Alzheimer's Disease

1. MOLECULAR BASIS OF
ALZHEIMER’S DISEASE
Dr Ambika Jawalkar
.

2. INTRODUCTION
• A progressive & fatal neurodegenerative
disorder characterized by memory loss
followed by general loss of cognitive &
other brain functions.
• The cognitive changes with AD tend to
follow a characteristic pattern, beginning
with memory impairment and spreading to
language and visuospatial deficits.

3. INTRODUCTION
• In elderly nearly 50% - 60% cases of
dementia are due to Alzheimer’s Disease
• Incidence is17% in 65-69 years old & 40%
in 95 years & above
• Named after Dr Alois Alzheimer in 1906
• Most cases are Sporadic but some are
Familial

4. INTRODUCTION
• Changes first begin in entorrhinal cortex &
hippocampus.
• Damage to projection from Nucleus Basalis
of Meynert to neocortex.
• As the disease progresses damage spreads
to areas of cerebral cortex that control
language, reasoning, sensory processing &
conscious thought.
• Stages – Preclinical, MCI, mild to moderate
& sever AD

5. Possible sequence of events
 Formation of Amyloid Plaques
 Formation of NFTs
 Inflammatory reaction
 Oxidative damage
 Loss of synapses & neurons in particular
the cholinergic neurons
 Dementia
 Progressive neuronal loss
 Cerebral atrophy

6. AMYLOID PLAQUES

7. AMYLOID PLAQUES
• Aβ1-42 - more neurotoxic, predominant in
parenchymal deposits
• Aβ1-40 – less neurotoxic, predominant in
vascular deposits
• exist in vivo at a concentration ratio of 1:10
• Increase in this ratio leads to early onset Familial
AD

8. NEUROFIBRILLARY
TANGLES
• Intracellular collections of twisted protein
threads
• Tau, containing phosphate molecules
binds to the microtubules & appears to
stabilize them.

9. NEUROFIBRILLARY
TANGLES
• In AD, hyperphosporylation of tau occurs
• P-tau threads form paired helical filaments
which become enmeshed with each other
forming tangles
• As a result microtubules disintegrate
collapsing neuron’s internal
transport network

10. GENETIC CONSIDERATIONS
• APP gene, Ch 21,
Early onset Familial AD
• Presenilins – PS1 & PS2
PS1 gene, Ch 14, encodes S182
PS2 gene, Ch 1, encodes STM2
• APOe gene, Ch 19, Late onset Familial AD
• has 3 alleles- APOe4 has strong
association with AD

11. DIAGNOSIS
 Cognitive Assessment
• Clinical Dementia Rating (CDR) (Morris 1993)
• Mini Mental State Examination (MMSE)
(Folstein et al 1975)
 Neuro Imaging
• MRI
• SPECT

12. Recent Progress in Diagnosis
of Early AD
• To diagnose early AD reliably, the
technique used should be,
reproducible, highly sensitive &
specific for AD relative to other forms of
dementia,
in expensive, easy to perform &
non-invasive.

13. 1. Brain glucose metabolism as an
imaging marker
 Functional imaging technique
 F18 labeled Fluoro-2-deoxy-Dglucose is
used as a tracer
2. Molecular probes as imaging markers
developing tracer compounds that bind
to abnormal brain deposits
Pittsburgh Compound B (PIB) – binds to
amyloid plaques & reveals their presence
& number in PET scan
(Klunt et al 2004; Mathis et al 2005)

14. 3. Metabolic markers
leading candidate biomarkers for early
AD are Aβ, tau, p-tau
ratio of Aβ42/Aβ40 has a higher
diagnostic accuracy for differentiating
patients with AD with a sensitivity of 94%
(lewczuk et al 2004)
but changes in their levels are not
specific for AD

15. Approved Therapy for
Alzheimer’s
1. Cholinesterase Inhibitors
Donepezil, Galantamine, Rivastigmine
& Tacrine
2. NMDA receptor modulation
Mementine – a non competetive NMDA
receptor antagonist
Though these drugs improve symptoms, they do so
only for a limited period of time & to a small extent
because destruction of neurons proceeds relentlessly

16. Experimental Therapy for
Alzheimer’s
• Approaches that interfere with the
fundamental causative patho-physiology of
AD are a primary focus of current drug-
development programmes.
• Leading approaches include,
Inhibition of Aβ production
Enhancement of Aβ clearance
Enhancement of Aβ degradation
Inhibition of Aβ assembly

17. 1. Inhibition of Aβ production
β secretase inhibition
γ secretase inhibition
α secretase stimulation
Statins – Atrovastatin administered at
80mg/day in 63 patients with mild to
moderate AD showed some improvement
in the cognitive functions.
(Sparks et al 2006a; Sparks et al 2006b)

18. 2. Enhancement of Aβ clearance
Immunotherapy:
Hypothesis proposed for mechanism of
plaque clearance by Aβ immunotherapy,
- Direct binding of antibodies to Aβ
- Fc-receptor mediated phagocytosis of
Aβ by microglial cells
- Peripheral sink action
Despite initial encouraging results in animal models, a phase II
clinical trial of active immunization therapy using aggregated
Aβ42 was halted because approximately 6% of the patients
participating in the trial developed severe meningoencephalitis
(Schenk 2002).

19. Immunotherapy Cont..
Advantages of Passive immunization :
 Avoidance of T-cell response
 Serum antibody titers can be monitored &
controlled more precisely
 Offers ability to choose Antibodies that
recognize & bind specific forms of Aβ
But Active immunization is a preferred long term
solution if better control can be gained over the
parameters

20. 3. Enhancement of Aβ degradation
Proteases that cleave Aβ & participate in Aβ
clearance,
Neprilysin (NEP)
Insulin-degrading enzyme (IDE)
Endothelin Converting Enzyme 1&2
Plasmin
Consequently, selective activation of these proteases has
become a target for anti-amyloid therapy (Tanzi et al.
2004; Eckman and Eckman 2005; Wang et al. 2006).

21. 4. Inhibition of Aβ assembly
a.Small molecule inhibitors – Tramiprosate
b.Metal Chelators – Cu/Zn chelators
Clioquinol, PBT-2
c. Polyphenols – Resveratrol, Curcumin,
Rosemarinic acid
d. Inositol Derivatives

22. Alternative Disease Modification
Strategies
 RNA interference
it is a process of mRNA degradation
induced by hybridization with a short
sequence of complementary RNA, there
by forming dsRNA
is useful in early onset FAD caused by
mutations in the APP gene & Presenilins

23. Alternative Disease Modification
Strategies
 Nerve Growth Factor Therapy
Cerebrolysin – porcine brain protein
NGF has been shown to improve memory functions in
animal models of AD (Hagg et al. 1989; Fischer et al.
1991; Koliatsos et al. 1991; Frick et al. 1997)
 Antioxidants
a retrospective review comparing treatment with
Donepezil along with vitamin E indicated that the
combination lowered the rate of Cognitive decline
significantly. (Klatte et al 2003)

24. CONCLUSION
• Currently, there are no disease-modifying
therapies approved for AD.
• A number of promising targets and
therapeutic strategies for the treatment of
AD are under active investigation.
• At present, it is too early to determine if
one strategy, and which strategy, will work
best.

25. CONCLUSION
• Medical fraternity is eagerly looking
forward for a breakthrough in the research
to provide a drug that could effectively
slow or stop the gradual loss of neurons in
the brain, and ultimately to stop the
progression of the disease.

26. References
 Review of Medical Physiology by William F.Ganong, 21st ed;
2003 by The McGraw-Hill Companies, Inc.
 Harrison’s Principles of Internal Medicine, 17th ed; 2008 The
McGraw-Hill Companies, Inc.
 Robbins and Cotran Pathologic Basis of Disease, 7th ed
 Development in Diagnostic and Therapeutic Strategies for
Alzheimer's Disease, Akila Shanmugam, Bernhard Monien,
and Gal Bitan, 2008 Nova Science Publishers, Inc.
 Amyloid Cascade in Alzheimer's Disease, Shankar P S;
Journal of Indian Academy of Geriatrics, Vol.4, No.1,
March,2008.
 http://www.nia.nih.gov/alzheimers/National Institute on
Ageing Web Site

27. THANK YOU