1. Alzheimer's disease (AD) is a progressive brain disorder that destroys memory and thinking skills. The hallmarks of AD in the brain are beta-amyloid plaques and neurofibrillary tangles. 2. There are two main hypotheses for what causes AD - the amyloid hypothesis and tau hypothesis. The amyloid hypothesis posits that beta-amyloid protein fragments clump together to form plaques outside neurons, killing them. The tau hypothesis suggests abnormal tau proteins form tangles inside neurons, disrupting nutrient transport and killing the cells. 3. AD progresses from the earliest preclinical stage through mild, moderate, and severe stages as more brain regions are affected and cognition declines further. Currently, available

1. ALZHEIMER’S
DISEASE
Presented by
Miss. Ashvini Vijay Govande
Assistant Professor
Kandhar College of Pharmacy, Kandhar

2. Although the risk of developing AD increases with age – in
most people with AD, symptoms first appear after age 60 –
AD is not a part of normal aging. It is caused by a fatal
disease that affects the brain.
Alzheimer’s disease is an irreversible, progressive brain
disease that slowly destroys memory and thinking skills.
What is AD?
Slide 4

3. • Plaques and Tangles
• The Changing Brain in AD
AD and the Brain
Slide 15

4. Plaques and Tangles: The Hallmarks of AD
The brains of people with AD have an abundance of two
abnormal structures:
An actual AD plaque An actual AD tangle
• beta-amyloid plaques, which are dense deposits of protein and
cellular material that accumulate outside and around nerve
cells
• Neurofibrillary tangles, which are twisted fibers that build up
inside the nerve cell
AD and the Brain
Slide 16

5. Two Major Hypotheses for AD:
b amyloid protein (BAP) v. tau
1. BAPtists:
The accumulation of a fragment of the amyloid precursor
protein or APP (the amyloid beta 42 residue fragment) leads to
the formation of plaques that someone kill neurons.
2. TAUists:
Abnormal phosphorylation of tau proteins makes them
“sticky,” leading to the break up of microtubules. The resulting
loss of axonal transport causes cell death.

6. Amyloid Hypothesis
(it’s the plaques)
1. The amyloid precursor protein (APP) is broken down by a series of
secretases. .
2. During this process, a non-soluble fragment of the APP protein
(called Ab-42) accumulates and is deposited outside the cell.
3. The non-soluble or “sticky” nature of Ab-42 helps other protein
fragments (including apoE, apolipoprotein E) to gather into
plaques
4. Somehow the plaques (or possible the migration of Ab-42 outside
the cell) cause neuronal death.

7. Enzymes cut the APP into fragments, the most important of which for AD is called b-amyloid (beta-amyloid) or
Ab.

8. Beta-amyloid is “sticky” so the fragments cling together along with other material outside of the cell,
forming the plaques seen in the AD brain.

9. b a g g
APP Protein:
a-secretase cuts APP protein, giving:
g-secretase cuts this residue, giving:
orSoluble
Soluble
a-secretase Pathway:

10. b a g g
APP Protein:
(1) b-secretase cuts APP protein, giving:
(2) g-secretase cuts this residue, giving:
or
Ab40 Fragment
Soluble
Ab42 Fragment
Un-soluble,
aggregates into
plaques
b-secretase Pathway:
(not drawn to scale)

11. Tau Hypothesis
(it’s the tangles)
1. Ordinarily, the tau protein is a microtubule-associated protein that
acts as a three-dimensional “railroad tie” for the microtubule. The
microtubule is responsible for axonal transport.
2. Accumulation of phosphate on the tau proteins cause “paired
helical filaments” or PHFs (like two ropes twisted around each
other) that accumulate and lead to the neurofibrillary tangles
(NFT). PHFs are the main component in NFTs.
3. Impaired axonal transport is the probable cause of cell death.
4. Focus on MAPT gene (microtubule-associated protein tau)

12. Microtubules are like railroad tracks that transport nutrition and other molecules. Tau-proteins
act as “ties” that stabilize the structure of the microtubules. In AD, tau proteins become
tangled, unstabilizing the structure of the microtubule. Loss of axonal transport results in cell
death.

13. 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
Slide 20

14. Mild to Moderate AD
AD spreads through the brain. The
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
Slide 21

15. 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. Care-givers can turn to a
hospital for help and palliative
care.
AD and the Brain
Slide 22

16. Classification of Anti-Alzheimer’s agents
Anti-Alzheimer’s agents are the agents which improve the
function of dementia and loss of cognitive abilities.
Slide 5
Reversible
Acetylcholinesterase inhibitor
Antialzheimer’s
NonselectiveSelective
Rivastigmine
Galantamine
Donepezil
Tacrine Memantine

17. Rivastigmine
It is carbamate derivatives
It is parasympathomimetics or cholinergic agent for the
treatment of mild to moderate dementia.
MOA-
It inhibits the enzymes both Buterylcholinesterase
(BuChE) and acetylcholinesterase (AChE) present in CNS
 It prevent the hydrolysis of acetycholine, and thus
leading to an increased concentration of acetylcholine at
cholinergic synapses.
Acetycholine is an important neurotransmiter in brain
region involved in memory
Slide 6

18.  Side effect-
 Nausea, vometing, decreased appetite, weight loss, bloody and tarry
stools, coughing up blood or vomit that looks like blood, feeling
light-headed, fainting, chest pain, confusion, agitation and extreme
fear.
 Pharmacokinetics-
 Well absorbed orally
 Bioavailability of about 40% in 3 mg dose
 Elimination through urine
 Uses-
 For treatment of alzheimer disease
Slide 9
Continue...

19.  It is benzazepine derived from norbelladine
 It is cholinesterase inhibitor that has been used to reserve the
muscular effects of gallamine triethiodide and tubocurarine
 MOA-
 It involve the reversible inhibition of acetylcholinesteras,
which prevents the hydrolysis of acetylcholine
 Leads to increase in conc. of Ach at cholinergic synapses
 It binds allosterically with nicotinic acetylcholine receptor
and may potiantiate the action of agonists (such as Ach) at
these receptor
Galantamine
Slide 10

20.  It is a centrally acting reversible acetyl cholinesterase
inhibitor
 It is piperdine derivative
 MOA-
 It involve the reversible inhibition of acetylcholinesteras,
which prevents the hydrolysis of acetylcholine
 Leads to increase in conc. of Ach at cholinergic synapses
Donepezil
Slide 11

21. It is centrally active cholinesterase inhibitor that has been
used to counter the effects of muscle relaxant, respiratory
stimulant and in treatment of alzheimer disease and other
CNS disorder
MOA-
Mechanism is not fully known
But it is proposed that the drug is an anticholinesterase
agent which reversibly binds with and inactivates
cholinesterase
This inhibit the hydrolysis of Ach, thus leading to an
accumulation of Ach at cholinergic synapse
Uses- to treat mild to moderate dementia of AD
Tacrine
Slide 12

22. It is an amantadine derivative with low to moderate affinity
for NMDA receptor.
It is noncompetitive NMDA receptor antagonist that binds
preferentially to NMDA receptor-operated cation channel
It blocks the excessive level of glutamate that may leads to
neuronal dysfunction.
MEMANTINE
Slide 13

23. MOA-
Continuous activation of the N-methyl-D-aspartate (NMDA) receptors in
the central nervous system caused by glutamate is thought to cause some
of the Alzheimer's disease symptoms. This overactivation is thought to
contribute to neurotoxicity due to the excitatory properties of glutamate.
The pharmacological effect of memantine likely occurs via the drug's
behavior as an uncompetitive (open-channel) NMDA receptor antagonist,
preventing glutamate action on this receptor.
Memantine has a preference for the NMDA receptor-operated cation
channels. Despite these antagonist effects, memantine has not been proven
to prevent or retard the neurodegeneration seen in patients diagnosed with
Alzheimer’s disease
Continue...
Slide 16

24. Continue...
 Pharmacokinetic-
 Well absorbed orally
 Bioavailabilty approximately 100%
 Peak plasma conc. Are reached in 3-7hrs
 Food has no effect on absorption
 Volume of distribution is 9 to 11 L/kg
 Protein binding 45%
 Excreated through urine .

25. Thank you