Alzhiemers

1. TREATMENT OF ALZHEIMER’S
DISEASE

2. HISTORY
• Dr.Alois Alzheimer-German psychiatrist &
neuropathologist
• Identified Alzhiemer’s disease in a patient at
the Frankfurt Asylum named Auguste Deter.

3. Dr.Alois Alzheimer
Auguste Deter

4. CLINICAL OVERVIEW
• Progressive loss of memoryloss of short
term memory that precedes loss of long term
memory
• Disordered cognitive functions
• Vegetative state
• Death asso. with complications of
immobility eg:pneumonia or pulmonary
embolism

5. Genetics
Early onset
• Autosomal dominant
• Mutations in
– APP –Amyloid beta precursor
protien
– PSEN1 –presenilin 1
– PSEN2-presenilin 2
• Aβ is generated by sequential
cleavage of APP by 2
enzymes,β secretase & γ
secretase
• Presenilins form the catalytic
core of γ secretase
Late onset
• Sporadic
• APOE-encodes lipid carrier
protien- Apolipoprotien E

6. PATHOPHYSIOLOGY
• Amyloid plaqueextracellular deposition of β
amyloid protien in cortex, hippocampus,
amygdala & sub cortical nuclei
• Intraneuronal neurofibrillary tangles Tau
protiens

7. PATHOPHYSIOLOGY
• Aβ & tau induce neuronal dysfunction by
– Direct impairment of synaptic transmission &
plasticity
– Excitotoxicity
– Oxidative stress
– neuroinflammation

8. NEUROCHEMISTRY
• Deficiency of Acetylcholine
• Due to atrophy & degeneration of subcortical
cholinergic neurons
• particularly in Nucleus basalis of Meynert in
the forebrain that projects to frontal cortex &
hippocampus

9. CHOLINERGIC NEURONS
Ach ↓

10. NEUROCHEMISTRY
• Excitotoxicity due to enhanced glutamate
transmission via NMDA receptors

11. TREATMENT
–Treatment of cognitive symptoms
–Treatment of behavioral symptoms

12. Treatment of cognitive symptoms

13. TREATMENT
• Augmentation of cholinergic transmission –
Mainstay
• Reversible choline esterase inhibitors that can
cross BBB
• First line of treatment
1. Tacrine-first drug approved,but rarely used now due
to hepatotoxicity
2. Donepezil
3. Rivastigmine
4. Galantamine-can stimulate nicotinic receptors,can
be used in later stage

14. TREATMENT
• Peripheral cholinergic side effects-
Diarrhoea,nausea,vomiting &↑ urination
• Memantine-
– Noncompetitive antagonist of NMDA receptor
– Better tolerated & less toxic

15. TREATMENT
• Peripheral cholinergic side effects-
Diarrhoea,nausea,vomiting &↑ urination
• Memantine-
– Noncompetitive antagonist of NMDA receptor
– Better tolerated & less toxic
• Vit E +Antioxidants-vit
C,vitA,Zn,Se,bioflavanoids,-↓ progression

16. TREATMENT
• Augmentation of cholinergic transmission –
Mainstay
• Reversible choline esterase inhibitors that can
cross BBB
• First line of treatment
1. Tacrine-first drug approved,but rarely used now due
to hepatotoxicity
2. Donepezil
3. Rivastigmine
4. Galantamine-can stimulate nicotinic receptors,can
be used in later stage

17. TREATMENT
• Antiamyloid monoclonal antibody-
bapineuzumab & solanizumab-failed in phase
III clinical trial
• Vaccination against human beta amyloid-
under study

18. TREATMENT
M1 agonist
1. Xanomeline –
– Improves cognition and reduces psychotic symptoms
– Failed during Phase II clinical test due to side-effects -
nausea and diarrhea.
2. Talsaclidine
– Enhances non-amyloidogenic processing of APP and
decreases CSF Aβ level in AD patients
– Discontinued due to side-effects - sweating and
salivation

19. TREATMENT
Gingko biloba-
• Plant extract
• Positive effects on neurons
• Have antioxidant and anti-inflammatory
properties.

20. TREATMENTTarget/Approach Candidate Name Trial Phase
Gamma Secretase
Modulator/NSAID
R-flurbiprofen
Phase III
(completed)
Gamma Secretase Inhibitor Semagacestat
Phase III
(completed)
Antibody to amyloid beta Bapineuzumab
Phase III
(completed)
Natural Antibodies to amyloid beta IVIg
Phase II
(completed)

21. TREATMENT
Treatment of behavioral impairment
• Antidepressants – SSRIs
• Atypical antipsychotics –
Risperidone, Olanzapine, Quetiapine 
For agitation and psychosis.
• Mood stabilizers –Lithium

22. THANKYOU