Troy Rohn, Associate

Professor
Department of Biology
Boise State University

Alzheimer’s disease: From the

Bench to the Clinic
 Americans are living longer
in the USA in 1900 the human life span was about 50
years; at present it is approximately 73 years for men and
78 for women.
with the increase in life span has come a significant
risk for Age-related disorders
General characteristics of Alzheimer’s dise
1901, a 51-year-old woman, Auguste D, was
admitted to the state asylum in Frankfurt. She
was suffering from cognitive and language
deficits, auditory hallucinations, delusions,
paranoia and aggressive behavior, and was
studied by Alois Alzheimer (1864–1915), a
doctor at the hospital.

Dr. Alzheimer asked her to write her name.

She failed several times before she looked up,
exasperated, and declared, "I have lost
myself"—an apt description of the fate that had
befallen her. After Auguste D.'s death, the
 What is Alzheimer’s Disease?

Alzheimer’s disease is an irreversible,

progressive brain disease that slowly destroys
memory and thinking skills.

Neurodegenerative disease
characterized by abnormalities
in the brain affecting neurons
Currently, AD is the 8th leading cause of death
in the USA

 Affects 10% of individuals who are 65 years

and older
 Affects 50% of individuals who are 85 years
and older
 The national cost of caring for people with AD is about $100
A series of self-
portraits done
between 1996 and
2000
 Inside the
Human Brain
To understand
Alzheimer’s disease,
it’s important to
know a bit about the
brain…
The Brain’s Vital Statistics
• Adult weight:
about 3 pounds
• Adult size:
a medium cauliflower
• Number of neurons:
100,000,000,000
(100 billion)
• Number of synapses
(the gap between neurons):
100,000,000,000,000
(100 trillion)
 Inside the
Human Brain
Neurons

• The brain has billions of

neurons, each with an axon
and many dendrites.
• To stay healthy, neurons
must communicate with
each other, carry out
metabolism, and repair
themselves.
• AD disrupts all three of
these essential jobs.
 Molecular causes of AD
, there is a profound loss of neurons
 the one over-riding pathological feature
associated with AD is a loss of neurons in
the brain areas associated with memory or
cognitive functions.

 this loss of neurons is reflected as a

pronounced loss of brain mass associated
with AD brains.
ses functional and structural changes in the
 The cerebral cortex, the outer wrinkled region
of the brain is the area hit hardest during the
disease. Normally, it is this region of the
brain that allows for all of the higher
functions in humans
euronal degeneration in AD
Not only are neurons dying in the AD brain,
but there is a significant amount of pruning
that also occurs, which in itself may affect
neural transmission.

y neuron AD ne
AD is characterized by several structural
abnormalities in the brain

Neurofibrillary tangles are one of the two major

 Normally tau
pathological assembles
features microtubules
associated with ADthat
support the structure of the nerve cell.
 In this manner, tau acts in a similar
fashion to a railroad tie stabilizing the
long microtubules that form the framework of
the neuron
Tangles result
when the scaffolding
of the neuron breaks
down. This occurs as
a result of the
inability of Tau, to
bind to
microtubules.

This may affect

neuronal function
and lead to neuronal
cell death
 AD and the Brain

Neurofibrillary
Tangles

Neurons have an internal support structure partly made up of

microtubules. A protein called tau helps stabilize microtubules. In AD,
tau changes, causing microtubules to collapse, and tau proteins clump
together to form neurofibrillary tangles.
The other major pathological
finding in the AD brain are
senile plaques

What is beta-amyloid?

 It is the toxic protein

fragment that is the
major suspect in AD.
Beta-amyloid accumulates
into the characteristic
amyloid plaques that
distinguish the brains
of people who die with
AD.
 AD and the Brain
Beta-amyloid Plaques

1. Amyloid precursor protein (APP) is the

precursor to amyloid plaque.
1. APP sticks through the neuron
membrane.
2. Enzymes cut the APP into fragments
of protein, including beta-amyloid.
2.
3. Beta-amyloid fragments come together
in clumps to form plaques.

In AD, many of these clumps form,

disrupting the work of neurons. This
3. affects the hippocampus and other areas
of the cerebral cortex.
Secretases: The good, the bad, and the ugly
 Beta-amyloid Hypothesis

Beta-amyloid Plaques Tangles Cell

death
AD and the Brain
Preclinical AD • Signs of AD are first noticed in
the entorhinal cortex, then
proceed to the hippocampus.
• Affected regions begin to shrink
as nerve cells die.
• Changes can begin 10-20 years
before symptoms appear.
• Memory loss is the first sign of
AD.
AD and the Brain
• AD spreads through the brain. The
Mild to Moderate AD cerebral cortex begins to shrink as
more and more neurons stop
working and die.
• Mild AD signs can include memory
loss, confusion, trouble handling
money, poor judgment, mood
changes, and increased anxiety.
• Moderate AD signs can include
increased memory loss and
confusion, problems recognizing
people, difficulty with language
and thoughts, restlessness,
agitation, wandering, and repetitive
statements.
AD and the Brain
Severe AD
• In severe AD, extreme shrinkage
occurs in the brain. Patients are
completely dependent on others for
care.
• Symptoms can include weight loss,
seizures, skin infections, groaning,
moaning, or grunting, increased
sleeping, loss of bladder and bowel
control.
• Death usually occurs from
aspiration pneumonia or other
infections. Caregivers can turn to a
hospice for help and palliative care.
Can we determine if
someone has AD while they
are still alive?

Will be covered by Medicare

Presently in clinical
trials and is not yet FDA
approved
urrently FDA-approved Treatments

These class of
drugs include
Exelon® and
Aricept®
Benefits are minimal: Can we do better?
Namenda (Memantine): Glutamate-receptor
antagonist

Drug was
approved in
the USA in
October, 2003

May achieve
additive
benefits when
taken
together with
Aricept
 Drugs in development that will attack
Beta-Amyloid

ugs that block plaque formation

Unclogging the drain: removing beta-amyloid

once it is produced

The drug, NC758 (Alzhemed, a product of

Neurochem Inc.) interferes with the
accumulation of amyloid in the brain and
appears safe in a Phase III clinical trail.
The drug appeared to lower levels of beta-
amyloid after three months of treatment.

Neurochem is now recruiting volunteers for

a Phase III trail. See website www.alz.org
 Unclogging the drain: removing
beta-amyloid once it is
produced
The idea here is
to use the body’s
immune system to
attack the plaques.

By injecting
beta-amyloid,
antibodies will be
made against it
which then will
bind to beta-
amyloid on plaques.

White blood cells

would then home in
The brains of vaccine-treated mice
contained no beta-amyloid deposits
 Immunized patient

Unimmunized patient
 Secretase inhibitors: Block
the Molecular Scissors that
Produce to Beta-Amyloid
Turning off the faucet: removing
beta-amyloid once it is produced
This strategy is still in the early
stages of testing
Eli Lilly reported on a Phase I study
in volunteer subjects without AD using
a compound, LY450139, which interferes
with one set of the “scissors”
responsible for producing beta-amyloid;
Gamma secretase.

No significant side-effects related to

the drug were noted. Blood levels of
beta-amyloid were reduced.

Merck presented data on the

development of a similar drug that
blocks the other set of scissors,
beta-secretase.
Phase II

Phase III

Phase III
The APP gene is on Chromosome 21,
and individuals with DS have an extra
copy (3 instead of 2). This is why they
eventually exhibit symptoms of AD
All individuals with DS over the age of
40 years have neuropathology consistent
with a diagnosis of Alzheimer’s disease