1. The amyloid cascade hypothesis proposes that amyloid-beta (Ab) aggregation drives Alzheimer's disease pathogenesis and has guided much research for 20 years. 2. Previous phase 3 clinical trials of drugs targeting Ab failed to show efficacy, questioning the hypothesis. 3. For an Ab-directed drug to demonstrate efficacy, it remains unclear what the minimum Ab reduction threshold must be and at what disease stage treatment would be most effective. Testing the amyloid cascade hypothesis in clinical trials continues to be challenging.

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.