- Alzheimer's disease (AD) is a progressive dementia characterized by cognitive decline and behavioral changes. It is the most common type of dementia and risk increases with age. - The pathology of AD involves beta-amyloid plaques and tau neurofibrillary tangles in brain regions critical for memory and cognition. This leads to deficits in the neurotransmitter acetylcholine. - While the exact causes are unknown, genetic and environmental factors likely contribute. Treatment focuses on managing symptoms with cholinesterase inhibitors or memantine, which target acetylcholine and glutamate pathways respectively. Currently there is no cure for AD.

1. ALZHEIMER’S DISEASE
Mahek Mistry
4th Pharm.D
Department of Pharmacy.

2.  Alzheimer’s disease (AD) is a non-
reversible, progressive dementia
manifested by gradual deterioration in
cognition and behavioral disturbances.
 AD is primarily diagnosed by exclusion of
other dementias.
 There is currently no cure for AD; however,
drug treatment can slow symptom
progression over time.
 The Alzheimer’s Association has developed
a checklist of common symptoms.

4. Epidemiology and Etiology
 AD is the most common type of
dementia.Table-2
 The prevalance of AD increases with age
and it is the most prevalent in persons age
65 years and older.
 The severity of AD also correlates with
increasing age and is classified as mild,
moderate or severe.
 The mean survival time of persons with AD
is reported to b approximately 6 years from
the onset of the symptoms until death.

5. Epidemiology and Etiology
 Although AD does not directly cause death,
it is associated with an increase in various
risk factors which often contribute to death
such as senility, sepsis, stroke, pneumonia,
dehydration, and decubitus ulcers.
 Exact etiology is unknown; however, it has
been suggested that genetic factors may
contribute to errors in protein synthesis
resulting in formation of abnormal proteins
involved in the pathogenesis of AD.

6. Epidemiology and Etiology
 Mutations in three genes, presenilin 1 on
chromosome 21, amyloid precursor protein
(APP) on chromosome 21, and presenilin 2
on chromosome 1, lead to an increase in β-
A4 peptide fragments of APP which forms
neuritic plaques that are the pathologic
hallmark of AD.
 Genetic susceptibility is more sporadic and
it may be more dependent on
environmental factors.

7. Epidemiology and Etiology
 The apolipoprotein E (apo E) gene on
chromosome19 has been identified as a
strong risk factor for late-onset AD.
 There are three variants of apo E; however,
carriers of two or more of the apo E4 allele
have an earlier onset of AD (approximately
6 years earlier) compared with non-
carriers.9 Only
 50% of AD patients have the apo E4 allele,
thus indicating it is only a susceptibility
marker.

8. Pathophysiology
 The pathologic hallmarks of the disease in
the brain include neurofibrillary tangles and
neuritic plaques made up of various
proteins, which result in a shortage of the
neurotransmitter acetylcholine.
 These are primarily located in brain regions
involved in learning, memory, and emotional
behaviours such as the cerebral cortex,
hippocampus, basal forebrain, and
amygdala.

9. Tangles
 Neurofibrillary tangles are intracellular and consist
of abnormally phosphorylated tau protein which is
involved in microtubule assembly.
 It interferes with neuronal function resulting in cell
damage, and their presence has been correlated
with severity of dementia.
 These tangles are insoluble even after the cell
dies, and they cannot be removed once
established.
 The neurons that provide most of the cholinergic
innervation to the cortex are most prominently
affected.
 Therefore, prevention is the key to targeted
therapy of these tangles.

10. Plaques
 Neuritic or senile plaques are extracellular protein deposits of
fibrils and amorphous aggregates of β-amyloid protein.
 This formed protein is central to the pathogenesis of AD.
 The β-amyloid protein is present in a non-toxic, soluble form
in human brains.
 In AD, conformational changes occur that render it insoluble
and cause it to deposit into amorphous diffuse plaques
associated with dystrophic neuritis.
 Over time, these deposits become compacted into plaques
and the β-amyloid protein becomes fibrillar and neurotoxic.
 Inflammation occurs secondary to clusters of astrocytes and
microglia surrounding these plaques.

11. Acetylcholine (Ach)
 It is responsible for transmitting message b/w certain
nerve cells in the brain.
 In AD, plaques and tangles damage these pathways,
leading to a shortage of Ach, resulting in learning and
memory impairment.
 The loss of Ach activity correlates with the severity of
AD.
 The basis of pharmacologic treatment of AD has been
to improve cholinergic neurotransmission in the brain.
 Acetylcholinesterase is the enzyme that degrades Ach
in the synaptic cleft. Blocking this enzyme leads to an
increased level of Ach with a goal of stabilizing
neurotransmission.
 In the United States, the four cholinesterase inhibitors
approved for the treatment of AD are tacrine, donepezil,
rivastigmine, and galantamine.

12. Glutamate
 Primary excitatory neurotransmitter in the central
nervous system (CNS) involved in memory, learning,
and neuronal plasticity.
 In AD, one type of glutamate receptor, N-methyl-D-
aspartate (NMDA), is less prevalent than normal. There
also appears to be over activation of unregulated
glutamate signalling.
 This results in a rise in calcium ions that induces
secondary cascades which lead to neuronal death and
an increased production of APP.
 The increased production of APP is associated with
higher rates of plaque development and
hyperphosphorylation of tau protein.
 The drug memantine is a non-competitive NMDA
antagonist which targets this pathophysiologic
mechanism.
 Memantine is presently the only agent in this class that
is approved for the treatment of AD.

13. Cholesterol
 Increased cholesterol concentrations have
been associated with AD.
 The cholesterol increases β-amyloid protein
synthesis which can lead to plaque
formation.
 Also, the apo E4 allele is thought to be
involved in cholesterol metabolism and is
associated with higher cholesterol levels.

14. Estrogen
 Estrogen appears to have properties that
protect against memory loss associated with
normal aging. It has been suggested that
estrogen may block β-amyloid protein
production and even trigger nerve growth in
cholinergic nerve terminals.
 Estrogen is also an antioxidant and helps
prevent oxidative cell damage.
 It is important to note, however, that the
Women’s Health Initiative Memory Study
reported that hormone replacement with either
estrogen alone or estrogen plus
medroxyprogesterone resulted in negative
effects on memory.

15. Clinical Presentation and
Diagnosis
 Diagnosing AD relies on a thorough medical and
psychological history, mental status testing, and
laboratory data to exclude other possible causes.
 There are no biological markers other than those
pathophysiologic changes found at autopsy that
can confirm AD.
 The diagnostic criteria are based on the Diagnostic
and Statistical Manual of Mental Disorders, Fourth
Edition, Text Revision (DSM-IV-TR) or the National
Institute of Neurological and Communicative
Diseases and Stroke/Alzheimer’s Disease and
Related Disorders Association (NINCDS-ADRDA).
 These diagnostic criteria are 85% to 90% accurate
in diagnosing AD.

16. Clinical Presentation and
Diagnosis
 AD is a progressive disease, which
overtime affects multiple area of cognition.
 The symptoms of AD can be divided in to
cognitive, non-cognitive and functional
symptoms.

22. Treatment
 The current gold standard of treatment for
cognitive symptoms includes pharmacologic
management with a cholinesterase (ChE)
inhibitor and/or an NMDA antagonist.
 There are currently four ChE inhibitors
available on the United States market: tacrine,
rivastigmine, galantamine, and donepezil.
 The use of tacrine is limited due to its
propensity for hepatotoxicity and difficult
titration schedule.
 Essential elements in the treatment of AD
include education, communication, and
planning with the family/caregiver of the
patient.

23. Nonpharmacological
Treatment
 Mainly this disease can be devastating to
both the patient and family.
 Upon the initial diagnosis, the patient and
family should be counselled on the course
of the illness, prognosis, available
treatments, legal decisions, and quality-of-
life issues.
 The life of a patient with Alzheimer’s
disease must become progressively more
simple and structured as the disease
progresses.

24. Pharmacological Treatment
 Different classes of drug which is
given in treatment of AD :
◦ Cholinesterase Inhibitors (Donezepil,
Rivastigmine, Galatamine, Tacrine).
◦ NMDA Receptor Antagonist (Memantine).

27. Cholinesterase Inhibitors
 All have the indication for the
treatment of mild to moderate
dementia of the Alzheimer’s type.
 Tx should begin as early as possible.
 ChE inhibitor therapy should be
discontinued in patients who
experience poor tolerance or
compliance, who show a lack of
clinical improvement after 3 to 6
months at optimal dosing.

28. Donezepil
 It is a piperidine cholinesterase
inhibitor, which reversibly and non-
competitively inhibits centrally acting
Acetylcholinesterase.
 Approved for tc of mild to moderate
dementia of the AD.
 ADR with donezepil includes nausea,
vomiting and diarrhea.

29. Rivastigmine
 Has central activity for both the
acetylcholinesterase and
butyrylcholinesterase enzyme.
 Approved for the treatment for mild to
moderate dementia of AD.
 Cholinergic side effects are common.

30. Galantamine
 It is a ChE inhibitor, which elevates
acrtylcholine in the cerebral cortex by
slowing the degradation of
acetylcholine.
 It also modulates the nicotinic
acetylcholine receptors to increase
acetylcholine from surviving
presynaptic nerve terminals.
 In addition, it may increase glutamate
and serotonin levels.

31. Galantamine
 It is approved for the treatment of mild
to moderate demtia of AD.
 ADR is nausea, vomiting, diarrhea.

34. NMDA Receptor Antagonist -
Memantine
 It is a non-competitive anatagonist oo the N-
methyl-D-aspartate type of glutamate
receptor.
 It regulates activity throughout the brain by
controlling the amount of calcium that enters
the nerve cell, a process essential for
establishing an environment required for
information storage.
 Overstimulation of the NMDA receptor by
excessive glutamate allows too much calcium
into the cell, disrupting information
processing.
 Blocking NMDA receptors with memantine
may protect neurons from the effects of
excessive glutamate without disrupting

35. NMDA Receptor Antagonist
 Memantine is indicated for the treatment of
moderateto-severe dementia of the Alzheimer’s
type.
 The initial dose is 5 mg/day with increases to 20
mg/day if needed, with a minimum of 1 week
between dosage increases.
 Doses greater than 5 mg/day should be given in
two divided doses. A suggested titration is: 5
mg/day for at least 1 week; 5 mg twice daily for
at least 1 week; 15 mg/day (5 mg in the morning
and 10 mg in the evening) for at least 1 week;
then 10 mg twice daily.
 If the patient has a creatinine clearance of 5 to
29 mL/minute, then the target dose should be 5
mg twice daily. It is likely to be given as
monotherapy, but can be given in combination
with ChE inhibitors.

36. NMDA Receptor Antagonist
 ADR includes constipation, confusion,
dizziness, headache, coughing and
hypertension.
 These adverse effects are similar to
those experienced with ChE inhibitors.
Extra monitoring should be done if
memantine is given concurrently with
a ChE inhibitor.

37. Thank You