ALZHEIMER'S DISEASE MANAGEMENT

1. CURRENT MANAGEMENT OF ALZHEIMER’S
DISEASE AND AMYLOID PEPTIDES
Dr Amit Mittal
Dept of Pharmacology
SMMH Medical College
SAHARANPUR (U.P.)
INDIA

2. ALZHEIMER’S DISEASE
 Medial temporal lobe, including entorhinal cortex and
hippocampus
 Anterograde episodic memory loss: repeated questions,
misplaced items, missed appointments, and forgotten details
of daily life
 Memory loss is one of the earliest symptoms
 Gradual decline of other intellectual and thinking abilities,
called cognitive functions

3. EPIDEMIOLOGY
 Most common cause of dementia amongst people aged 65
and older
 Starting with 0.5% prevalence at 55 yrs, it goes on doubling
every five years (60yrs-1%; 65yrs-2%; 70yrs- 4%; 75yrs- 8%
and so on)
 Average prevalence of dementia in india: 3.7%
 At present nearly 47.5 million people worldwide with
dementia.
 It is expected to be 74.7 million by 2030 and 131.5 million by
2050.
 A new case detected in every 3 seconds somewhere in
world. (WHO)

4.  Dr. Aloysius "Alois" Alzheimer was a
German psychiatrist and
neuropathologist
 Alzheimer is credited with identifying
the first published case of "presenile
dementia", which Kraepelin would
later identify as Alzheimer’s disease.
History
Emil Kraepelin

5.  In 1901, dr. Alzheimer observed a
patient at the frankfurt asylum named
auguste deter. The 51-year-old
patient had strange behavioral
symptoms, including a loss of short-
term memory.
 Therefore it was named as
alzheimer‘s disease.
Alois Alzheimer's patient
Auguste Deter in 1902.

6. Clinical Features

7. FAST SCALE (FUNCTIONAL ASSESSMENT STAGING)
 STAGE 1: No impairment
 STAGE 2: Complaints of forgetting location of objects
 STAGE 3:
 Decreased job functioning evident to co-workers
 Difficulty in traveling to new places
 Decreased organizational capacity.
 STAGE 4:
 Decreased ability to perform complex tasks, e.g., planning dinner for guests
 handling personal finances
 difficulty in marketing etc.

8. FAST SCALE (FUNCTIONAL ASSESSMENT STAGING)
 STAGE 5: Requires assistance in choosing proper clothing to
wear for the day, season or occasion, e.g., patient may wear
the same clothing repeatedly, unless supervised.
 Stage 6:
a) Unable to bath properly
b) Inability to handle mechanics of toileting
c) Urinary incontinence
d) Fecal incontinence

9. FAST SCALE (FUNCTIONAL ASSESSMENT STAGING)
 Stage 7:
a) Speech ability limited (may repeat the word over and
over)
b) Cannot sit up without assistance
c) Loss of ability to smile
d) Loss of ability to hold up head independently

10.  based on the person's medical history
 history from relatives
 behavioural observations.
Diagnosis

11.  Advanced medical imaging
a) CT
b) MRI
d) PET-used to help exclude other cerebral pathology
 The diagnosis can be confirmed with very high
accuracy post-mortem when brain material is available and
can be examined histologically.

12.  about 5 - 10% of cases are familial
 early-onset disease - autosomal dominant
 late-onset group –polygenic inheritance
Genetics

13.  Mutations in three genes have been identified as causes of autosomal
dominant, early-onset AD:

 APP - encodes amyloid- precursor protein
 PSEN1 and PSEN2 -encoding presenilin 1 and 2.
 All three genes are involved in the production of amyloid- peptides
(Aβ)

14. Pathophysiology

15.  Pathological hallmarks
 Amyloid plaques - extracellular accumulations of Aβ
 Neurofibrillary tangles – intracellular composed of the microtubule-
associated protein tau
 The current consensus is that Aβ accumulation is an upstream event
that triggers tau pathology, resulting in impaired neuronal function
and cell loss

16. AMYLOID HYPOTHESIS
 Amyloid hypothesis postulated that extracellular amyloid beta
(Aβ) deposits are the fundamental cause of the disease.
 Support for this postulate comes from the location of the gene
for APP on chromosome 21, together with the fact that people
with trisomy 21 almost universally exhibit AD by 40 years of
age.

18.  Exactly how disturbances of production and aggregation
of the beta-amyloid peptide gives rise to the pathology of
AD is not known.

20.  The mechanism of tangle injury to neurons remains poorly
understand but two possible pathway have been suggested
 Aggregates of tau protein elicit a stress response
 Microtubule stabilizing function of tau protein is lost

22. CHOLINERGIC
HYPOTHESIS
 The oldest, on which most currently available drug therapies are based,
is cholinergic hypothesis, which proposes that AD is caused by
 marked decrease in choline acetyltransferase
 Loss of cholinergic neurons in brain

24. TREATMENT:
There is NO CURE for
Alzheimer’s disease!!!

25.  Focus is on long-term amelioration of associated behavioral and
neurologic problems, as well as providing caregiver support

26.  Family members should
emphasize activities that are
pleasant while curtailing those
that increase stress on the
patient.
 In the early stages of AD,
memory aids such as notebooks
and posted daily reminders can
be helpful.

27.  Communication and
repeated calm reassurance
are necessary.
 Use of adult day care
centers can be helpful.

28. Intellectual activities such as
playing chess or regular social
interaction have been linked to a
reduced risk of AD in
epidemiological studies, although
no causal relationship has been
found.

29. TARGETS OF DRUG ACTION

32.  Cholinesterase inhibitors:-
a) Tacrine (1993),
b) Donepezil (1996),
c) Rivastigmine (2000)
d) Galantamine (2001).

33.  Tacrine
 It is the first centrally acting anti-ChE to be introduced for AD.
 In clinical trials tacrine produced significant improvement in memory,
attention, and language.
 However, it does not alter the course of underlying disease process.
 Frequent side effects and hepatotoxicity have restricted its use.

34.  Donepezil
 The benefit is ascribed to elevation of ACh level
 Long t½ (~70 hr)
 Administered once daily at bed time
 It can be used even in relatively severe case of AD.
 Generally well tolerated and is not hepatotoxic
 Dose: 5 mg OD HS (max 10 mg OD)

35.  Rivastigmine :
 carbamate derivative of physostigmine inhibits both AChE and
BuChE
 indicated in mild to moderate cases of AD, but not in advanced
disease.
 Dose: initially 1.5 mg BD, increase every 2 weeks by 1.5 mg/day
upto 6 mg/BD

36.  Galantamine: natural alkaloid which selectively inhibits cerebral
AChE
 It is well tolerated, but needs twice daily dosing.
 Dose: 4 mg BD (max 12 mg BD)

37. N-methyl-D-aspartate receptor (NMDA) antagonist
Memantine:
o Restore the function of damaged nerve cells
o reduce abnormal excitatory signals by the modulation of the
NMDA receptor activity.
 It is indicated in moderate-to-severe AD
 Dose: initially 5 mg od, increase gradually upto 10 mg bd; stop
if no clinical benefit in 6 months.

38.  Acetyl-L-Carnitine
 A structural analogue of ACh
 Increase cholinergic transmission
 Antioxidant
 Slows down the progression of the disease

39. NOOTROPIC DRUGS
 Smart drugs or cognitive enhancers
 Drugs, supplements, or other substances that improve cognitive
function, memory, creativity, or motivation in healthy individuals
 exert a regulatory effect on neuronal metabolism, and influence
learning behavior
 Drugs- racetams, nicotine, ginkgo biloba

40.  Racetams-
 piracetam, oxiracetam, aniracetam
 Marketed as cognitive enhancers
 Sold over-the-counter
 Poorly understood mechanisms of action appear to modulate
cholinergic systems
 Effective in animal models, probably ineffective in AD

41. Recent Advances

42. CHOLINESTERASE INHIBITOR
 Phenserine: increased cognition and regional cerebral metabolic
rate for glucose
 Dimebon: also a NMDA-antagonist, showed improved cognitive
functions while diminishing the psychopathic symptoms
 Huperzine A: A Chinese herb with reversibly and selectively
acetylcholinesterase inhibition activity
 PMS777: A new cholinesterase inhibitor with anti-PAF activity is also
in clinical trial

43.  a) β-secretase inhibitors:
 i) BACE (β- site APP cleaving enzyme): Lateral ventricular
injection of this inhibitor led to a significant lowering of brain Aβ40
and Aβ42
 ii) KMI-429: Injection of this inhibitor into the hippocampus of APP
transgenic mice reduced Aβ production.
 iii) GSK188909: Oral administration results in a significant
reduction in the level of Aβ40 and Aβ42 in the brain of transgenic
mice.
Aβ-targeting strategies

44.  γ-secretase inhibitors
i) BMS-299897
ii) MRK-560
iii) LY450139
 Aβ-aggregation inhibitor
 iAβ5p: intra hippocampal injection of it resulted in decreased
amyloid plaque deposits.
 Tramiprosate: binds to soluble Aβ and inhibits the formation of
neurotoxic aggregates

45.  Aβ-degrading enzymes
i) Neprilysin (NEP),
ii) Plasmin,
iii) Endothelin converting enzyme (ECE) 1 and 2
 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.

46.  Ginkgo biloba:
 The dried extract of this Chinese plant contains a mixture of
ginkgo flavon glycosides, which have PAF antagonistic action.
 Since PAF has been implicated in cerebral thrombosis and
infarcts, it is professed that G. biloba will prevent cerebral
impairment in cerebrovascular insufficiency.
 It has been promoted for a variety of cognitive and behavioural
disorders in the elderly.
 Dose: 40–80 mg TDS for a minimum period of 4 weeks.

47. ROLE OF THIZOLIDINEDIONES
 NSAIDs have been considered to delay the onset and reduce the risk
to develop AD, while they also directly activate PPARγ
 This led to the hypothesis that NSAIDs protection in AD may be partly
mediated by PPARγ
 Several lines of evidence have supported this hypothesis, using AD-
related transgenic cellular and animal models.
 Stimulation of PPARγ receptors (thiazolidinediones) inducing anti-
inflammatory, antiamyloidogenic, and insulin sensitizing effects may
account for the observed effects

48. ROLE OF STATINS
 β- and γ-secretase enzymes found predominantly in the cholesterol rich
micro domains of the cell membrane
 Risk factors for AD - dyslipidaemia, coronary artery and cerebrovascular
disease.
 Statins are widely prescribed for their cholesterol lowering ability
 In experimental models of AD, statins reduce the production of Aβ by
disrupting secretase enzyme function
 Epidemiological studies suggest that statins may reduce the incidence of
AD

49. ROLE OF ESTROGEN
 Postmenopausal decline in estrogen levels contribute to
detrimental cognitive effects and a higher risk profile for AD
development.
 Hence, prolonging premenopausal estradiol levels could serve
to delay, or perhaps prevent ad by preventing Aβ
neurotoxicity.

50. ROLE OF 5-HT6 ANTAGONIST
 5-HT6 receptor is the most recently identified member of the 5-HT
receptor superfamily
 In situ hybridization and northern blot studies revealed an exclusive
distribution of 5-HT6 In the rat CNS (olfactory tubercle frontal and
entorhinal cortices, dorsal hippocampus)
 5-HT6 receptor is involved in affective disorders, anxiety and
depression, epilepsy and obesity
 It has been reported that dysregulation of 5-HT6 receptor activation
by 5-HT in the temporal cortex may be related to behavioral
symptoms in AD
 Drugs - SB399885, GSK215083, SB-271046

51. Immunotherapy
 Repeated intravenous administration of human
immunoglobulin against Aβ peptide resulted in stopped
cognitive decline
LY2062430: On Phase I and II clinical trials
Bapineuzumab: After a phase II clinical trial it shows decreased
total and phosphorylated tau levels in CSF without affecting
Aβ level.

52.  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.
 Clioquinol –
 A phase II clinical trial
 a metal-protein-attenuating compound that inhibits zinc and copper ions
from binding to Aβ
 decreased plasma Aβ42 level and zinc concentration as compared with
control group.
 Other metal chelators includs XH1, DP-109, PBT2.

53.  Treatments based on tau pathology
a) Prevention of phosphorylation of tau
b) Prevention of the aggregation of tau
c) Prevention the misfolding of tau
d) Tau immunotherapy
 Cyclin-dependent kinase-5 (CDK5): It is a kinase suggested to
phosphorylate tau
 As report, inhibitors of CDK5 appear to have some influence on the
development of pathology in some tau transgenic mice

54.  Recent studies using cell models have demonstrated that certain drug
inhibitors are able to prevent tau protein aggregation and even
dissolve the developed aggregates, which include-
 Anthraquinones,
 Polyphenols,
 Thiacarbocyanine dyes,
 N-phenylamines,
Prevention of the aggregation of tau

55. Nicotine
 Published studies in humans have reported the effects of
intravenous or subcutaneous nicotine administration on people with
AD.
 Significant improvements were reported in several cognitive tasks
such as free recall, visual attention and perception and in mood
although not on memory.

56.  Cell transplantation and gene therapy
 In AD rat model, transplantation of cholinergic-rich tissue or
peripheral cholinergic neurons ameliorates abnormal behavior and
cognitive function. But no clinical trials in AD patients have been
initiated with this method.