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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.
APP
           PS1/PS2 FAD     +           +      APP FAD mutations
           mutations                          Trisomy 21
                          Ab42 aggregation
                   ?
Soluble forms                      ?                Amyloid
of oligomeric Ab                                    plaque

                         AGGREGATE STRESS


                          Tau dysfunction

                           PHF formation


                   Neuronal dysfunction and death



                               DEMENTIA
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’
Two key questions
1. 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?
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?
But the questions became
1. 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?
APP          N               GF     CuBD                  KPI                            Ab               C



                                                                             g-secretase
                     b-secretase
                                                                                                  GSM
                                                                         g      g    z     e
                     BI                                                                               GSI
                EISEVKMDAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIATVIVITLVMLKKKQYTS

FAD 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
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
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
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
Age of onset versus duration of disease
                           Effect of FAD mutations/ApoE4 genotype

Demented

                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
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*.
Hypothetical effect of an early therapeutic intervention
                                                                                        Ab
Tau         Small increase in Ablonger/shorter   Small decrease in Ablonger/shorter
            ratio caused by FAD mutation         ratio or amount of Ablonger            pathology
pathology
                                                 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
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.

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Ek slides for aa webinar 230911pdf

  • 1.
  • 2. 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.
  • 3. APP PS1/PS2 FAD + + APP FAD mutations mutations Trisomy 21 Ab42 aggregation ? Soluble forms ? Amyloid of oligomeric Ab plaque AGGREGATE STRESS Tau dysfunction PHF formation Neuronal dysfunction and death DEMENTIA
  • 4. 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’
  • 5. Two key questions 1. 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?
  • 6. 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?
  • 7. But the questions became 1. 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?
  • 8. APP N GF CuBD KPI Ab C g-secretase b-secretase GSM g g z e BI GSI EISEVKMDAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIATVIVITLVMLKKKQYTS FAD 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
  • 9. 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
  • 10. 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
  • 11. 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
  • 12. Age of onset versus duration of disease Effect of FAD mutations/ApoE4 genotype Demented 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
  • 13. 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*.
  • 14. Hypothetical effect of an early therapeutic intervention Ab Tau Small increase in Ablonger/shorter Small decrease in Ablonger/shorter ratio caused by FAD mutation ratio or amount of Ablonger pathology pathology 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
  • 15. 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.