1. Resolving Controversies on the
Path to Alzheimer Therapeutics
Dennis J. Selkoe
Center for Neurologic Diseases
Brigham and Women’s Hospital
Harvard Medical School

2. β-amyloid deposits in normal people
Mostly diffuse, i.e., lacking fibrillar amyloid, microgliosis, dystrophic neurites
Soluble oligomer levels not quantified in such brains
Absence of subtle memory deficits before death not confirmed; indeed, PET+ Aβ
deposits seen in “normal elderly” often associated with subtle cognitive changes
All chronic diseases (CAD, cancer, etc.) show
substantial pathology prior to earliest symptoms

3. Amyloid as both a cause and an effect of AD
Systemic amyloidoses can occur as primary or secondary disorders
(e.g., transthyretin: mutant vs. wild-type)
Similarly, Aβ accumulation is a primary cause in pts. with APP or PS mutations;
in LOAD, it occurs secondary to other causes (e.g., ApoE4, BACE activity?)
Aging (time on the planet) may be a key pathogenic factor: time gradually
overcomes the energy barrier to the initial oligomerization of
the physiologically secreted Aβ monomer in long-lived primates

4. It’s not oligomers or plaques – it’s both
The now widely confirmed bioactivity of soluble oligomers (including from
AD cortex) does not mean that plaques play no role in the
progressive degeneration of neurons and their processes
Diffusible, oligomeric assemblies of Aβ immediately surround the plaques
and are intimately associated with local spine loss and neuritic dystrophy
Indeed, bioactive dimers and larger oligomers have been shown to be “trapped”
within AD plaque cores, suggesting that plaques serve as local reservoirs
of small oligomers that can diffuse away from them

5. Aβ receptors: an embarrassment of riches
Most studies implicating a specific receptor have used synthetic Aβ (high nM to low
uM) without defining its precise assembly state at the time of receptor binding
Exposed hydrophobic residues on an oligomer (ready to receive another monomer)
predict that they would bind far more avidly to lipid membranes than the
hydrophilic ectodomains of protein receptors
Initial binding of soluble oligomers in vivo probably involves lipids, but membrane
proteins may promote, stabilize or otherwise modulate oligomer-lipid interactions
Receptor(s) for soluble Aβ monomers should be distinct from those for
oligomers, given their quite different structures (Study Αβ40, not Aβ42!)

6. AD – the most common tauopathy
Tau expression appears necessary for Aβ oligomers to induce neuronal/neuritic
changes and behavioral deficits
Histopathology is inextricably linked with biochemistry: the subunit proteins of
the two classical lesions of AD play a decisive role in inducing dementia together
Therapeutics that down-regulate pathological features of tau (hyper-
phosphorylation, oligomerization, etc) should complement Aβ-lowering agents

7. Recent trial failures are not predicative of the future
-- Alzhemed had very weak POC trails and questionable MOA
-- R-flurbiprofen had a very poor IC50 and entered CNS poorly
-- Semagacestat had a Th. Index <3 (and thus had to be dosed q.d., not
b.i.d), so patients had Notch (and other substrate-based?) SAE’s
Most importantly, patients must be treated in the mild stage of AD
(e.g., MMSE of 21-27 -- plus high tau/low Aβ in CSF at entry), and
many patients must be tested.
Secondary prevention trials should be started soon, but they have
substantial logistical, regulatory and ethical challenges and high costs

8. Basic
research
to
iden.fy
Screen
for
agents
Assess
ADME
and
safety
and
characterize
a
(compounds,
biologics)
to
iden.fy
agent
with
op.mal
poten.al
pathogenic
that
can
up-­‐
or
down-­‐ Therapeu.c
Index
in
rodents,
step
(target)
regulate
the
target
then
larger
mammals
AD
Drug
Discovery
Discover
how
to
up-­‐
and
Confirm
that
potent
agents
engage
Only
advance
down-­‐regulate
the
target
the
target
in
mice
and
lessen
AD-­‐like
compounds
that
meet
biochemically
in
AD
mice
phenotypes
(neuropath,
all
above
preclinical
biochemistry,
behavior,
biomarkers)
criteria
to
INDs
Secondary
MCI
Mild
AD
Clinical
Trials:
Preven(on
Trials
Trials
Trials
Hypothe(cal
Rising
Aβ42
oligomers,
diffuse
&
fibrillar
Aβ
Time
Course
deposi.on
associated
Worsening
Aβ
and
tau
with:
microgliosis,
biochemistry
&
pathology
of
AD:
altered
tau,
PHF
with
more
neuronal
loss.
accumula.on,
subtle
Altered
CSF
biomarkers
Worsening
biochemical
Slowly
rising
neuri.c
dystrophy,
(falling
Aβ42,
changes
(including
tau)
As
in
prior
stage,
brain
Aβ42
levels
astrocytosis,
altered
ionic
then
rising
tau).
and
neuronal/neuri.c
Worsening
neuronal/ plus
and
early
Aβ42
homeostasis,
oxida.ve
Subtle
cogni.ve
deficits
glial
pathology.
neuri.c/glial
changes.
Increasing
oligomeriza.on
injury,
many
2o
detected
only
with
Mild
cogni.ve
Progressive
cogni.ve
behavioral
&
with
membrane
biochemical
changes
(but
challenging
tests.
symptoms,
signs.
deficits.
motor
signs.
associa.on.
limited
neuronal
loss).
LATE
PRESYMPTOMATIC
AD
MCI
MILD
AD
MOD
AD
~40
years
old
~50
~60
~70
~75
~80
40