2. • Alzheimer’s disease (AD) was first described in 1906 by Alois
Alzheimer.
• 13% of people over 65 suffer from this disease in developed countries.
• WHO estimates, the overall projected prevalence reaching 114 million
patients by 2050 .
Introduction
3. • Familial AD (FAD) is an early-onset (sometimes as early as 40 years
of age).
• The vast majority of patients suffer from the sporadic AD, which is
subdivided into early- and late-onset forms.
• In FAD, mutations in genes coding for amyloid precursor protein
(APP; chromosome 21), presenilin 1 (PS1; chromosome 14) and
presenilin 2 (PS2; chromosome 1).
Introduction
6. • In AD, clinical manifestation of dementia takes more than a decade
after amyloid plaques start depositing.
• There are no diagnostic tools available to diagnose patients who are
in the initial stage of AD.
• Not all MCI subjects necessarily progress to AD .
8. • Up to 50% of old patients show a substantial overlap between AD
and (FTD), LBD, and VaD.
• More than 50% of AD patients show extensive intracellular Lewy
body deposits.
• Amyloid plaques are reported in other dementias including Vascular
dementia, PD, HD and CJD.
• Amyloid is not deposited in all AD cases.
10. • Several studies reported decreases in choline acetyltransferase (ChAT),
acetylcholine (ACh) release, as well as reductions in nicotinic and
muscarinic receptors in the cerebral cortex and hippocampus of
postmortem AD brains .
11. • To date, three CIs are approved for the treatment of mild to moderate
AD: donepezil ,rivastigmine and galantamine .
• Although tacrine was the first CI drug approved for AD in 1993, it is
no longer used due to hepatotoxicity .
12. • A further therapeutic option for moderate to severe AD is memantine .
• This drug is (NMDA) antagonist believed to protect neurons from
excitotoxicity.
• The most frequently reported adverse events in memantine trials were
dizziness, headache and confusion.
18. Inhibitors and Modulators of β-Secretase.
• The development of β-secretase inhibitors is a challenge because,
besides the APP, neuregulin-1, which is involved in the myelination of
CNS axons and synaptic plasticity, is a target of β-secretase.
• None of β-secretase inhibitors have reached the market so far.
19. Inhibitors and Modulators of γ-Secretase.
• Notch protein, is one of the targets of the γ-secretase.
• Semagacestat is a γ-secretase inhibitor that decreased Aβ levels in
blood and CSF in humans .
• It was reported that semagacestat treatment was associated with the
worsening of cognition , weight loss, increased incidence of skin
cancer, and a higher risk of infection.
20. • Avagacestat is another γ-secretase inhibitor the development of
which was discontinued as a result of a lack of efficacy.
• Pinitol is claimed that the compound improves cognitive function
and memory in preclinical models of AD neuropathology, independent
researchers have not yet confirmed these results.
Inhibitors and Modulators of γ-Secretase.
21. Inhibition of β-Amyloid Peptide Aggregation
• Tramiprosate antagonize the interaction of soluble Aβ with
endogenous glycosaminoglycans. However, the disappointing results
of the phase III clinical trial have led to the suspension of this
compound in Europe.
• Colostrinin, inhibits aggregation of Aβ and improves cognitive
performance in mice models , this beneficial effect was not maintained
after another 15 months .
22. • Metal chelating 8-hydroxiquinolines (8-HQ) was hypothesized
to prevent Aβ aggregation while simultaneously restoring homeostasis
in cellular levels of copper and zinc ions .
• Unfortunately, these molecules failed in the phases II and III of
clinical development due to lack of efficacy.
Inhibition of β-Amyloid Peptide Aggregation
23. Activation of Enzymes That Degrade Amyloid Plaques
• Aggregates and amyloid plaques are degraded by multiple proteases
including neprilysin, plasmin, endothelin converting enzyme,
angiotensin converting enzyme, and metalloproteinases.
• no compounds with this MOA have ever reached advanced clinical
development due to the lack of specificity.
24. Anti-amyloid Immunotherapy
• Active immunization with the first-generation vaccine has produced
serious cerebral inflammation which turned out to be aseptic
meningoencephalitis.
• Second-generation vaccines were designed using a shorter Aβ(1-6)
peptide segment, designed by Novartis. However, the pharmaceutical
company has abandoned the plans for further development of this.
25. • Passive Immunization. It is the administration of monoclonal or
polyclonal antibodies directed against Aβ.
• Bapineuzumab phase III clinical trials had failed because of a lack of
efficacy in patients with mild-to-moderate AD.
• Currently solanezumab is in phase III trials in patients with AD
(NCT01127633 and NCT01900665) and in older individuals who may
be at risk of developing AD in the future (NCT02008357).
Anti-amyloid Immunotherapy
26. • Gantenerumab, is being investigated in people at risk of
developing presenile AD due to genetic mutations. NCT01760005 trial
is still recruiting participants .
Anti-amyloid Immunotherapy
28. • Aβ peptides are the normal residents of human nervous system, and
believed to have an essential role in synaptic plasticity, learning and
memory.
Is it neurotoxic??
29. • Some consider plaques to be relatively benign species that capture
toxic soluble forms of Aβ peptides and hence are protective in nature.
• One study reports that Aβ production has a critical role in sustaining
the neuronal survival in rat brain
• Aβ is found in abundance are different than the functional brain
regions where AD-related memory problems originate.
• some AD patients too do not show amyloid deposits in PET scans.
32. • Tau proteins are highly soluble and abundant in the neurons where
they play a critical role in microtubule stabilization, particularly in
axons .
• Tau hyperphosphorylation leads to the formation of insoluble paired
helical filaments (PHF) which form neurofibrillary tangles.
• The loss of microtubule-binding capacity provokes cytoskeleton
destabilization, which eventually causes neurodegeneration and
neuronal death .
33. • In clinically asymptomatic subjects, NFTs are confined to the
entorhinal cortex ,while in symptomatic subjects tend to be relatively
far more widespread and correlated well with the AD-affected
functional brain circuits. In comparison, plaque deposition tends to
be widespread in asymptomatic subjects.
34. Inhibitors of Tau Hyper-phosphorylation
• Tideglusib, an irreversible inhibitor of GSK3β, in patients with
mild-to-moderate AD did not show clinical efficacy, and the
compound has since been discontinued for this indication.
35. Inhibitors of Tau Aggregation
• Methylene blue dye derivatives have shown some promise in
inhibiting the formation of Tau aggregates.
• Several clinical trials are currently underway to evaluate the potential
efficacy of (Rember) in AD.
36. Microtubule Stabilizers
• Paclitaxel is a microtubule-stabilizing drug currently in use in the
oncology field. Unfortunately, this compound is incapable of crossing
the BBB .
• Epothilone D is a microtubule-stabilizing compound which
improved axonal transport, reduced axonal dystrophy, however, drug
development for AD was discontinued in 2013 after a failed clinical
trial.
37. Anti-Tau Immunotherapy
• In rodents, treatment with monoclonal antibodies directed against
hyper-phosphorylated Tau has led to improvements in cognition and
was not associated with significant adverse effects.
• Axon Neuroscience began a phase I trial to evaluate the safety and
tolerability of AADvac-1, an active immunotherapy
39. • Rises in CSF tau (like AD) has not been shown in pure tauopathies
such as (CBD) and PSP for reasons that are not known.
• The most recent finding that NFTs containing neurons can survive
for decades and are integrated functionally in cerebral cortical
circuitry
41. Presenilin mutations
Total number of families with APP mutations
throughout the world is less than 100, while the ones
with PS mutations are several hundreds.
42. APP mutations
i. APP mutation of the Dutch type: (E693Q)in APP gene does not
increase Aβ and mutation leads to the fatal syndrome of hereditary
cerebral haemorrhage.
ii. APP mutation of the London (V717I) type results in somewhat little
increases in Aβ, but interestingly induces AD.
iii. APP mutations of Italian types: associated with FAD and cerebral
haemorrhage but with no evidence of elevated Aβ production .
44. • Microglia, perivascular myeloid cells, and astrocytes act as
trigger for AD pathogenesis either independently or in
combination with amyloid .
• Aβ is engulfed and degraded by microglia but after-wards a
surge of IL1, IL-6, tumour necrosis factor , reactive
oxygen/nitrogen species, proteolytic enzymes and other
immune mediators .
45. • The Aβ-rich hippocampus and parietal cortex demonstrate
elevated oxidative stress and neuronal damage, while
cerebral regions with scarce Aβ deposits, such as
cerebellum, pons or midbrain do not.
46. • long-term treatment with ibuprofen and indomethacin significantly
decreased Aβ 1–40 and Aβ 1–42 levels in both cortex and
hippocampus of APP transgenic (Tg2576) mice .
• Recent clinical trials with selective COX-2 inhibitors and the mixed
COX-1/COX-2 inhibitor naproxen have been uniformly
disappointing
48. • Clinical studies suggest that diabetes is a major risk factor that contributes
to AD pathology.
• Impaired central insulin signaling in the hippocampal circuits, is present in
AD
• In animal models, pioglitazone did not slow down the cognitive decline
• Intranasal insulin had also been considered as a treatment option for AD.
• A currently ongoing clinical trial is intranasal insulin (Humulin R U-100) in
mild AD.
50. What age brings?
• Decrease in spine and synapse density.
• Accumulation of lipofuscin .
• Decline in the function of astrocytes and less responsive immune
systems.
• Deleterious changes in mitochondria
• Alter insulin function.
• Tau overproduction.
• Cerebral vascular changes.
• Decrease in DNA methylation