The document discusses recent advances in the pharmacotherapy of Alzheimer's disease, including its epidemiology, pathogenesis, and various pharmacotherapeutic strategies. Key therapies such as cholinesterase inhibitors and new drug candidates targeting amyloid-beta aggregation and tau pathology are highlighted, emphasizing the complexity of Alzheimer's treatment. The ultimate goal of pharmacotherapy is to change disease progression rather than merely alleviate symptoms.

1. Dr. Mohit Kulmi
Postgraduate resident
Department of
Pharmacology
SAMC & PGI, Indore

2. RECENT ADVANCES IN THE
PHARMACOTHERAPY OF ALZHEIMER’S
DISEASE

3. INTRODUCTION & BRIEF
HISTORY

4. “Alzheimer’s disease
(AD) is the commonest
progressive, dementing
neuro-degenerative
disease in the elderly
characterised by memory
loss, language
difficulty and

5. ▪Alois Alzheimer, a
German physician, is
credited with being the
first to describe AD.
▪In 1906, Dr. Alzheimer
observed a patient,
Auguste Deter, in a
local asylum who
exhibited strange
behaviours. He followed
her care and noted her
memory loss, language
difficulty and

6. ▪ After her death at the age of 51,
he examined her brain tissue. The
slides showed what are now known as
plaques and tangles.
▪ In 1911, Doctors were using Dr.
Alzheimer’s research to base
diagnosis.
▪ In the 1960’s British pathologists
determined that AD was not a rare
disease of the young but rather
what had been termed “senility.”
▪ In the 1990’s researchers
identified that the beta amyloid
protein was a factor in AD.

7. EPIDEMIOLOGY
▪ MC cause of dementia, > 65yr.
▪ Risk at the age of 80 years is
around 15 to 20%.
▪ About 7.7 million new cases of
dementia each year. A new case
detected in every 4 seconds
somewhere in world.

9. THE STAGES OF ALZHEIMER’S DISEASE
Mild Moderate Severe
• Memory Loss
• Language
Problems
• Mood and
Personality
Changes
• Diminished
Judgement
• Behavioral,
Personality
Changes
• Unable to
Learn or
Recall New
Information
• Long-Term
Memory
Affected
• Wandering,
Agitation,
Aggression,
Confusion
• Require
Assistance
with ADLs
• Unstable
Gait
• Incontinence
• Motor
Disturbances
• Bedridden
• Dysphagia
• Mute
• Poor/No ADLs
• Vacant
• LTC
Placement
• Common
ADL = activities of
daily living
LTC = long-term care

10. RISK
FACTORS
▪ Every 5 yrs. beyond 65,
the % of people with AD
doubles
▪ Strong genetic component
▪ Early onset – fully
penetrant
▪ Late onset – reduced
penetrant
▪ Gender – women, ?
Estrogen
▪ Tobacco
▪ Head injury
▪ Obesity
▪ Hypertension , diabetes
▪ Elevated serum
cholesterol
▪ Elevated serum
homocysteine
▪ Depression
▪ Lack of intellectual
stimulation/education

11. PROTECTIVE
FACTORS
▪ Physical activity
▪ Caffeine consumption
▪ Antioxidants – VITAMIN C, E, B6 and
B12
▪ Folate
▪ Omega 3 fatty acid intake
▪ Speaking > 2 languages

12. PATHOGENESIS AND PATHOPHYSIOLOGY
AD is characterized by generalized
cerebral cortical atrophy, neuronal
loss, widespread cortical neuritic
plaques and neurofibrillary tangles.
Following mechanisms have been attributed
for the development of Alzheimer’s
dementia:
▪ Amyloid cascade theory
▪ Cholinergic hypothesis
▪ Excitotoxicity
▪ Genetic factors

13. AMYLOID CASCADE
THEORY
▪ Alzheimer’s disease begins with the
abnormal build-up of an amyloid protein
in the brain from APP (amyloid precursor
protein).
▪ APP is normally found in the cell
membranes of neurons and normally
metabolised by a protease enzyme
α-secretase.
▪ In AD, the metabolism of APP is altered
by two other enzymes β and γ-secretase
and is called β amyloid (Aβ).

14. ▪ Amyloid-β is originated by the
alternative cleavage of the amyloid
precursor protein (APP) into smaller
peptides (Aβ1-40 and Aβ1-42) by enzymes
β and γ-secretase.
▪ Aβ1-42 is more prone to form insoluble
aggregates (and therefore more toxic)
than Aβ1-40.
▪ Once Aβ is formed, it accumulates into
insoluble sheets (called β-pleated
sheets).

15. ▪ Ageing, seems to affect the balance
between production and clearance of
toxic Aβ peptides.
▪ These deposits are neurotoxic and
activate inflammatory reaction
resulting in the formation of senile or
neuritic plaque.
▪ This is accompanied by
hyperphosphorylation of tau protein,
supporting the microtubules.

16. ▪ Hyperphosphorylated Tau aggregates into
oligomers to form NFTs.
▪ Several protein kinases are involved in
this process, namely glycogen synthase
kinase-3 beta (GSK3β).
▪ GSK-3β, the most important Tau kinase in
neurons, is overactive in AD

17. • Amyloid
precursor
protein (APP)
is a membrane
protein
• Sits in the
membrane and
extends
outward.
• It is thought
to be
important for
neuronal
growth,
survival, and
repair

18. • Secretases
cut the APP
into
fragments
• The most
important
of which
for AD is
called
beta-
amyloid Or
Aβ

19. ▪ Beta-
amyloid is
“sticky”
▪ The
fragments
cling
together
along with
other
material
outside of
the cell
▪ Forms the
Plaques
seen in
the AD

21. ALZHEIMER BRAIN vs. NORMAL
BRAIN

22. CHOLINERGIC
HYPOTHESIS
▪ Levels of acetylcholine, noradrenaline,
serotonin, γ-aminobutyric acid (GABA),
glutamate, somatostatin, neuropeptide
Y, and substance P have all been
documented to be reduced in the brains
of AD patients.
▪ Reductions in acetylcholine and choline
acetyltransferase are the most
profound.
▪ Neuronal loss in the basal forebrain,
which is the major region from which
cholinergic projections originate.

23. EXCITOTOXICITY
▪ Excessive release of glutamate into the
synapses.
▪ Excessive influx of calcium into the
cells leading to cell death called
excitotoxicity.
▪ Also lead to excessive production of Aβ
and tau phosphorylation.

25. PHARMACOTHERAPY
DRUGS FOR THE TREATMENT OF ALZHEIMER’S

26. CHOLINESTERASE
INHIBITORS
▪ Tacrine (1993)
▪ Donepezil (1996)
▪ Rivastigmine (2000) and
▪ Galantamine (2001)

27. ▪ Tacrine: It is the first centrally acting
anti-ChE to be introduced for AD.
▪ In clinical trials tacrine produced
significant improvement in memory,
attention, praxis, reason and language.
▪ Frequent side effects and hepatotoxicity
have restricted its use.
▪ Donepezil: This is a cerebroselective and
reversible anti-AChE drug.
▪ Because of long t½ (~70 hr), donepezil is
administered once daily at bed time; a
distinct advantage over rivastigmine and
galantamine which need twice daily
dosing. Moreover, it can be used even in
relatively severe case of AD.

28. ▪ Rivastigmine: This carbamate derivative
of physostigmine inhibits both AChE and
BuChE.
▪ The carbamyl residue introduced by
rivastigmine into AChE molecule
dissociates slowly resulting in
inhibition of cerebral AChE for upto 10
hours despite the 2 hr plasma t½ of the
drug.
▪ Galantamine: It is a natural alkaloid
which selectively inhibits cerebral
AChE and has some direct agonistic
action on nicotinic receptors as well.

29. ▪ Memantine: It appears to restore the
function of damaged nerve cells and
reduce abnormal excitatory signals by the
modulation of the NMDA receptor activity.
▪ It is indicated in moderate-to-severe AD,
either to replace anti-AChEs or to
supplement them.
▪ Piracetam : This cyclic GABA derivative
has no GABA like activity. It selectively
improves efficiency of higher
telencephalic neurons.
▪ Pyritinol (Pyrithioxine) : It consists of
two pyridoxine molecules joined through a
disulfide bridge, but has no vit. B6
activity.
▪ It is claimed to activate cerebral

30. ▪ Dihydroergotoxine : It is a
semisynthetic ergot alkaloid having α
adrenergic blocking property; claimed to
increase cerebral blood flow
selectively.
▪ Citicoline: It is a compound derived
from choline and cytidine, that is
involved in biosynthesis of lecithin.
▪ Citicoline is believed to improve
cerebral function by increasing blood
flow to the brain and enhancing cerebral
metabolism.
▪ Ginkgo biloba: The dried extract of this
Chinese plant contains a mixture of
ginkgoflavon glycosides, which have PAF
antagonistic action.

31. ▪Piribedil: It is a dopaminergic agonist
claimed to improve memory, concentration,
vigilance, giddiness and tinnitus in the
elderly due to circulatory insufficiency.

32. RECENT
ADVANCES

33. CLASSIFICATI
ON
 Cholinesterase
inhibitor
 Aβ-TARGETING
STRATEGIES-
 β-secretase
inhibitors
 γ-secretase
inhibitors/modulators
 α-secretase
activators/modulators
 Aβ-aggregation
inhibitors
 M1 muscarinic
agonists
 Aβ-degrading enzymes
 Apolipoprotein E
(ApoE)
 Drug development based
on the metals
hypothesis
 HMG-CoA reductase
inhibitors
 MAO inhibitors
 Treatments based on
tau pathology
 Non-steroidal
antiinflammatory drugs
(NSAIDs)
 Estrogens, Nicotine,
Melatonin
 Cell transplantation
and gene therapy
 Docosahexaenoic acid
(DHA), Clioquinol,

34. CHOLINESTERASE
INHIBITOR
▪ Phenserine: Phenserin treatments
increased cognition and regional cerebral
metabolic rate for glucose in AD patients.
▪ Dimebon: A cholinesterase inhibitor and
also a NMDA-antagonist, showed improved
cognitive and self-service functions while
diminishing the psychopathic symptoms in
AD patients.
▪ Huperzine A: A Chinese herb with
reversibly and selectively
acetylcholinesterase inhibition activity.

35. ▪ Ladostigil : A multimodal drug, combined
neuroprotective effects with monoamine
oxidase (MAO) -A and -B and
cholinesterase inhibitory activities in a
single molecule, was tested and now in
Phase II clinical trial.
▪ PMS777: A new cholinesterase inhibitor
with anti-PAF activity is also in
clinical trial

36. Aβ-TARGETING
STRATEGIES

37. β-SECRETASE
INHIBITORS
▪ BACE (β- site APP cleaving enzyme):
Lateral ventricular injection of this
inhibitor led to a significant dose- and
time-dependent lowering of brain Aβ40
and Aβ42, a robust decreased sAPPβ and an
increased sAPPα secretion.
▪ KMI-429: Injection of this inhibitor
into the hippocampus of APP transgenic
mice reduced Aβ production.
▪ GSK188909: Oral administration of this
non-peptidic BACE1 inhibitor results in
a significant reduction in the level of

38. γ-SECRETASE INHIBITORS
▪ BMS-299897
▪ MRK-560.
▪ LY450139 dehydrate
α-SECRETASE ACTIVATORS/MODULATORS
▪ Since α-secretase and β-secretase
compete for the same substrate of APP,
upregulation of α-secretase activity may
decrease the amount of APP available
for β-secretase, and thus decrease Aβ
secretion and have therapeutic
potential.

39. ▪ Many studies had indicated that members
of the adamalysin family of proteins
ADAM (A Disintegrin And
Metalloproteinase) mainly ADAM10, ADAM
17 and ADAM 9, fulfill some of the
criteria required of α-secretase.
▪ Deprenyl: A neuroprotective agent used
to slow AD progress, was shown to
increase α-secretase activity by
promoting ADAM10 activity.

40. Aβ-aggregation
inhibitor
▪ iAβ5p: This is the first drug was a β-
sheet breaker, which showed that intra
hippocampal injection of it resulted in
improved spatial memory and decreased
amyloid plaque deposits.
▪ Tramiprosate: It is a compound that
binds to soluble Aβ and inhibits the
formation of neurotoxic aggregates that
lead to amyloid plaque deposition in
the brain.

41. M1 MUSCARINIC AGONISTS
M1 muscarinic receptors play a role in an
apparent linkage of three major hallmarks
of AD: Aβ peptide; tau
hyperphosphorylation and loss of
cholinergic function.
▪ Talsaclidine: It is a functionally
selective muscarinic M1 agonist that
stimulates non-amyloidogenic α-secretase
processing in vitro.
▪ Treatment with talsaclidine decreased
CSF Aβ about 20% as compared with the
baseline, suggesting its therapeutic
potential.

42. Aβ-DEGRADING
ENZYMES
▪ Neprilysin (NEP),
▪ Insulin degrading enzyme (IDE),
▪ Plasmin,
▪ Endothelin converting enzyme (ECE) 1
▪ Angiotensin-converting enzyme.

43. ▪ Imatinib: A tyrosine kinase inhibitor,
cause increase of NEP protein, mRNA
levels, and activity.
▪ Valproic acid: A widely used drug in
the treatment of epilepsy, was capable
of up-regulating NEP expression, seen
in experimental rats.
▪ Estrogen and green tea all could
increase NEP activity and suggest
their potential in AD treatment but
there is a long way before their final
clinical application.

44. ▪ Apolipoprotein E (ApoE) promotes Aβ
clearance
▪ The ApoE activates microglia and/or
astrocyte to degrade Aβ. It decreased
brain amyloid plaque burden and
improved behaviour functions in AD
transgenic mice.
▪ Bexarotene: Is a nuclear receptor
modulator and ApoE activator.
APOLIPOPROTEIN E
(ApoE)

45. Aβ BLOOD–BRAIN BARRIER
TRANSPORT
▪ The receptor for advanced glycation
end products (RAGE) resides in the
blood vessel wall cells and transport
Aβ across the blood brain barrier from
systemic circulation to facilitate
their accumulation in brain.
▪ In contrast to RAGE, low-density
lipoprotein receptor-related protein-1
(LRP-1) mediates transport of Aβ
peptide out of brain.
▪ Thus inhibition of RAGE and/or

46. IMMUNOTHERAPY
▪ Passive immunotherapy in AD patients
with repeated intravenous
administration of human immunoglobulin
against Aβ peptide resulted in stopped
cognitive decline and slight
improvement in functional scores.
▪ Bapineuzumab: It shows decreased total
and phosphorylated tau levels in CSF
without affecting Aβ level.
▪ LY2062430 and AN1792A : On Phase I and
II clinical trials.

47. DRUGS DEVELOPMENT BASED ON
THE METALS HYPOTHESIS:
▪ There is increasing evidence that metal
(mainly Cu, Zn and Fe) metabolism is
involved in the major pathophysiological
events of AD: APP processing and tau
hyperphosphorylation.
▪ Several chelators of Zn/Cu have been
shown to inhibit Aβ aggregation in vitro
and in vivo.
▪ A phase II clinical trial with
clioquinol, a metal-protein-attenuating
compound that inhibits zinc and copper
ions from binding to Aβ, led to improved

48. HMG-CoA REDUCTASE INHIBITORS (THE
“STATINS”)
▪ Clinical trial with atorvastatin
provides some clinical benefit in AD
patients. Treatment with lovastatin
resulted in decreased plasma Aβ level.
MONOAMINE OXIDASE INHIBITORS
▪ MAO inhibitor deprenyl is an anti-
Parkinson drug used to inhibit dopamine
degradation in the brain. Also as a
neuroprotective agent, deprenyl has been
used to slow the progress of
neurodegenerative diseases such as AD
for many years.

49. PREVENTING THE MISFOLDING OF
TAU
▪ Chaperones: The results from a study by
Dou and colleagues suggested that
increasing the activation of molecular
chaperones might prevent the misfolding
of tau, which would then reduce the
development of NFTs.
▪ Heat shock proteins: They have been
shown to activate chaperones that
prevent misfolding and even promote tau
binding with microtubules.

50. NON-STEROIDAL ANTI-INFLAMMATORY DRUGS
(NSAIDS)
▪ Many epidemiological studies, have
suggested that the prolonged intake of
NSAIDs may be associated with a reduced
incidence of AD.
ESTROGENS
▪ Merlo et al. reported that estrogen can
activate matrix metalloproteinases-2 and
−9 to increase beta amyloid degradation.
NICOTINE
▪ Many studies have reported the effects
of intravenous or subcutaneous nicotine
administration on people with AD.
▪ Significant improvements were reported

51. MELATONIN
▪ In AD patients, melatonin
supplementation has been suggested to
improve circadian rhythmicity, and to
produce beneficial effects on memory.
CELL TRANSPLANTATION AND GENE THERAPY
▪ In AD rat model, transplantation of
cholinergic-rich tissue or peripheral
cholinergic neurons ameliorates abnormal
behavior and cognitive function.
▪ Nerve growth factor (NGF) administration
rescues neurons from injury-induced cell
damage and leads to associated memory
improvements and thus NGF is good for

52. DOCOSA-HEXAENOIC ACID (DHA)
▪ DHA is the most abundant omega 3 fatty
acid in the brain. Data from animal
models support the hypothesis that DHA
maybe an effective treatment for AD by
means of antiamyloid, antioxidant, and
neuroprotective mechanisms.
RESVERATROL
▪ Resveratrol, a red wine polyphenol,
recent studies on red wine bioactive
compounds suggest that resveratrol
modulates multiple mechanisms of AD
pathology.
▪ Exert its neuroprotective role through

53. VACCINES
▪ AN-1792: Phase I studies of AN-1792
in humans indicated that the vaccine
was well tolerated, and a portion of
the patients developed amyloid
antibodies.
▪ Passive immunization: By using
antibodies to Aβ4-10.
▪ Intravenous immunoglobulin (IVIg):
IVIg infusion may have long-term
benefits for the treatment of
cognitive decline in Alzheimer’s
disease.

55. The ultimate goal
for Alzheimer’s
disease
pharmacotherapy is
not merely to
ameliorate
symptoms, but to
alter the onset or
progression of the
disease.
There are four
drugs (donepezil,
galantamine,
rivastigmine, and
CONCLUSION

56. CONCLUSION
The numerous
complex and
interrelated
biochemical
pathways underlying
neurodegeneration
in Alzheimer’s
disease can provide
numerous potential
targets for
therapeutic
intervention.
Several
investigational
compounds have

57. CONCLUSION
Gradual elucidation
of the exact
mechanisms of
neurodegeneration
will result in
increasingly
focused drug
development
efforts.

58. Thank
sQuestions?