Emerging Trends in Alzheimer’s Disease discusses the pathogenesis and treatment approaches for Alzheimer's disease (AD). There are currently medications to treat mild to moderate AD symptoms, while research explores new treatments. The document outlines several hypotheses for AD causes, including amyloid plaques, neurofibrillary tangles, and cholinergic dysfunction. Therapies target these pathways through secretase inhibitors, vaccines, and other methods. Epidemiological studies examine lifestyle factors that may influence AD risk or protection. Advances in diagnosis include neuroimaging and biomarkers to detect signs of AD earlier.

1. Emerging Trends in Alzheimer’s
Disease
Dr. Seema Bansal
Professor, Department of Pharmacology,
MM College of Pharmacy, Mullana

2. • What is AD?
• Hypothesis of AD Pathogenesis
• Cholinergic hypothesis based therapeutic approaches
• Amyloid cascade hypothesis based therapeutic approaches
• Tau hypothesis based therapeutic approaches
Alzheimer’s Disease
Slide 3

3. AD develops when genetic, lifestyle, and environmental factors
work together to cause the disease process to start.
Although the risk of developing AD increases with age – in most
people with AD, symptoms first appear after age 60
Causes: Amyloid plaques and neurofibrillary tangles
Degeneration of cholinergic neurons
Alzheimer’s disease is an irreversible,
progressive neurodegenerative brain
disease that slowly destroys memory
and thinking skills.
What is AD?
First described by German
psychiatrist -Alois Alzheimer (1906)

4. The Four As
Alzheimer's disease has also been described using four
words that begin with A:
 Amnesia: Memory loss
 Aphasia: Impaired communication
 Apraxia: Physical functioning (motor skills)
 Agnosia: Difficulty understanding information from
the senses, such as vision or smell

5. • AD spreads through the brain. The
cerebral cortex begins to shrink as
more and more neurons stop
working and die.
• Mild AD signs can include memory
loss, confusion, trouble in handling
money, poor judgment, mood
changes and increased anxiety.
• Moderate AD signs can include
increased memory loss and
confusion, problem for recognizing
people, difficulty with language
and thoughts, restlessness,
agitation, wandering, and repetitive
statements.
AD and the Brain

6. •In severe AD, extreme shrinkage
occurs in the brain. Patients are
completely dependent on others for
care.

7. Types of Alzheimer’s Disease
1. Familial Alzheimer's disease (FAD) is a rare form
of Alzheimer's that is entirely passed down
through genetics, being inherited from a parent.
FAD accounts for 2-3% of all cases of Alzheimer's and
usually has a much earlier onset than other types
of Alzheimer's, with symptoms developing in people in their
30s or 40s.
Familial Alzheimer's disease is a very rare genetic
condition, caused by a mutation in one of several genes.
2. Sporadic Alzheimer's disease can affect adults at any
age, but usually occurs after age 65 and is the most common
form of Alzheimer's disease.

8. Cholinergic Hypothesis
Oldest hypothesis based upon cholinergic dysfunction
• Decreased ChAT
• Increased AChE
• Decreased Choline
uptake
• Decreased Ach
receptors

9. Therapeutic Approaches:
 Four cholinesterase inhibitors have been approved by
FDA for treatment of mild to moderate AD
 Tacrine, donepezil, rivastigmine and galantamine.
 Tacrine was first widely used inhibitor but later on
abandoned due to short half-life, hepatotoxicity and
cholinergic side effects
 Donepezil, rivastigmine and galanthamine have fewer
side effects, longer half-lives, and greater efficacy
 However, long-term administration of cholinesterase
inhibitors to patients with Mild Cognitive Impairment
resulted in failure to reduce the risk or delay the onset of
Alzheimer's disease .
 Adverse effects: gastrointestinal, cardiovascular,
neuromuscular risks

10. LossofCholinergicfunctionsduetolackof
Neurotrophichormone
• Neurotrophic hormone: Nerve growth factor (NGF), brain-
derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3),
neurotrophin-4 = 5 (NT-4 = 5) and neurotrophin-6 (NT-6)
• Increasing supply of neurotrophins could be an effective
therapy in AD. Limitation: Neurotrophins are relatively large,
polar molecules that cannot readily cross blood brain barrier
(BBB)
• Alternatively genetically modified autologous fibroblasts have
been used and secrete human NGF which stimulates
cholinergic function, improve memory and prevent
cholinergic degeneration.
• Genetically modified encapsulated cells (NsG0202) that
secrete NGF

11. Amyloid precursor protein (APP) is the
precursor to amyloid plaque.
• APP sticks through the neuron
membrane.
• Enzymes cut the APP into fragments
of protein, including beta-amyloid.
• Beta-amyloid fragments come
together in clumps to form plaques.
1.
2.
3.
In AD, many of these clumps form,
disrupting the work of neurons. This
affects the hippocampus and other areas
of the cerebral cortex.
Amyloid (Aβ) cascade hypothesis

13.  APP gene: The APP gene is located on chromosome 21 and
those individuals suffer from Down's syndrome (trisomy 21)
with an extra copy of this chromosome develops an early-onset
familial AD
 The presenilins 1 (PSEN1) and presenilins 2 (PSEN2)
proteins: genes present on chromosomes 14 and 1 respectively.
PSEN1 gene mutation altered cleavage pattern of γ-secretase
which has resulted into higher Aβ1–42 production and loss of
PSEN dependent function
 Apolipoprotein E (ApoE): ApoE encoded by APOE gene
present on chromosome 19. ApoE plays a key role in lipid
metabolism.
 Studies suggest that ApoE4 can increase Aβ peptide aggregation
and impair Aβ clearance in the brain
Amyloid(Aβ) cascadehypothesis:Genetic Studies

14. AmyloidBasedTherapeutic Approaches
1. Decreasing Aβ production
 Inhibition of β or γ secretase
 Activation of α secretase
 Inhibition of Aβ oligomerization
2. Increasing Aβ degradation and clearance

15. β secretase inhibitors
 OM99-2: First potent β secreatase inhibitors
 Hydroxyethylene-based inhibitors
 Hydroxyethylamine based inhibitors
 Carbinamine-based inhibitors
 Macrocyclic inhibitors
 Non-peptidomimetic β-secretase inhibitors
 CTS-21166: first publicly announced phase I clinical trial
on β-secretase inhibitor
Limitation:
o Inability to penetrate blood–brain barrier
o β-secretase inhibitors not entirely specific to β-
secretase only but they also inhibit other aspartate
proteases

16. γ-Secretaseinhibitors
 The sulfonamide based inhibitors
 L685458
 BMS-299897
 MRK-560
 LY45139
Limitation: γ-secretase inhibitors interfere with
numerous physiological processes

17. Activation of α-secretase
The α-secretases specifically cleaves amyloid precursor
protein in the transmembrane region. Several proteases such
as, ADAM family (A disintegrin and metalloprotease)
ADAM17, ADAM10, ADAM9 and tumor necrosis factor-α
convertase (TACE) fulfills some of the criteria of α-
secretases.
 The PKC activator TPPB
 Sirtuin-1
Limitation: We do not have clear information about the
cellular mechanisms of α-secretase cleavage

18. Inhibitors of Aβ oligomerization
After the action of γ-secretase on APP the released Aβ peptide
monomers rapidly self-aggregates to form oligomers, protofibrils,
fibrils and then leads to form Aβ plaques
o The Aβ fibril binding dye Congo red reduces fibril formation and
neurotoxicity
o Group of sulfonated dyes such as benzofuran-based compounds,
sulfonated anions and amphiphilic surfactants have been used as
Aβ aggregation inhibitors
o Melatonin, nicotine, estrogen and anthracycline 49-iodo-49-
deoxydoxorubicin inhibits Aβ aggregation or reduce Aβ
neurotoxicity
o iAβ5p: recently developed β sheet breaker
o Bapineuzumab and Solanezumab: Humanized IgG1 antibodies in
Phase 3 trials
Limitations: lack of specificity, toxicity and unknown mechanism of
action

19. Aβ degradationand Clearance
Proteases that alter Aβ degradation: These Aβ degrading
enzymes can cleave Aβ peptides at single or multiple sites. The
cleavage products are less neurotoxic and less likely to
aggregate than Aβ itself
• Neprilysin (NEP)
• Insulin Degrading Enzyme (IDE)
• Endothelin Converting Enzyme (ECE-1)
• Plasmin
• Angiotensin Converting Enzyme (ACE)
• Cathepsin B
• Aminopeptidase
• Gelatinase A
• Matrix metalloendopeptidase-9
• Coagulation factor Xia
• α2-macroglobulin complexes

20. Neurofibrillary
Tangles
Neurons have an internal support structure partly made up of
microtubules. A protein called tau helps stabilize microtubules. In AD,
tau changes, causing microtubules to collapse, and tau proteins clump
together to form neurofibrillary tangles.
Tau Hypothesis

21. Inhibition of tau phosphorylation:
• Glycogen synthase kinase-3 inhibitor = Lithium and valproate
have inhibitory actions on GSK3 and when administered they
reduce tau pathology
• Tideglusib (NP031112) an irreversible inhibitor of GSK3-beta
is in phase II clinical trials
Targeting microtubule stabilization:
Paclitaxel
Epothilone D
Some neuropeptides like NAP (NAPVSIPQ) and D- SAL 294
(SALLRSIPA) are available that boasts microtubule stabilization
effects.
Blocking tau oligomerization: Astemizole, lansoprazole,
methylene blue dye has also known to prevent tau interactions, it
also inhibiting Aβ aggregation, improving electron transport,
decreasing oxidative stress, prevent mitochondrial damage,
regulate autophagy and inhibition of AChEs

22.  Glutamatergic neurons regulate synaptic plasticity, neuronal
growth and differentiation, cognition, learning and memory.
 Memantine is clinically approved drug in moderate to severe AD.
Experimental evidences show that memantine treatment
improves spatial learning in animal models of AD, protects
neurons from Aβ induced toxicity, decreases apoptosis, free
radical mediated damage and restored synaptic degeneration.
 A current trial of memantine and donepezil combination in
moderate to severe stages of AD is on going (NCT00866060).
 ADS-8704 (Adamas pharmaceuticals) is currently in phase III
trials
NMDA receptor antagonism

23. Miscellaneous
Targeting mitochondrial dysfunction and oxidative stress: Aβ
accumulation inhibits certain mitochondrial import channels and
increasing ROS production.
 Some natural antioxidants including vitamins (E, C, and
carotenoids)
 Phyto-chemicals and synthetic compounds
 Combination of vitamin E with memantine is in Phase III trials.
 Vitamin E and selenium is in Phase III trials.
 Flavonoids like rutin and carotenoids.
 Melatonin (NCT00940589) currently in phase II trial.
 Recently novel melatonin agonist Neu-P11 that has attenuated
neuronal loss and improved memory performance in rats has
been discovered

24. Miscellaneous ……contd.
 Anti-inflammatory Drugs: Preclinical studies show that
administration of SC-560, a COX-1 selective inhibitor, in triple
transgenic mice has reduced inflammation, neuropathology and
improved cognitive performance
 Cholesterol lowering drugs: Statins
 Gonadotropin Hormones: Testosterone, estrogen and
progesterone
 Multi-target directed ligands: Ladostigil (TV3326), a
multifunctional compound, acts by blocking AChE, and hence
increase cholinergic neurotransmission, with the inhibitory
effect on monoamineoxidase (MAO)-A and B. It decreases
amyloidogenic APP processing. It offers neuroprotective and
neurorestorative activities and decreases apoptosis.

25. Scientists examine characteristics,
lifestyles, and disease rates of groups of
people to gather clues about possible
causes of AD.
• Mentally stimulating activity protects the brain
in some ways.
• In early life, higher skills in grammar and
density of ideas are associated with protection
against AD in late life.
Epidemiologic Studies
AD Research

26. AD Research
Scientists examine characteristics,
lifestyles, and disease rates of groups of
people to gather clues about possible
causes of AD.
• Mentally stimulating activity protects the
brain in some ways.
• In early life, higher skills in grammar and
density of ideas are associated with
protection against AD in late life.
Epidemiologic Studies

27. AD Research: Diagnosing AD
Physicians today use a number of
tools to diagnose AD:
• Detailed patient history
• Information from family and
friends
• Physical and neurological
exams and lab tests
• Neuropsychological tests
• Imaging tools such as CT scan,
or magnetic resonance
imaging (MRI). PET scans are
used primarily for research
purposes
Slide 30

28. AD Research: Diagnosing AD
Experienced physicians in specialized AD centers can now
diagnose AD with up to 90 percent accuracy. Early diagnosis
has advantages:
• Doctors can rule out other conditions that may cause dementia.
• If it is AD, families have more time to plan for the future.
• Treatments can start earlier, when they may be more effective.
• It helps scientists learn more about the causes and
development of AD.

29. ASIMPLEEYETESTCOULDALERTYOUOFONSET
ALZHEIMER'SYEARSBEFORESYMPTOMSEMERGE
• Since the retina is a central nervous system organ directly
connected with the brain, it was exciting to demonstrate
the feasibility of detecting amyloid plaques — early signs of
Alzheimer’s disease — noninvasively, inexpensively,
conveniently, and with unprecedented details via retinal
imaging in living patients
Maya Koronyo-Hamaoui, Associate professor in the departments of
Neurosurgery and Biomedical Sciences at Cedars-Sinai, USC, UCLA
The results, published in the journal JCI Insight,
August 2017, were based on a clinical trial involving
16 Alzheimer’s disease patients.

30. Neuroimaging and Biomarkers of AD
Initiative
• Using MRIs and PET scans conducted
at regular intervals, researchers hope
to learn precisely when and where in
the brain problems occur.
• Researchers will also examine blood
samples to check for higher levels of
abnormal substances that could be
considered “biomarkers” of AD.

31. Drugs used to treat mild to moderate AD symptoms include:
• Donepzil
• Rivastigmine
• Galantamine
An additional drug, Memantine, has been approved to treat
symptoms of moderate to severe AD. These drugs can help
improve some patients’ abilities to carry out activities up to a
year or so, but they do not stop or reverse AD.
Scientists are also studying agents that some
day may be useful in preventing AD. For
example, vaccine against AD.
AD Research: the Search for Treatments

32. • Cholesterol-lowering drugs called
statins
• Anti-oxidants (vitamins) and folic
acid
• Anti-inflammatory drugs
• Substances that prevent
formation of beta-amyloid
plaques
• Nerve growth factor to keep
neurons healthy
AD Research: the Search for New
Treatments

33. Timelineoftheemergenceofvariousexperimental
andclinicaltherapiesforAlzheimer'sdisease

34. Summary
• Our understanding of the etiology and pathogenesis of AD
continues to expand
• There are currently 5 options available for the treatment of
cognitive symptoms of AD and numerous options available for
the treatment of comorbid behavioral symptoms
• Recent advancements in neuroimaging and CSF biomarkers
have dramatically improved our ability to detect AD early in the
course of the disease and make a differential diagnosis
• Early detection (prior to the onset of clinical symptoms) is
essential so that potentially disease modifying treatments can
be utilized before too much pathology has accumulated
• Many novel therapeutic strategies, including immunization, are
in development

35. THANK YOU