2. !
CONTENTS
Executive
Summary
................................................................................................................
5
Overview
................................................................................................................................
6
Imperative
to
Advance
Alzheimer’s
Research
...................................................................................................
6
Population
Burden
...............................................................................................................................................
6
Economic
Burden
.................................................................................................................................................
7
AD
Awareness
Falls
Behind
Compared
to
Other
Diseases
.................................................................................
8
Public
Policies
Adressing
AD
Unmet
Needs
..............................................................................
9
National
Alzheimer's
Project
Act
......................................................................................................................
9
Alzheimer’s
Accountability
Act
.......................................................................................................................
10
Risk,
Diagnosis,
and
Progression
...........................................................................................
11
Risk
Factors
....................................................................................................................................................
11
Three
Stages
of
Alzheimer’s
disease
...............................................................................................................
11
Preclinical
AD
.....................................................................................................................................................
12
Mild
Cognitive
Impairment
Due
to
AD
...............................................................................................................
12
Dementia
Due
to
AD
..........................................................................................................................................
12
Measuring
Cognitive
Impairment
for
Diagnosis
..............................................................................................
13
Disease
Biology
....................................................................................................................
14
Beta
Amyloid
Protein
Build-‐Up
in
the
Brain
Leads
to
Plaques
.........................................................................
14
Tau
Protein
Build-‐Up
in
the
Brain
Leads
to
Tangles
........................................................................................
15
Neurotransmitter
Dysfunction
.......................................................................................................................
16
Treatments
...........................................................................................................................
17
Clinical
Trials
and
Investigational
Therapies
.........................................................................
18
Clinical
Trials
-‐
Overview
................................................................................................................................
18
Investigational
Therapies
...............................................................................................................................
18
3. !
Amyloid-‐Targeting
Therapies
.............................................................................................................................
19
Tau-‐Targeting
Therapies
....................................................................................................................................
19
Neurotransmitter
Targeting
Therapies
..............................................................................................................
20
Immunotherapy
.................................................................................................................................................
21
Stem
Cells
...........................................................................................................................................................
22
Nutraceuticals
....................................................................................................................................................
22
Challenges
Impeding
AD
Research
and
Key
Philanthropic
Opportunities
...............................
24
Lack
of
Reliable
Biomarkers
...........................................................................................................................
24
The
Problem
.......................................................................................................................................................
24
Potential
Solutions
.............................................................................................................................................
24
Examples
of
Corresponding
Philanthropic
Opportunities
..................................................................................
25
Inadequate
Preclinical
Models
.......................................................................................................................
25
The
Problem
.......................................................................................................................................................
25
Potential
Solutions
.............................................................................................................................................
25
Examples
of
Corresponding
Philanthropic
Opportunities
..................................................................................
25
Identifying
New
Druggable
Molecular
Targets
................................................................................................
26
The
Problem
.......................................................................................................................................................
26
Potential
Solutions
.............................................................................................................................................
26
Examples
of
Corresponding
Philanthropic
Opportunities
..................................................................................
26
AD
Research
Is
Conducted
in
Silos
..................................................................................................................
26
The
Problem
.......................................................................................................................................................
26
Potential
Solutions
.............................................................................................................................................
27
Examples
of
Corresponding
Philanthropic
Opportunities
..................................................................................
27
Key
Stakeholders
in
the
Alzheimer’s
Community
...................................................................
28
Research
Grantmaking
Organizations
.............................................................................................................
28
Alzheimer’s
Association
.....................................................................................................................................
28
4. !
Alzheimer’s
Drug
Discovery
Foundation
............................................................................................................
29
BrightFocus
Foundation
.....................................................................................................................................
29
Cure
Alzheimer’s
Fund
.......................................................................................................................................
29
New
York
Stem
Cell
Foundation
.........................................................................................................................
29
Key
Initiatives
and
Strategic
Partnerships
.......................................................................................................
30
Alzheimer’s
Disease
International
......................................................................................................................
30
Dementia
Discovery
Fund
..................................................................................................................................
30
Global
Alzheimer’s
and
Dementia
Action
Alliance
.............................................................................................
30
Global
CEO
Initiative
on
Alzheimer’s
..................................................................................................................
30
US
Against
Alzheimer’s
.......................................................................................................................................
31
World
Dementia
Council
....................................................................................................................................
31
Academic
Consortia
.......................................................................................................................................
31
Alzheimer’s
Disease
Neuroimaging
Initiative
.....................................................................................................
31
Cohorts
for
Alzheimer’s
Prevention
Action
........................................................................................................
32
Global
Alzheimer’s
Association
Interactive
Network
.........................................................................................
32
Global
Biomarker
Standardization
Consortium
.................................................................................................
32
Alzheimer's
Disease
Cooperative
Study
.............................................................................................................
32
Glossary
...............................................................................................................................
34
References
............................................................................................................................
36
5. !
EXECUTIVE
SUMMARY
Alzheimer’s
disease
(AD)
is
the
sixth
leading
cause
of
death
in
the
United
States
and
claims
the
lives
of
more
than
500,000
people
in
the
United
States
alone
each
year.
Currently,
more
than
5
million
Americans
are
living
with
this
disease.
The
economic
impact
of
AD
is
significant,
costing
the
United
States
$214
billion
in
2014
and
on
pace
to
escalate
to
more
than
$1
trillion
over
the
next
four
decades.
Despite
significant
attention
and
investment
from
government
and
industry,
progress
in
the
areas
of
clinical
research
and
integrated
care
has
been
modest
at
best.
Our
society
remains
at
the
mercy
of
this
disease
as
a
result
of:
• poor
understanding
of
disease
onset
and
progression,
• gaps
in
funding
to
support
high-‐risk
research
efforts,
• insufficient
research
tools
and
companion
resources,
• lack
of
disease-‐modifying
treatment
options,
and
• limited
public
awareness
of
the
societal
impact
of
this
disease.
It
is
imperative
that
we
significantly
improve
upon
the
aforementioned
deficiencies
to
avoid
the
economic
and
social
catastrophe
that
accompanies
AD.
Strategic
focus
on
funding
high-‐impact
research
and
critical
infrastructure
to
support
both
AD
research
and
patients
will
be
essential
to
reaching
this
goal.
The
FasterCures
Philanthropy
Advisory
Service
has
developed
this
Giving
Smarter
Guide
for
Alzheimer’s
disease
with
the
specific
aim
of
empowering
patients,
supporters,
and
stakeholders
to
make
strategic
and
informed
decisions
with
respect
to
directing
their
philanthropic
investments
and
energy
into
research
and
development
efforts.
Readers
will
be
able
to
use
this
guide
ultimately
to
pinpoint
research
solutions
aligned
with
their
interests.
The
guide
will
help
to
answer
the
following
questions:
• Why
is
it
important
to
invest
in
AD
research?
• What
key
things
should
I
know
about
the
disease?
• What
is
the
current
state
of
care?
• What
is
the
state
of
research?
• What
are
the
barriers
to
progress?
• How
can
philanthropy
advance
new
therapies
for
AD?
6. !
OVERVIEW
AD
is
a
neurodegenerative
disease
that
severely
impairs
memory,
cognition,
and
a
person’s
ability
to
conduct
common
daily
activities.
As
the
nerve
cells
of
an
AD
patient
become
diseased
and
ultimately
die,
communication
among
the
cells
that
direct
memory,
speech,
and
executive
function
(motor
skills,
speech,
swallowing,
etc.)
is
lost,
ultimately
leading
to
the
death
of
the
patient.
AD
most
commonly
occurs
in
people
aged
65
or
older;
however,
some
individuals,
especially
those
with
a
familial
gene
for
Alzheimer’s,
experience
symptoms
before
the
age
of
65.
This
is
commonly
referred
to
as
early
onset
Alzheimer’s
disease.
Because
age
is
one
of
the
most
important
risk
factors
for
AD,
the
burden
of
AD
will
increase
with
longer
life
expectancies
and
the
aging
of
baby
boomers.
It
is
estimated
that
by
2050,
nearly
15
million
people
will
suffer
from
the
disease
in
the
United
States,
which
will
lead
to
significant
population
and
economic
burdens.
IMPERATIVE
TO
ADVANCE
ALZHEIMER’S
RESEARCH
POPULATION
BURDEN
In
2014,
the
Alzheimer’s
Association
estimated
that
there
are
5.2
million
AD
patients
in
the
United
States.
It
is
estimated
that
one
in
three
people
(33
percent)
age
85
and
older
have
Alzheimer’s,
and
one
in
nine
people
(11
percent)
age
65
and
older
is
stricken
with
this
disease.
By
2025,
the
number
of
people
age
65
and
older
with
AD
is
expected
to
more
than
triple
from
5
million
to
nearly
16
million
if
there
are
no
significant
medical
breakthroughs
to
slow,
prevent,
or
cure
the
disease.
Alzheimer’s
is
the
sixth
leading
cause
of
death
in
the
United
States,
claiming
the
lives
of
more
than
500,000
people
each
year.
According
to
the
Alzheimer’s
Association,
deaths
attributed
to
AD
increased
dramatically
between
2000
and
2010,
increasing
by
68
percent,
while
deaths
from
other
major
diseases
decreased
during
this
decade.
Among
the
top
10
leading
causes
of
death
in
the
United
States,
AD
is
the
only
disease
that
cannot
be
prevented,
slowed,
or
cured.
Subjectively,
it
is
without
question
that
the
overall
burden
of
AD
is
catastrophic;
however,
objective
evaluation
of
disease
burden
based
on
disability-‐adjusted
life
years
(DALYs)
underscores
the
magnitude
of
this
burden
and
highlights
the
steep
upward
trajectory
of
continued
burden
in
the
coming
decades.
Figure
1:
Proportion
of
people
with
AD
in
the
United
States
according
to
age.
Source:
Alzheimer’s
Association,
2014
Alzheimer’s
Disease
Facts
and
Figures,
Alzheimer’s
&
Dementia,
Volume
10,
Issue
2.
4%
15%
38%
43%
Alzheimer's
Pa`ent
Popula`on
Breakdown
by
Age
Under
65
65-‐74
75-‐84
85+
7. !
DALYs
are
the
sum
of
the
number
of
years
of
life
lost
due
to
premature
mortality
and
the
number
of
years
lived
with
disability.
According
to
an
article
published
in
the
Journal
of
the
American
Medical
Association
by
the
U.S.
Burden
of
Disease
Collaborators,
AD
was
ranked
as
the
25
th
most
burdensome
disease
in
the
United
States
in
1990.
In
2010,
the
ranking
of
AD
rose
to
the
12
th
most
burdensome
disease.
It
is
important
to
note
that
no
other
disease
or
condition
has
increased
in
rank
that
much
within
a
10-‐year
time
span.
When
the
same
study
exclusively
evaluated
years
of
life
lost
due
to
premature
mortality,
the
data
showed
that
the
AD
ranking
rose
from
32
nd
to
9
th
,
the
largest
increase
for
any
disease.
Overall,
these
data
punctuate
the
point
that
AD
is
not
only
taking
the
lives
of
an
increasing
number
of
Americans,
but
it
is
also
attributing
to
increased
incidence
and
prevalence
of
poor
health
and
disability
in
the
Unites
States.
ECONOMIC
BURDEN
Alzheimer’s
disease
is
the
most
costly
disease
to
the
American
healthcare
system.
The
National
Institutes
of
Health
(NIH)
estimated
the
direct
annual
cost
of
AD
during
the
1990s
to
be
more
than
$100
billion.
Today
the
annual
cost
of
AD
has
more
than
doubled
to
$214
billion
and
is
on
track
to
surge
to
$1.2
trillion
(today’s
dollars)
by
2050
if
we
cannot
find
a
suitable
intervention
to
prevent,
slow,
or
cure
this
disease.
Given
that
this
disease
primarily
affects
the
elderly,
more
than
half
of
the
$214
billion
cost
is
borne
by
the
Centers
for
Medicare
&
Medicaid
Services
through
Medicare
and
Medicaid
reimbursements
(Figure
2).
According
to
the
Alzheimer’s
Association,
the
average
per-‐person
Medicare
spending
for
those
with
Alzheimer's
and
other
dementias
is
three
times
higher
than
for
those
without
these
conditions.
The
average
per-‐person
Medicaid
spending
for
seniors
with
Alzheimer's
and
other
dementias
is
19
times
higher
than
average
per-‐person
Medicaid
spending
for
all
other
seniors.
It
is
important
to
remember
that
AD
significantly
impacts
both
the
patient
and
caregivers.
Given
the
physical,
mental,
and
emotional
strain
of
caring
for
someone
with
Alzheimer’s,
the
health
of
caregivers
often
declines
steadily
throughout
the
duration
of
care.
In
addition
to
suffering
from
physical
illness,
caregivers
are
more
likely
to
experience
depression
and
abuse
substances.
These
physical
manifestations
on
the
health
of
caregivers
add
to
the
cost
of
AD
to
our
healthcare
system
and
our
overall
economy.
Furthermore,
due
to
the
intense
level
of
care
that
many
AD
patients
require,
caregivers
must
often
reduce
working
hours,
take
less
demanding
jobs,
or
discontinue
work
altogether.
While
this
often
creates
financial
hardship
for
the
caregiver,
employers
are
also
impacted.
According
to
the
Alzheimer’s
Association,
businesses
lose
more
than
$61
billion
per
year
as
a
result
of
costs
related
to
caregiver
absenteeism,
employee
replacement,
related
productivity
loss,
and
employee
assistance
programs.
Figure
2:
Impact
of
Alzheimer’s
disease
on
the
U.S.
healthcare
system.
Source:
Alzheimer’s
Association,
2014
Alzheimer’s
Disease
Facts
and
Figures,
Alzheimer’s
&
Dementia,
Volume
10,
Issue
2.
Medicaid
17%
Medicare
53%
Out-‐of-‐pocket
17%
Other
13%
Breakdown
of
Alzheimer's
$214
Billion
Impact
on
the
US
Healthcare
System
Medicaid
Medicare
Out-‐of-‐pocket
Other
8. !
AD
AWARENESS
FALLS
BEHIND
COMPARED
TO
OTHER
DISEASES
People
are
often
under
the
misconception
that
AD
is
a
disease
that
only
affects
older
people,
and
that
dementia
in
general
is
a
normal
part
of
the
aging
process.
We
now
know
that
dementia
is
caused
by
specific
neurodegenerative
diseases
and
is
thus
not
a
normal
part
of
aging.
In
addition,
while
it
is
true
that
this
disease
predominantly
affects
the
elderly
population,
the
societal
and
economic
consequences
of
the
disease
affects
all
generations.
The
emotional
and
financial
strain
that
this
disease
places
on
the
families
of
loved
ones
with
Alzheimer’s
in
addition
to
the
economic
strain
placed
on
our
healthcare
system
will
cripple
our
society
if
we
cannot
cure
or
prevent
this
disease
in
the
near
term.
By
raising
awareness
among
individuals
not
yet
affected
by
Alzheimer’s
and
educating
those
who
are,
the
community
can
better
mobilize
the
masses
to:
• advocate
to
policymakers
for
additional
resources
to
boost
research
efforts
and
improve
infrastructures
to
support
AD
patients
and
families;
• participate
in
healthy
brain
aging
studies
to
help
researchers
better
understand
factors
that
may
either
protect
against
AD
and
other
forms
of
dementia,
or
increase
susceptibility
to
these
disorders;
and
• participate
in
clinical
research
studies
aimed
at
preventing
and/or
curing
AD.
In
order
to
attenuate
the
massive
threat
that
AD
poses
to
global
health
and
the
global
economy,
commitment
of
focused
resources
aimed
at
raising
awareness,
supporting
research,
and
encouraging
citizen
participation
in
clinical
research
studies
is
imperative.
9. !
“We
spend
one
penny
on
research
for
every
dollar
the
federal
government
spends
on
care
for
patients
with
Alzheimer’s.
That
just
doesn’t
make
sense.
We
really
need
to
step
up
the
investment.”
–
Senator
Susan
Collins
(R-‐
Maine),
National
Alzheimer’s
Project
Act
co-‐sponsor
OUR
DOLLARS
MUST
MAKE
SENSE
PUBLIC
POLICIES
ADRESSING
AD
UNMET
NEEDS
To
face
the
growing
problem
that
is
AD,
public
policies
are
needed
to
address
the
systemic
issues
that
impede
research
progress.
Core
challenges
that
make
Alzheimer’s
research
especially
difficult
to
study
include
large-‐scale
funding
of
research,
regulatory
issues,
and
improving
care
for
patients.
Despite
the
growing
understanding
of
the
burden
of
AD,
there
are
major
impediments
to
progress
toward
effective
treatment.
First,
AD
necessitates
massive
large-‐scale,
long-‐term
studies
that
are
coordinated
nationally
to
identify
the
best
molecular
targets
for
the
disease
and
ultimately
treatments
and
interventions
that
will
be
successful.
Second,
the
ability
to
properly
diagnose
and
study
targets
and
progress
toward
successes
has
proven
extremely
difficult
using
the
traditional
clinical
trial
framework.
Finally,
barring
a
dramatic
shift
in
the
trajectory
of
this
disease,
combined
with
an
aging
population,
the
growing
burden
of
this
disease
will
vastly
outpace
the
care.
A
number
of
policy
solutions
that
seek
to
address
some
of
these
issues
have
recently
been
signed
into
law
in
the
United
States.
Those
that
are
notable
include
the
National
Alzheimer's
Project
Act
(NAPA)
and
the
Alzheimer’s
Accountability
Act.
NATIONAL
ALZHEIMER'S
PROJECT
ACT
NAPA
was
signed
into
law
in
2011
after
unanimous
passage
by
both
houses
of
Congress.
The
law
mandates
the
creation
of
a
national
strategic
plan
to
address
the
Alzheimer’s
crisis
with
the
specific
goal
of
preventing
and/or
effectively
treating
AD
by
2025.
This
act
created
the
opportunity
to
improve,
leverage,
and
coordinate
existing
U.S.
Department
of
Health
and
Human
Services
programs
and
other
federal
efforts
with
the
aim
of
changing
the
trajectory
of
AD.
The
law
calls
for
a
National
Plan
for
AD
with
input
from
a
public-‐private
Advisory
Council
on
Alzheimer's
Research,
Care
and
Services.
This
plan,
first
completed
in
2012
and
revised
annually,
presents
a
recurring
opportunity
for
Congress
to
assess
the
efforts
to
combat
AD.
Unfortunately,
Congress
has
not
mandated
funding
to
support
activities
outlined
in
the
NAPA
strategic
plan.
Alzheimer’s
advocacy
groups,
such
as
the
Alzheimer’s
Association,
has
recommended
to
Congress
that
NAPA
include
at
least
a
$2
billion
annual
increase
to
Alzheimer’s
research
funding,
in
order
to
have
the
desired
impact
on
AD;
however,
this
recommendation
has
gone
largely
unsupported
by
lawmakers,
to
the
detriment
of
taxpayers
and
the
U.S.
economy.
To
jumpstart
the
plan,
the
Obama
administration’s
fiscal
year
2014
budget
proposal
included
$100
million
in
additional
funding
for
research,
awareness,
education,
outreach,
and
caregiver
support.
While
the
investment
falls
far
short
of
what
is
necessary
for
actual
impact,
the
inclusion
in
the
budget
helped
to
refocus
attention
on
this
very
important
problem
and
the
strategic
framework
poised
to
potentially
provide
solutions.
To
learn
more
about
NAPA,
please
visit
http://aspe.hhs.gov/daltcp/napa/.
10. !"
ALZHEIMER’S
ACCOUNTABILITY
ACT
Building
on
the
coordinated
goals
of
NAPA,
the
Alzheimer’s
Accountability
Act,
signed
into
law
at
the
end
of
2014,
requires
the
director
of
the
NIH
to
submit
to
the
President
for
review
and
transmittal
to
Congress
an
annual
budget
estimate
for
the
NIH
initiatives
under
NAPA.
The
secretary
of
Health
and
Human
Services
and
the
Advisory
Council
on
Alzheimer's
Research,
Care
and
Services
are
provided
an
opportunity
to
comment
on
the
budget
but
cannot
change
the
content.
The
Alzheimer’s
Accountability
Act
creates
a
formal
process
for
NAPA
recommendations
to
directly
impact
government
funding
allocation
for
AD
each
year
until
2025.
Again
it
is
important
to
note
that
this
provision
does
not
increase
funding
to
the
recommended
level
of
an
additional
$2
billion
annually,
but
it
does
help
to
strategically
reallocate
resources
toward
the
strategic
plan
put
forth
by
NAPA.
11. !!
RISK,
DIAGNOSIS,
AND
PROGRESSION
RISK
FACTORS
While
the
cause
of
Alzheimer’s
disease
is
not
well
understood,
research
has
shown
that
there
are
both
general
and
genetic
factors
that
increase
the
risk
of
developing
AD.
General
risk
factors
include
the
following:
• Age
–
The
risk
of
developing
AD
doubles
every
five
years
starting
at
age
65.
• Education
–
Lower
educational
attainment
has
been
linked
with
higher
risk
of
developing
AD.
• Medical
conditions
–
Medical
conditions
such
as
head
trauma,
diabetes,
depression,
high
cholesterol,
and
cardiovascular
diseases
(including
stroke)
are
associated
with
a
higher
risk
of
developing
AD.
There
are
also
genetic
risk
factors
that
have
been
shown
to
play
a
role
in
the
development
of
AD.
Based
on
our
understanding
of
AD
to
date,
researchers
have
found
that
there
are
two
primary
forms
of
Alzheimer’s
that
can
be
categorized
based
on
age
of
onset
and
genetic
mutations.
• Early
onset
/
familial
AD
–
affects
people
under
the
age
of
65.
Mutations
in
the
following
genes
are
strongly
associated
with
this
form
of
AD:
§ Amyloid
precursor
protein
(APP)
§ Presenilin
1
(PSEN1)
§ Presenilin
2
(PSEN2)
• Late
onset
AD
/
sporadic
AD
–
affects
people
over
the
age
of
65
and
is
the
most
common
form
of
AD.
There
are
currently
two
genetic
alleles
(regions
of
DNA)
shown
to
be
strongly
associated
with
this
form
of
AD:
§ ApoE
epsilon
4
(ApoE4)
The
genes
listed
above
are
only
a
subset
of
genes
thought
to
be
involved
in
the
development
of
AD.
Researchers
are
continuously
identifying
new
genes
through
the
use
of
cutting-‐edge
sequencing
technologies
that
enable
mapping
of
genetic
mutations
to
clinical
manifestations
of
AD.
THREE
STAGES
OF
ALZHEIMER’S
DISEASE
In
2011,
Alzheimer’s
diagnostic
guidelines
were
updated
for
the
first
time
in
nearly
30
years.
The
previous
guidelines
published
in
1984
were
the
first
official
criteria
to
outline
diagnosis;
however,
the
guidelines
defined
AD
as
a
single-‐stage
disease
that
only
included
dementia.
In
addition,
diagnostic
criteria
were
based
solely
on
clinical
symptoms,
and
diagnosis
could
only
be
confirmed
upon
autopsy
of
the
brain.
As
a
result
of
modern
research,
we
now
know
that
AD
is
a
multi-‐stage
disease
that
may
cause
changes
in
the
brain
a
decade
or
more
before
the
display
of
clinical
symptoms;
however,
these
symptoms
do
not
always
relate
to
abnormal
changes
in
the
brain
caused
by
AD.
The
updated
guidelines
cover
the
full
spectrum
of
the
disease,
outlining
diagnostic
criteria
for
dementia
due
to
AD,
mild
cognitive
impairment
due
to
AD,
and
preclinical
AD.
The
guidelines
also
now
address
the
use
of
imaging
and
biomarkers
(biochemical
and
genetic
characteristics
that
can
12. !"
• Age-‐Associated
Memory
Impairment/Cognitive
Decline
• Parkinson’s
Disease
• Lewy
Body
Dementia
• Cerebrovascular
Disease
• Frontotemporal
Lobar
Degeneration
OTHER
CAUSES
OF
MCI
be
used
to
track
disease-‐related
changes)
in
blood
and
spinal
fluid.
Additional
descriptions
of
each
of
the
three
stages
of
AD
are
provided
in
the
sections
below.
PRECLINICAL
AD
Preclinical
is
the
earliest
stage
of
AD.
This
stage
refers
to
instances
where
AD-‐related
changes
in
the
brain
are
underway
but
clinical
symptoms,
such
as
memory
impairment
or
behavioral
alterations,
are
not
yet
evident.
While
the
guidelines
identify
these
preclinical
changes
as
an
Alzheimer's
stage,
they
do
not
currently
establish
diagnostic
criteria
that
doctors
can
use
to
categorize
patients.
Instead
these
guidelines
apply
only
in
a
research
setting.
The
key
challenge
faced
by
the
AD
community
is
that
it
is
clear
that
early
intervention
will
be
essential
to
optimally
preserving
cognition.
The
amendment
of
the
guidelines
to
address
this
issue
is
helpful
to
the
research
community
as
it
presents
a
framework
for
additional
research
on
biomarkers
to
determine
which
ones
can
be
used
to
track
AD-‐related
changes
in
the
brain
and
how
best
to
measure
them.
MILD
COGNITIVE
IMPAIRMENT
DUE
TO
AD
Patients
suspected
of
having
mild
cognitive
impairment
(MCI)
due
to
AD
generally
experience
mild
changes
in
memory
and
thinking
that
are
enough
to
be
noticed
and
measured
using
mental
status
tests,
but
are
not
severe
enough
to
compromise
personal
independence
or
overall
executive
function
in
daily
life.
People
with
MCI
may
or
may
not
progress
to
Alzheimer’s
dementia.
It
is
important
to
note
that
MCI
may
be
attributed
to
one
or
more
etiologies
(causes)
outside
of
AD
(see
Figure
3);
however
AD
accounts
for
60
to
80
percent
of
all
dementia
cases.
Clinicians
may
incorporate
the
use
of
biomarkers
to
help
identify
with
more
certainty
whether
or
not
a
patient
is
experiencing
MCI
due
to
AD
or
other
disorders
that
can
lead
to
MCI.
DEMENTIA
DUE
TO
AD
Dementia
due
to
Alzheimer’s
refers
to
the
final
stage
of
the
disease.
In
this
stage,
impairments
in
memory,
thinking,
and
behavior
decrease
a
person's
ability
to
function
independently
in
everyday
life.
At
this
stage,
biomarker
test
results
may
be
used
in
some
cases
to
increase
or
decrease
the
level
of
certainty
about
a
diagnosis
of
Alzheimer’s
dementia;
however,
these
biomarker
tests
are
primarily
used
as
a
complementary
tool
for
clinicians
rather
than
an
official
diagnostic.
Figure
3:
Alternative
causes
of
mild
cognitive
impairment
13. !"
MEASURING
COGNITIVE
IMPAIRMENT
FOR
DIAGNOSIS
Multiple
clinical
tests
have
been
developed
to
measure
mental
decline
by
asking
patients
to
memorize
and
associate
words,
complete
simple
mathematical
calculations,
or
draw
an
object
that
can
simultaneously
enable
the
evaluation
of
multiple
brain
functions.
Such
tests
include
but
are
not
limited
to
the
following:
• The
Mini
Mental
State
Examination
(MMSE)
• Clock
Drawing
Test
and
Mini-‐Cog
Test
• Montreal
Cognitive
Assessment
Once
mental
decline
is
confirmed,
standard
medical
tests
are
conducted
to
dismiss
other
potential
causes
of
dementia,
such
as
stroke,
Parkinson’s
disease,
or
tumors.
Such
tests
include
blood
tests
and
neuro-‐diagnostic
tests
such
as
brain
screening.
14. !"
DISEASE
BIOLOGY
Alzheimer’s
is
a
form
of
dementia,
which
is
an
umbrella
term
used
to
describe
a
state
in
which
there
is
a
loss
in
cognitive
function
–
thinking,
reasoning,
memory,
etc.
–
and
behavioral
abilities
to
the
extent
where
these
losses
interfere
with
routine
daily
activities.
There
are
a
number
of
disorders
categorized
as
forms
of
dementia
(Figure
4);
however,
AD
is
the
most
common,
accounting
for
60
to
80
percent
of
all
cases
of
dementia.
AD
is
caused
by
irreversible
loss
of
neurons.
Neurons
are
nerve
cells
responsible
for
processing
and
transmitting
information
through
electrical
and
chemical
signals.
These
signals
can
be
transmitted
from
neuron
to
neuron
by
traveling
through
cellular
appendages
called
axons
and
exiting
through
synapses.
Transmission
of
neuronal
signals
is
essential
to
all
processes
involving
the
central
nervous
system.
While
the
cause
of
AD
is
unclear,
there
are
some
key
pathological
features
of
the
disease
that
scientists
strongly
believe
can
lead
to
Alzheimer’s.
These
hallmark
features
of
Alzheimer’s
include
the
following:
• Build-‐up
of
beta-‐amyloid
protein
in
the
brain
• Abnormal
modification
of
tau
protein
in
the
brain
These
events
can
lead
to
disruption
in
neuronal
communication
and/or
neuronal
death,
which
ultimately
brings
about
the
clinical
symptoms
of
Alzheimer’s
–
memory
impairment,
cognitive
decline,
and
behavioral
problems
that
impair
or
prohibit
independent
living.
Detailed
descriptions
of
each
of
the
aforementioned
hallmarks
are
provided
below.
BETA
AMYLOID
PROTEIN
BUILD-‐UP
IN
THE
BRAIN
LEADS
TO
PLAQUES
Beta-‐amyloid
protein
is
derived
from
a
larger
protein
called
amyloid
precursor
protein
(APP),
which
is
found
in
the
synapses
of
neurons.
The
role
of
APP
is
not
altogether
clear;
however,
various
research
studies
suggest
that
it
plays
a
role
in
regulating
synapse
formation,
neural
plasticity,
and
iron
export.
Beta-‐amyloid
protein
is
generated
when
APP
is
severed
in
the
cell
by
other
proteins
called
enzymes.
Cleavage
of
APP
into
the
truncated
beta-‐amyloid
form
encourages
the
protein
to
assume
a
new
three-‐dimensional
structure
that
allows
the
surfaces
of
beta-‐amyloid
to
attract
to
other
beta-‐amyloid
molecules,
forming
a
sticky
aggregate
that
clumps
together
to
form
what
is
commonly
referred
to
as
amyloid
plaques
(Figure
5).
We
now
know
that
beta-‐amyloid,
which
deposits
in
senile
plaques,
can
promote
formation
of
neurofibrillary
tangles
and
inflammation,
leading
to
neuronal
cell
death.
Clumps
of
beta-‐amyloid
called
oligomers
can
also
impair
transmission
of
signals
across
neuronal
synapses.
Figure
4:
Select
forms
of
dementia
15. !"
Figure
5:
Amyloid
precursor
protein
(APP)
being
snipped
by
enzymes
to
form
beta-‐amyloid
proteins
that
stick
together
to
form
beta-‐amyloid
plaques.
Source:
National
Institute
on
Aging,
National
Institutes
of
Health.
TAU
PROTEIN
BUILD-‐UP
IN
THE
BRAIN
LEADS
TO
TANGLES
Tau
proteins
are
essential
to
stabilizing
microtubules
–
the
scaffolding
structure
of
neurons
(Figure
6).
The
abnormal
modification
of
tau
(namely
the
addition
of
phosphorous
group)
leads
to
a
structural
change
that
impedes
the
ability
of
tau
to
stabilize
microtubules,
leading
to
structural
collapse
of
the
neuron.
This
collapse
prohibits
the
delivery
of
nutrients
to
the
neuron,
ultimately
leading
to
neuronal
death.
In
addition,
the
abnormal
tau
proteins
aggregate
such
that
they
tangle
together
to
form
what
is
referred
to
as
neurofibrillary
tangles
(Figure
7).
Figure
6:
Healthy
neurons
–
Microtubule
scaffold
of
the
neuron
is
stabilized
by
tau
protein
molecules.
Source:
Alzheimer’s
Disease
Education
and
Referral
Center,
National
Institute
on
Aging.
Figure
7:
Diseased
neurons
in
AD
–
Tau
proteins
are
modified
with
phosphate
groups,
which
change
the
structure
of
tau
and
compromises
its
ability
to
stabilize
microtubules
leading
to
neuron
collapse
and
the
formation
of
tangled
fibers.
Source:
Alzheimer’s
Disease
Education
and
Referral
Center,
National
Institute
on
Aging.
16. !"
NEUROTRANSMITTER
DYSFUNCTION
In
addition
to
amyloid-‐beta
and
tau
build-‐up
in
the
brain,
neurotransmitter
deficiency
is
also
an
important
pathological
feature
of
AD.
Neurotransmitters
are
responsible
for
carrying
information
from
one
cell
to
another.
In
AD,
the
processes
by
which
neurotransmitters
are
produced
and/or
function
are
disrupted.
Studies
show
that
neurotransmitter
deficiency
over
time
leads
to
memory
and
cognition
deficits
commonly
observed
in
AD.
Treatment
strategies
to
date
have
focused
on
targeting
the
following
neurotransmitters:
• Acetylcholine
• Glutamate
• Serotonin
As
shown
in
Table
1,
all
currently
U.S.
Food
and
Drug
Administration
(FDA)-‐approved
therapies
for
the
treatment
of
AD
target
either
acetylcholine
or
glutamate.
New
drugs
targeting
serotonin
are
currently
in
late-‐stage
clinical
trials.
17. !"
TREATMENTS
There
is
no
cure
for
AD,
and
currently
approved
therapies
by
the
FDA
treat
only
the
symptoms
of
AD
rather
than
modifying
the
disease
to
cure
or
slow
it
down.
Consequently
one
of
the
largest
unmet
needs
for
AD
patients
is
access
to
effective
disease-‐modifying
therapies.
Currently,
there
are
four
FDA-‐approved
drugs
for
the
treatment
of
AD
(Table
1).
Three
of
these
agents
–
donepezil,
galantamine,
and
rivastigmine
–
target
the
process
by
which
the
neurotransmitter,
acetylcholine,
is
broken
down
by
an
enzyme
called
cholinesterase.
The
hypothesis
behind
the
use
of
this
agent
is
that
the
inhibition
of
the
breakdown
of
acetylcholine
will
consequently
slow
down
mental
degradation
that
leads
to
impaired
learning,
memory,
and/or
judgment.
Cholinesterase
inhibitors
are
believed
to
delay
the
disease
process
by
6
to
12
months,
but
the
symptoms
eventually
worsen
with
additional
destruction
of
neurons
through
other
AD
pathological
pathways,
such
as
amyloid-‐beta
and
tau
buildup.
Memantine
differs
from
the
other
agents
in
that
it
inhibits
glutamate,
a
neurotransmitter
that
controls
communication
among
neurons
by
regulating
calcium
ion
levels
in
the
cells.
Excess
glutamate
can
lead
to
an
imbalance
in
calcium
ions
in
neurons,
ultimately
resulting
in
their
death.
This
effect
is
called
excitotoxicity.
By
interfering
with
the
action
of
glutamate,
memantine
reduces
this
toxic
effect
of
calcium
ion
imbalance.
As
mentioned
previously,
the
efficacy
and
benefits
of
all
of
the
current
FDA-‐approved
treatment
options
for
AD
are
marginal
at
best
and
work
only
to
alleviate
the
symptoms.
New
and
effective
AD
treatment
options
are
desperately
needed.
Table
1:
FDA-‐approved
treatments
for
Alzheimer’s
disease
Stage
of
Disease
Treated
Drug
Name
Mechanism
of
Action
Mild
Moderate
Severe
Donepezil
Cholinesterase
Inhibitor
X
X
X
Galantamine
Cholinesterase
Inhibitor
X
X
Rivastigmine
Cholinesterase
Inhibitor
X
X
X
Memantine
Glutamate
receptor
antagonist
X
X
*
Tacrine,
a
cholinesterase
inhibitor,
was
previously
approved
for
AD,
but
was
withdrawn
from
the
U.S.
market
in
May
2012
18. !"
CLINICAL
TRIALS
AND
INVESTIGATIONAL
THERAPIES
CLINICAL
TRIALS
-‐
OVERVIEW
Clinical
research
is
research
in
human
subjects
aiming
toward
approved
products
for
use
in
patients.
Clinical
trials
determine
whether
a
particular
product
is
as
effective
in
people
as
it
is
in
the
laboratory
or
in
animal
models,
which
often
fail
to
adequately
mimic
human
responses.
Further,
clinical
trials
provide
information
on
potential
adverse
reactions
or
side
effects
that
need
to
be
weighed
against
the
potential
benefits.
Clinical
research
for
drugs
and
vaccines
is
broken
into
four
key
phases.
Each
phase
is
described
in
Table
2.
Table
2:
Phases
of
clinical
development
Clinical
Phase
Description
Number
of
Patients
Phase
I
Examines
the
safety
of
the
product
in
a
very
small
group
of
healthy
volunteers
or
patients
afflicted
with
a
specific
disease.
Also
used
to
determine
appropriate
dose
ranges.
20-‐80
Phase
II
Evaluates
the
safety
and
efficacy
of
the
product
at
a
pre-‐determined
dose
in
comparison
to
the
current
standard
of
care
treatment
(commercially
available
therapies
commonly
used
to
treat
the
same
disorder
or
disease).
100-‐300
Phase
III
Evaluates
the
product
compared
to
the
standard
of
care
in
a
large
diverse
population
to
determine
broader
efficacy
and
develop
usage
guidelines.
1,000-‐3,000
Phase
IV
Evaluates
the
long-‐term
effects
of
a
drug
post-‐FDA
approval
for
public
use.
All
patients
prescribed
the
drug
by
a
treating
physician
INVESTIGATIONAL
THERAPIES
As
of
March
2015,
there
were
115
products
in
clinical
development
for
AD.
Figure
8
illustrates
the
distribution
of
these
trials
by
phase
of
clinical
development.
In
the
sections
below
we
discuss
key
therapeutic
strategies
that
are
being
explored
in
AD
clinical
trials.
Figure
8:
Agents
in
research
and
clinical
development
for
AD.
48
3
46
3
15
Phase
I
Phase
I/II
Phase
II
Phase
II/III
Phase
III
AD
Drug
Development
Pipeline
19. !"
AMYLOID-‐TARGETING
THERAPIES
There
are
a
number
of
drugs
in
development
for
AD
that
specifically
target
beta-‐amyloid
proteins.
The
goal
of
this
therapeutic
strategy
is
to
clear
beta-‐amyloid
build-‐up
in
the
brain
to
deter
plaque
formation
by
either:
• decreasing
the
production
of
beta-‐amyloid
protein,
or
• increasing
removal
of
beta-‐amyloid
protein
from
the
brain.
As
mentioned
previously,
the
cleavage
of
amyloid
precursor
protein
(APP)
gives
rise
to
a
short
toxic
form
of
the
protein
–
beta-‐amyloid.
There
are
three
enzymes
that
are
primarily
responsible
for
cleaving
APP
to
form
beta-‐
amyloid:
• beta-‐secretase,
• gamma-‐secretase,
and
• alpha-‐secretase.
These
proteins
have
been
key
targets
in
AD
drug
development
because
of
their
role
in
regulating
the
production
of
beta-‐amyloid
and
ultimately
plaque
formation.
Table
3
outlines
the
type
of
therapeutic
required
for
impact
on
beta-‐amyloid
production
and
drug
class
descriptors
commonly
used
by
the
research
and
drug
development
communities.
Table
3:
AD
drug
classes
targeting
specific
proteins
critical
to
the
production
of
beta-‐amyloid
Protein
name
Function
with
respect
to
beta-‐amyloid
production
Type
of
targeted
therapeutic
required
for
impact
on
beta-‐
amyloid
Drug
class
descriptor
Beta-‐secretase
Increases
production
of
beta-‐amyloid
Inhibitor
of
beta-‐secretase
BACE1
inhibitors
Gamma-‐secretase
Increases
production
of
beta-‐amyloid
Inhibitor
of
gamma-‐secretase
GSI
and
GSM
Alpha-‐secretase
Decreases
production
of
beta-‐amyloid
Activator
of
alpha-‐secretase
Alpha
secretase
activators
Challenges
While
a
number
of
drugs
targeting
beta-‐amyloid
have
been
evaluated
in
AD
clinical
trials,
there
is
not
yet
any
clear
indication
that
these
drugs
can
improve
Alzheimer’s
symptoms
or
protect
brain
cells.
TAU-‐TARGETING
THERAPIES
As
mentioned
previously,
tau
proteins
play
a
key
role
in
stabilizing
the
walls
of
neurons.
The
abnormal
modification
of
tau,
primarily
phosphorylation
(deposit
of
phosphorous
and
oxygen
groups
onto
a
protein
by
molecules
called
kinases
–
see
Figure
9),
leads
to
the
collapse
of
the
neuronal
wall,
neuronal
dysfunction
and/or
death,
and
neurotransmitter
deficits.
In
addition,
the
accumulation
of
abnormal
tau
protein
leads
to
neurofibrillary
tangles
that
are
also
toxic
to
neurons
and
is
a
key
hallmark
of
AD.
20. !"
Tau-‐targeting
therapies
prevent
tau
aggregation
or
dissolve
existing
aggregates
to
interfere
with
the
aforementioned
pathological
consequences
of
abnormal
tau.
Given
the
key
role
that
kinases
play
in
tau
pathology,
a
number
of
tau-‐targeting
therapies
aim
to
modulate
the
process
by
which
kinases
phosphorylate
tau.
There
are
many
types
of
kinases;
however,
research
studies
have
shown
that
GSK3-‐beta
(GSK3β)
and
cyclin
dependent
kinase
5
(cdk5)
play
key
roles
in
tau
phosphorylation
and
tangle
formation.
Tau
antibodies
(also
referred
to
as
tau
immunotherapy)
have
the
potential
to
target
synaptic
tau
and
interfere
with
the
spread
of
tau
among
neurons.
The
development
of
tau
antibodies
and
drugs
that
inhibit
the
aforementioned
kinase
targets
have
been
of
intense
focus
in
Alzheimer’s
research
and
are
currently
in
clinical
development.
Challenges
The
development
of
kinase
inhibitors
is
an
approach
riddled
with
inherent
challenges.
As
mentioned
previously,
there
are
numerous
variations
of
kinases,
many
of
which
play
a
redundant
role
in
targeting
and
phosphorylating
various
proteins
such
as
tau.
Because
kinases
interact
with
many
different
proteins,
inhibition
of
these
molecules
will
invariably
inhibit
kinase
interactions
necessary
for
normal
cellular
functions
throughout
the
body.
This
inhibition
of
normal
function
leads
to
unintentional
and
potentially
severe
side
effects.
The
redundant
roles
of
kinases
also
add
to
the
challenge,
that
is,
the
inhibition
of
one
kinase
that
phosphorylates
tau
does
not
necessarily
lead
to
the
inhibition
of
another
kinase
that
also
phosphorylates
tau.
Researchers
have
attempted
to
circumvent
this
challenge
by
developing
drugs
that
can
target
more
than
one
kinase.
The
multi-‐
targeting
approach
has
been
to
chemically
link
together
two
drugs
that
target
different
kinases.
The
outcome
of
this
type
of
approach
has
been
poor
to
date,
primarily
because
this
technique
leads
to
large
drugs
with
high
molecular
weights,
which
are
less
than
optimal
for
penetrating
the
blood-‐brain
barrier.
While
protein
kinases
are
promising
drug
targets,
more
work
needs
to
be
done
to
develop
kinase
inhibitors
that
have
the
following
properties:
• can
target
multiple
kinases,
• low
molecular
weight
so
the
drug
can
efficiently
enter
the
brain,
and
• focused
targeting
of
specific
kinases
to
minimize
cellular
toxicity
as
a
result
of
off-‐target
effects.
NEUROTRANSMITTER
TARGETING
THERAPIES
As
mentioned
previously,
the
processes
by
which
neurotransmitters
are
produced,
released,
and/or
used
are
disrupted
in
AD.
Many
of
the
key
neurotransmitters
affected
by
AD
pathology
are
critical
to
learning,
memory,
and
cognition.
It
is
debated
that
acetylcholine
is
perhaps
the
most
critical
neurotransmitter
affected
by
AD
pathology.
The
vital
neurotransmitter
is
of
particular
importance
to
AD
as
it
is
the
primary
neurotransmitter
utilized
by
memory
systems
of
the
hippocampus,
a
key
structure
affected
in
AD.
The
emphasis
on
acetylcholine
does
not
completely
overshadow
the
role
of
the
other
aforementioned
neurotransmitters
–
glutamate
and
serotonin
–as
many
of
them
are
also
involved
in
the
overall
metabolism
(production,
use,
and
breakdown)
of
acetylcholine.
To
strengthen
the
Figure
9:
Proteins
called
kinases
deposit
phosphorous
groups
onto
tau.
Structural
modification
of
tau
with
phosphoryl
groups
compromises
tau’s
ability
to
hold
together
neuronal
walls.
21. !"
argument
that
acetylcholine
metabolism
is
central
to
AD
progression,
multiple
research
studies
strongly
link
acetylcholine
deficiency
to
loss
of
brain
volume
and
the
severity
of
dementia.
Challenges
While
FDA-‐approved
AD
treatments
to
date
exclusively
target
neurotransmitter
deficiencies,
these
drugs
have
proven
to
be
ineffective
in
modifying
the
disease
or
significantly
slowing
progression.
While
an
identified
link
between
neurotransmitter
deficiency
and
AD
progression
provides
strong
evidence
that
the
research
is
on
the
right
track,
real-‐world
clinical
experience
demonstrating
limited
efficacy
of
these
agents
suggests
that
they
may
need
to
be
used
in
combination
with
other
treatment
strategies.
IMMUNOTHERAPY
As
mentioned
previously,
much
of
the
focus
of
Alzheimer’s
research
has
been
figuring
out
ways
to
prevent
and/or
slow
down
the
process
by
which
amyloid
beta
and
tau
build
up
in
the
brain.
In
addition
to
exploring
small
molecule
drugs
to
serve
this
purpose,
researchers
have
also
identified
ways
to
activate
the
immune
system
to
target
amyloid
beta
and
tau.
These
strategies,
referred
to
as
immunotherapy,
work
by
soliciting
either
an
active
or
passive
immune
response.
Active
immunotherapy
involves
the
administration
of
a
substance
(drug,
vaccine,
etc.)
into
the
body
that
induces
an
immune
response
leading
to
the
natural
production
of
antibodies
against
the
target
(i.e.,
amyloid
beta
or
tau).
Passive
immunotherapy
differs
in
that
the
desired
antibodies
against
the
target
are
manufactured
outside
of
the
body
and
administered
as
a
drug.
While
immunotherapy
strategies
targeting
amyloid
beta
have
been
extensively
studied,
tau-‐directed
immunotherapies
are
not
as
advanced.
Despite
encouraging
pre-‐clinical
and
early-‐stage
data
demonstrating
that
this
approach
can
successfully
clear
amyloid
beta
build-‐up
in
mice,
success
in
human
trials
has
been
moderate
at
best.
A
key
challenge
to
this
approach
is
managing
the
immune
response
such
that
the
immune
system
does
not
over-‐react
to
the
treatment.
This
can
lead
to
excessive
brain
inflammation,
brain
hemorrhaging,
and
other
severe
side
effects.
In
addition
to
these
challenges,
it
is
also
unclear
when
patients
should
be
treated
to
fully
benefit
from
these
treatments.
Data
from
two
late-‐stage
trials
of
passive
immunotherapies
that
failed
to
meet
their
goals
of
improving
cognition
in
patients
with
mild
to
moderate
AD
underscore
the
common
belief
that
the
pathology
(amyloid
or
tau
buildup)
may
be
too
far
advanced
for
significant
clinical
benefit
at
this
stage.
Much
of
the
data
generated
thus
far
suggest
that
patients
should
be
treated
well
before
they
display
clinical
symptoms.
However,
identifying
high-‐risk
AD
patients
with
reasonable
confidence
that
they
will
develop
AD
and
determining
when
to
treat
is
a
highly
complicated,
long-‐term
undertaking.
22. !!
STEM
CELLS
Scientists
are
currently
exploring
the
use
of
stem
cells
to
study
the
molecular
features
of
Alzheimer’s
and
as
a
potential
treatment
option
for
patients.
Using
Stem
Cells
to
Model
AD
and
Screen
New
Therapies
Research
has
shown
that
the
pathological,
molecular,
and
genetic
features
of
AD
can
vary
significantly
among
patients,
and
it
is
important
to
study
the
mechanisms
driving
the
heterogeneity
of
the
disease
in
order
to
find
a
cure.
The
tremendous
progress
in
stem
cell
research
–
including
breakthrough
work
on
three-‐dimensional
cell
culture
systems
that
can
recapitulate
Alzheimer’s
–
has
enabled
researchers
to
use
this
technology
to
create
patient-‐specific
models
of
AD
in
a
petri
dish.
This
is
done
by
taking
skin
cells
from
an
Alzheimer’s
patient
(donor)
and
reprogramming
them
to
make
a
type
of
stem
cell
called
induced
pluripotent
stem
(iPS)
cells.
These
iPS
cells
can
be
programmed
to
become
all
different
types
of
cells
in
the
body,
but
for
the
purpose
of
AD
research,
they
are
reprogrammed
to
become
neurons.
Because
the
cells
are
derived
directly
from
a
patient,
despite
being
grown
in
petri
dishes,
they
display
the
same
molecular
and
pathological
features
as
identified
in
the
donor
patient.
The
coupling
of
the
patient’s
clinical
symptoms
to
the
biology
and
behavior
of
the
stem
cells
could
provide
new
insights
into
the
key
mechanisms
of
Alzheimer’s.
These
iPS
cells
can
also
be
used
to
test
new
drugs.
The
use
of
iPS
cells
to
screen
drugs
that
may
be
effective
against
AD
provides
an
additional
method
to
validate
results
observed
in
animals
studies.
This
is
important
because
a
major
impediment
to
Alzheimer’s
research
is
the
poor
translation
of
animal
results
to
humans.
This
occurs
because
the
biology
of
mice
and
other
small
animals
is
different
from
that
of
humans,
thus
positive
results
observed
in
animal
models
often
cannot
be
recapitulated
in
humans.
Using
Stem
Cells
to
Treat
Alzheimer’s
Stem
cells
are
not
currently
used
to
treat
AD,
but
researchers
are
pursuing
this
possibility.
Treatment
with
neuronal
stem
cells
could
theoretically
replace
brain
cells
damaged
by
AD
and
encourage
the
generation
of
new
healthy
neurons.
While
the
technology
holds
great
promise,
there
are
significant
challenges
that
must
be
overcome
before
this
type
of
treatment
can
become
a
reality.
The
first
challenge
is
that
AD
affects
many
different
types
of
neurons
in
various
parts
of
the
brain.
Therefore,
the
stem
cells
would
not
only
need
to
be
able
to
generate
a
wide
variety
of
neurons,
but
would
also
have
to
travel
specifically
to
regions
of
the
brain
damaged
by
AD.
In
addition,
the
new
neurons
would
need
to
integrate
effectively
into
the
complex
network
of
the
brain
in
order
to
complete
synaptic
circuits
that
control
communication
between
neurons
in
the
brain.
Finally,
there
has
not
yet
been
a
safe
protocol
developed
for
conducting
these
types
of
neural
stem
cell
transplants.
NUTRACEUTICALS
There
is
evidence
that
suggests
that
properties
of
certain
foods
may
provide
protection
against
neurodegenerative
disorders
such
as
Alzheimer’s.
These
foods
or
food
components
are
commonly
referred
to
as
nutraceuticals.
Key
nutraceuticals
that
have
been
studied
for
their
neuroprotective
effects
against
AD
include
the
following:
• Flavonoids
are
a
group
of
compounds
commonly
found
in
fruits,
vegetables,
and
several
types
of
tea,
cocoa,
and
wine.
These
compounds
have
been
shown
to
modulate
several
neurological
processes
including
inducing
changes
in
cerebral
blood
flow,
increasing
antioxidants
involved
in
synaptic
plasticity
23. !"
and
neuronal
repair,
and
inhibiting
neuro-‐pathological
processes
in
brain
regions
typically
involved
in
AD
pathogenesis.
• Resveratrol
is
a
compound
found
in
seeds
and
fruit
skins.
Evidence
has
shown
that
resveratrol
can
increase
activity
of
serotonin,
reduce
inflammation,
and
protect
neurons
from
death.
• Curcumin
is
the
most
active
element
of
turmeric
and
has
antioxidant
and
anti-‐inflammatory
properties.
It
has
been
shown
to
reduce
amyloid-‐beta
cerebral
burden
and
inflammation
in
AD
mouse
models.
• B
vitamins
(B6
and
B12)
have
been
shown
to
be
essential
for
maintaining
the
integrity
of
the
nervous
and
hematopoietic
systems
and
are
involved
in
the
regulation
of
mental
function
and
mood.
Some
studies
suggest
that
the
metabolite
homocysteine
is
a
risk
factor
for
dementia
or
cognitive
impairment
and
that
supplementation
with
B
vitamins
can
reduce
homocysteine
levels
in
the
blood.
While
there
is
significant
interest
in
the
neuroprotective
properties
of
nutraceuticals,
evidence
supporting
their
use
to
prevent
or
delay
Alzheimer’s
remains
inconclusive.
There
is
very
little
standardization
among
clinical
trials
evaluating
the
effect
of
these
dietary
agents
on
cognitive
impairment,
which
makes
it
very
difficult
to
meaningfully
analyze
and
compare
results
across
trials.
While
the
potential
for
nutraceutical
development
is
promising,
more
work
needs
to
be
done
to
improve
clinical
trial
design
and
make
it
uniform.
24. !"
CHALLENGES
IMPEDING
AD
RESEARCH
AND
KEY
PHILANTHROPIC
OPPORTUNITIES
There
are
a
number
of
challenges
and
unmet
needs
that
stand
in
the
way
of
desperately
needed
progress
in
Alzheimer’s
research.
In
January
2015,
FasterCures
convened
12
world-‐renowned
Alzheimer’s
experts
to
discuss
the
state
of
science
relevant
to
AD
and
the
challenges
currently
impeding
research
progress.
Below
we
present
the
key
issues
that
were
prioritized
by
the
group
and
recommendations
to
address
these
challenges
with
strategic
philanthropic
investments.
It
is
important
to
note
that
the
list
below
is
in
no
way
exhaustive,
and
the
philanthropic
opportunities
presented
here
should
be
considered
carefully
with
respect
to
your
philanthropic
goals
and
discussed
in
detail
with
a
philanthropic
advisor.
LACK
OF
RELIABLE
BIOMARKERS
THE
PROBLEM
The
AD
community
is
in
desperate
need
of
biomarkers
that
will:
• help
clinicians
diagnose
and
measure
AD
progression,
• determine
whether
drugs
are
engaging
intended
molecular
targets
to
better
predict
side
effects
and
inform
dosing
strategies,
and
• enable
accurate
monitoring
of
treatment
responses.
At
this
time
there
is
not
a
single
biomarker
that
can
be
used
confidently
for
these
purposes.
Current
methods
used
to
track
AD
pathology
(primarily
brain
imaging
along
with
amyloid
beta
and
tau
biomarkers
found
in
the
cerebral
spinal
fluid,
or
CSF),
are
compromised
by
variability.
These
challenges
significantly
impede
both
standard
of
care
and
clinical
development
in
that
we
do
not
have
a
reliable
way
to
track
disease
progression
in
patients,
nor
do
we
have
the
tools
necessary
to
effectively
evaluate
behavior
and
performance
of
drug
candidates
in
pre-‐clinical
models.
The
inherent
limitations
of
the
preclinical
data
due
to
lack
of
biomarkers
have
partially
led
to
the
large
number
of
failed
clinical
trials.
POTENTIAL
SOLUTIONS
Biomarker
validation
and
standardization
–
A
concerted
effort
to
both
validate
and
standardize
current
imaging
and
CSF
biomarkers
to
raise
confidence
levels
and
mitigate
variability
will
be
key
to
addressing
this
challenge.
Identification
of
new
biomarkers
–
There
is
a
need
for
a
strategic
clinical
program
that
would
incentivize
the
collection
of
fluids
(blood,
plasma,
serum,
platelets,
CSF,
saliva,
urine)
as
a
standard
to
enable
researchers
to
rationally
explore
various
protocols
that
may
unveil
not
only
new
biomarkers,
but
also
new
ways
to
quantify
current
biomarkers.
Studies
correlating
genotype,
phenotype,
and
biomarkers
–
Collection
of
the
various
types
of
fluids
mentioned
above
would
enable
an
integrated
research
program
that
would
allow
researchers
to
correlate
the
relationship
between
an
individual
patient’s
genes
(genotype),
clinical
display
of
AD
symptoms
(phenotype),
disease
stage,
and
various
biomarkers.
This
will
improve
clinicians’
understanding
of
AD
patient
subpopulations
with
the
aim
of
25. !"
elucidating
which
groups
of
patients
may
respond
better
or
worse
to
various
treatments.
This
method
will
also
help
to
unveil
biomarkers
that
can
be
used
to
diagnose
and
monitor
progression
and/or
treatment
response.
EXAMPLES
OF
CORRESPONDING
PHILANTHROPIC
OPPORTUNITIES:
• Support
initiatives
that
focus
on
standardizing
imaging
parameters
and
CSF
biomarkers.
• Support
researchers
who
are
willing
to
validate
old
and
new
biomarkers
by
attempting
to
replicate
the
original
data
and
publishing
the
results,
whether
they
are
positive
or
negative.
• Support
a
team
of
researchers
that
proposes
the
best
plan
for
conducting
a
large-‐scale
genotype-‐
biomarker-‐phenotype
correlation
study
in
various
patient
populations,
stratified
by
stage
of
disease,
using
fluid
and
imaging
samples.
INADEQUATE
PRECLINICAL
MODELS
THE
PROBLEM
Both
cellular
and
animal
models
used
to
test
agents
before
entering
clinical
trials
do
not
adequately
recapitulate
AD
pathology.
Part
of
the
reason
is
that
it
is
very
difficult
to
mimic
the
complexity
of
the
brain
in
laboratory
models.
As
a
result,
drugs
that
seemingly
modify
the
disease
in
animals
or
conventional
cell
lines
do
not
have
the
same
effect
in
humans,
and
a
large
number
these
agents
fail
in
clinical
trials.
POTENTIAL
SOLUTIONS
Humanized
cells
as
an
alternative
to
animal
models
–
In
this
approach,
induced
pluripotent
stem
cells
are
made
from
skin
cells
and
reprogrammed
to
become
neurons.
These
neuronal-‐like
cells
can
be
used
to
study
genetic
variants
of
AD
that
are
specific
to
individual
patients.
These
patient-‐
and
disease-‐specific
human
iPS
cells
can
be
used
as
a
drug
discovery
platform
that
will
ultimately
enable
a
personalized
medicine
approach
for
AD
and
potentially
shave
years
off
of
the
drug
development
timeline.
While
this
approach
is
exciting
and
considered
to
be
a
major
breakthrough,
more
work
needs
to
be
done
to
validate
the
likeness
of
these
cells
to
human
tissue.
EXAMPLES
OF
CORRESPONDING
PHILANTHROPIC
OPPORTUNITIES
• Support
studies
that
validate
iPS
cells
as
models
of
in
vivo
human
cells
by
comparing
the
transcriptional
profile
(the
pattern
by
which
the
cells
make
DNA)
of
cells
from
human
tissue
samples
with
that
of
differentiated
iPS
cell
transcriptional
profiles.
• Support
a
personalized
medicine
study
using
iPS
cells
from
a
specific
patient,
enabling
researchers
to
recreate
the
patient’s
specific
disease
pathology
in
a
petri
dish
and
allow
for
testing
of
experimental
and/or
repurposed
drugs.
26. !"
IDENTIFYING
NEW
DRUGGABLE
MOLECULAR
TARGETS
THE
PROBLEM
The
identification
of
new
molecular
targets
is
critical
to
the
development
of
new
agents
for
AD.
Historically,
AD
drug
discovery
has
primarily
focused
on
amyloid
beta
and
tau
proteins
as
key
drug
targets.
While
there
is
evidence
that
drugs
targeting
amyloid
beta
and
tau
can
successfully
engage
these
molecules,
they
demonstrate
very
little
efficacy
with
respect
to
mitigating
the
clinical
manifestations
of
AD.
As
a
result,
these
drugs
have
largely
failed
in
clinical
trials.
POTENTIAL
SOLUTIONS
Rather
than
continuing
to
explore
the
same
avenues
of
AD
pathology
that
have
led
to
no
treatment
breakthroughs,
other
processes
suspected
of
playing
a
role
in
AD
pathology
must
be
studied
in
greater
detail.
These
processes
include
but
are
not
limited
to
synaptic
interaction,
vascular
changes
in
the
brain,
the
role
of
inflammation,
and
the
study
of
genetic
mutations
that
protect
against
Alzheimer’s.
EXAMPLES
OF
CORRESPONDING
PHILANTHROPIC
OPPORTUNITIES
• Support
studies
that
evaluate
the
role
of
synaptic
biology
in
healthy
and
AD-‐affected
brains
using
optogenetics
and
other
cutting-‐edge
technologies.
• Support
studies
that
explore
the
role
of
vascular
changes
on
AD
onset
and
progression,
including
the
identification
of
genes
relevant
to
AD
that
affect
vascular
function.
• Support
studies
that
explore
the
role
of
the
immune
system
by
studying
the
communication
between
the
peripheral
and
central
immune
systems
and
how
this
communication
relates
to
AD
susceptibility.
• Support
genotyping
of
individuals
who
are
at
high
risk
for
the
development
of
AD
but
who
have
maintained
normal
cognition
into
old
age.
These
studies
can
potentially
identify
mutational
variants
that
can
protect
against
AD.
• Support
longitudinal
studies
focused
on
deepening
understanding
of
the
physiology
of
healthy
brain
aging
with
the
purpose
of
comparing
results
to
the
physiological
changes
of
AD
brains
and
potentially
identifying
physiological
processes
and/or
genes
that
protect
against
AD.
AD
RESEARCH
IS
CONDUCTED
IN
SILOS
THE
PROBLEM
Alzheimer’s
research
is
currently
conducted
in
silos,
meaning
that
research
conducted
on
different
aspects
of
the
disease
is
not
always
linked
together
in
an
efficient
way.
For
example,
a
researcher
studying
tau
pathology
may
not
regularly
communicate
with
a
researcher
studying
vascular
system
changes
in
AD
patients.
These
silos
also
unintentionally
facilitate
duplication
of
efforts.
For
example,
drug
leads
that
are
either
highly
similar
or
the
same
are
often
developed
at
multiple
institutions
because
there
is
no
efficient
way
of
knowing
27. !"
exactly
which
molecules
have
been
created
and
tested
if
the
results
are
not
published.
This
is
an
enormous
waste
of
resources
and
time,
particularly
if
the
drug
lead
has
failed
testing
and
the
data
have
not
been
shared.
Often,
researchers
are
only
able
to
build
on
the
work
of
others
once
that
work
has
been
published
or
shared
pre-‐
publication
through
an
agreed
collaboration
between
researchers.
POTENTIAL
SOLUTIONS
The
silos
that
are
currently
impacting
acceleration
of
AD
research
can
be
broken
down
by:
• Providing
more
in-‐person
opportunities
to
communicate
and
share
ideas
among
experts
working
in
areas
of
the
field
that
are
currently
not
well
connected.
• Providing
additional
centralized
infrastructures
to
support
sharing
of
ideas
and
data
among
researchers.
• Developing
and
using
a
systems-‐based
infrastructure
that
can
be
populated
with
all
published
information
on
AD
research
with
the
aim
of
creating
a
knowledge
network
that
will
enable
the
assembly
of
a
more
complete
picture
of
the
etiology,
pathology,
and
progression
patterns
of
AD.
EXAMPLES
OF
CORRESPONDING
PHILANTHROPIC
OPPORTUNITIES
• Support
interactive
workshops
for
AD
experts
working
in
diverse
fields,
as
well
as
outside
experts
working
in
related
fields
(e.g.,
immunologists,
data
scientists,
etc.),
to
come
together
to
present
their
work,
discuss
research
roadblocks,
identify
ways
to
address
these
roadblocks,
and
potentially
build
collaborations.
• Support
initiatives
that
incentivize
sharing
of
medicinal
chemistry
data,
which
can
serve
as
key
starting
points
for
motivated
stakeholders
in
the
AD
community
to
develop
new
chemical
entities
and
ultimately
diverse
drug
classes.
Consider
funding
projects
that
will:
§ Provide
an
infrastructure
for
academic
centers
to
catalogue
agents
being
developed
in
their
labs
and
incentivize
the
use
of
this
type
of
resource.
§ Incentivize
drug
development
companies
to
share
structural
safety
databases.
• Support
the
development
of
a
“Bloomberg-‐like”
data
infrastructure
that
can
be
populated
with
all
published
information
on
AD
research
and
used
to
create
a
knowledge
network
that
will
enable
rational
testing
of
drug
candidates
based
on
human
AD
pathology
and
molecular
pharmacology.
This
will
attenuate
(but
not
completely
alleviate)
the
AD
community’s
current
dependence
on
seemingly
encouraging
results
from
animal
models,
which
often
do
not
translate
to
humans,
leading
to
failed
clinical
trials.
