1 P P P L1* Ab therapeutic slows or halts AD progression P by lowering brain Ab from Lx to Lx*. 40 Years 60 80 Ab therapeutic does not affect AD O progression by lowering brain Ab from Lx to Lx*.
  13. 13. Hypothetical effect of an early therapeutic intervention AbTau Small increase in Ablonger/shorter Small decrease in Ablonger/shorter ratio caused by FAD mutation ratio or amount of Ablonger pathologypathology mediated by therapeutic. Familial Sporadic AD – AD AD onset delayed FAD mutation Ab therapeutic 0 40 60 80 100 120 Age/Years Clinical Clinical Clinical symptoms symptoms symptoms
  14. 14. Conclusion• The amyloid cascade hypothesis needs to be tested in the clinic.• How to test the hypothesis depends on your view of the role that Ab plays in the disease: trigger, threshold or driver?• It might be that treating early in the disease process with an Ab therapeutic is not ‘better’ but a prerequisite for demonstrating efficacy.