Alzheimer's disease

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 vivoat 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 tauoccurs
•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
F18labeled 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/Aβ40has 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
γsecretase inhibition
αsecretase 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 sinkaction
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, 21
st
ed;
2003 by The McGraw-Hill Companies,Inc.
Harrison’s Principles of Internal Medicine, 17
th
ed; 2008 The
McGraw-Hill Companies, Inc.
Robbins and Cotran Pathologic Basis of Disease, 7
th
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