Seminar presented while pursuing MD Pharmacology

1. Pharmacotherapy of Alzheimer’s Disease

2. Definition:
 Alzheimer's disease: A primary degenerative cerebral
disease of unknown etiology with characteristic
neuropathological & neurochemical features
 Alzheimer’s disease - Most common type of dementia
accounts for 60 to 80 % of cases
 Dementia: A clinical syndrome of loss or decline in
memory, intellectual deterioration & other cognitive
abilities with changes in personality & behavioural
abnormalities
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3. Alzheimer’s disease
 1st described by German psychiatrist Alois Alzheimer in 1906
 Dementia in Alzheimer's disease with early onset:
Onset before the age of 65 with a relatively rapid
deteriorating course & with marked multiple disorders of
higher cortical functions
 Dementia in Alzheimer's disease with late onset: Onset
after the age of 65 usually in late 70s or thereafter with a slow
progression & with memory impairment as principal feature
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4. Prevalence
 Prevalence of dementia in India & South Asia is 1.9% in
those ≥60 years with an annual incidence of 4.3/1000
 The prevalence is estimated to reach 3.6 million by 2020
and 7.5 million by 2040 in this region
 The rate of increase was estimated to be 3-4 times
higher in developing countries than in developed
countries
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5. Symptoms of AD
 Gradually worsening difficulty in remembering
new information
 Confusion, disorganized thinking, impaired
judgment, trouble expressing themselves
 Disorientation to time,
space & location
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6. Diagnostic criteria
 Multiple cognitive deficits manifested by memory
impairment and one or more of aphasia, apraxia,
agnosia or disturbance in executive functioning
 Significant impairment in social or occupational
functioning
 Gradual onset and continuing cognitive decline
 Symptoms not due to neurologic, systemic or
substance abuse conditions known to cause dementia
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7. Etiology
 Advancing Age
 Female sex
 Family history
 Trauma
 Education
 Environmental factors: Aluminum, Mercury, Viruses
 Vascular diseases: Stroke
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8.  Genetic factors:
APP gene present on chr. 21
Adults with trisomy 21 develop typical neuropathologic
hallmarks of AD if they survive beyond age 40
Investigations of multigenerational FAD led to
discovery of 2 additional AD genes termed as
preseninlins
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Cont.

9. Presenilins
 Presenilin-1 on chr. 14 involved in cleavage of APP at
γ-secretase site
 Mutations of this gene are more common than PS-2 & leads
to early onset, shorter & rapidly progressive course
 Presenilin-2 on chr. 1 encodes protein called STM2
 Mutations of Presenilins rarely involved in late onset of
Disease
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Cont.

10. Apo-ε gene
Apo-ε gene on Chr. 19 responsible for late onset familial
& sporadic forms of AD
Its involved in cholesterol transport and has 3 alleles:
2, 3 & 4
Apo-ε4 has strong association with AD
Apo-ε4: Single most important biomarker associated
with risk of AD
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Cont.

11. Neurochemistry of AD
 Direct analysis of neurotransmitter content in cerebral
cortex of AD patients shows a reduction of many
transmitter substances that parallels neuronal loss
 A striking & disproportionate deficiency of ACh due to
atrophy & degeneration of subcortical cholinergic
neurons particularly those in basal forebrain is seen
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12. Pathogenesis
 Amyloid precursor protein (APP) is a type-I
transmembrane glycoprotein
 Function of APP is still unclear & believed to be
important during development of CNS & in response to
stress or injury
 APP undergoes proteolytic processing through
physiologic i.e. non-amyloidogenic or amyloidogenic
pathway
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13. 10th February 2009 Pharmacotherapy of Alzheimer's disease 13

14.  During physiologic pathway membrane bound enzyme
α-secretase cleaves APP within its Aβ domain resulting
in extracellular secretion of soluble APP-α (sAPP-α) &
production of a short, membrane-bound COOH-
terminal fragment (CTF), α-CTF or C83
 Subsequent γ-secretase cleavage of C83 results in the
secretion of a peptide termed p3 out of cell & release of
the APP intracellular domain (AICD) into the cytoplasm
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Contd.

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16.  The amyloidogenic pathway is initiated when β-secretase
cleaves APP at N-terminal part of Aβ domain
 This cleavage leads to the extracellular release of sAPPβ,
while β-CTF or C99 fragment remains membrane bound
 Sequential γ-secretase cleavage of C99 allows shedding
of AICD & secretion of Aβ into the lumen or extracellular
space which aggregates to form amyloid plaques
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Contd.

17.  Tau is a normal constituent of neurons associated with
intracellular microtubules
 In AD it becomes abnormally phosphorylated &
deposited intracellularly as paired helical filaments
 When the cells die, these filaments aggregate as
extracellular neurofibrillary tangles
 Addition of fibrillar Aβ to mature hippocampal neurons
results in progressive neuritic degeneration accompanied
by enhanced phosphorylation of adult τ-isoforms
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Contd.

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19. Pathological features
 Brain shrinkage & localised loss of neurons, mainly in
the hippocampus & basal forebrain
 Loss of cholinergic neurons in the hippocampus &
frontal cortex
 Diffuse atrophy of cerebral cortex & enlargement of
ventricular system
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20. Gross Appearance
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21. Microscopic Features
 Extracellular amyloid plaques consisting of β amyloid
protein (Aβ)
 Intraneuronal neurofibrillary tangles comprising of
filaments of phosphorylated form of a microtubule-
associated protein (Tau)
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Hallmark of AD:

22. Microscopic features
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23. Current Pharmacotherapy
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24. The main goals of treatment
 Symptomatic improvement, consist of enhanced
cognition, more autonomy & improvement in
neuropsychiatric & behavioural dysfunction
 Disease modification with slowing or arrest of
symptom progression of the dementing process
 Primary prevention of disease by intervention in key
pathogenic mechanisms at a pre-symptomatic stage
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25. Current treatment
 Acetylcholinesterase inhibitors (AChEIs):
Tacrine, Donepezil, Galantamine, Rivastigmine &
Huperzine A
 Non-competitive N-methyl-D-aspartate (NMDA)
receptor antagonist:
Memantine, Dimebolin
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26. Acetylcholinesterase inhibitors
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AChEI

27. Contd.
 Mechanism of action: The AChEIs act by preventing
the enzymatic degradation of the neurotransmitter
acetylcholine (ACh) resulting in increased ACh
concentrations in the synaptic cleft & enhanced
cholinergic transmission
 AChEIs may be divided into 3 groups: Noncovalent or
“reversible” inhibitors, carbamoylating inhibitors &
organophosphorus compounds
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28.  1st AChEI approved by FDA for treatment of AD was
Tacrine which is a reversible inhibitor & no longer
used now due to hepatotoxicity
 Major side effects: GI symptoms (Nausea, Diarrhea,
Cramps), altered sleep, bradycardia & muscle cramps
 Caution when using in people with cardiac conduction
conditions such as symptomatic bradycardia, or with a
history of falls or syncope
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Cont.

29. Rivastigmine
 Reversible Carbamate Inhibitor
 Rivastigmine tartrate: Oral: approved for mild &
moderate AD only
 It has a recently FDA-approved Transdermal patch that
has been shown to eliminate GI side effects
 Rivastigmine can be safely given to patients not
tolerating or not responding to donepezil
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30.  It is a reversible inhibitor bind with higher affinity to
the active center
 It is more hydrophobic & has longer duration of action
 Readily cross blood–brain barrier to inhibit AChE in
the CNS
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Donepezil

31.  Intranasal galantamine achieved therapeutically
relevent drug levels exceeding that of oral dosing &
avoided GI side effects
 Huperzine A is a natural AChEI derived from the
Chinese herb Huperzia serrata, also acts as a NMDA
receptor antagonist
 It has antioxidant and neuroprotective properties that
suggests its usefulness as a disease-modifying
treatment for AD
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Contd.

32. NMDA receptor antagonist
 Acts by blocking overexcited NMDA receptors which
blocks entry of Ca++ thereby decreasing glutamate
release & inhibiting processes which led to
neurotoxicity
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33. Memantine
 Mechanism of action: Voltage dependent, low-
moderate affinity, uncompetitive NMDA receptor
antagonism with fast blocking/unblocking kinetics
 Fast on/off kinetics & low-moderate affinity blocks
effect of excessive glutamate preserving physiologic
activation of NMDA receptors required for learning &
memory
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34.  It also inhibits & reverses protein phosphatase(PP)-2A
inhibition-induced abnormal hyperphosphorylation &
accumulation of tau
 Adverse effects are mild & reversible and may include
headache or dizziness
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Cont.

35. Dimebolin
 An antihistamine drug
 Multiple mechanisms of action:
Blocks the action of neurotoxic Aβ & inhibits L-type
calcium channels
Modulates the action of AMPA and NMDA glutamate
receptors
Exert a neuroprotective effect by blocking a novel
target that involves mitochondrial pores
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36. 10th February 2009 Pharmacotherapy of Alzheimer's disease 36

37. Guidelines for Alzheimer’s disease
management
 California Workgroup on Guidelines for Alzheimer’s
Disease Management has an update report in 2008
 This report updates & expands the Guidelines for
Alzheimer’s Disease Management (California
Workgroup on Guidelines for Alzheimer’s Disease
Management, 2002)
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38. It has the following recommendations:
 Assessment
 Monitor Changes
 Reassess Frequently
 Identify Support
 Identify Culture & Values
 Assess Capacity
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39.  Treatment
 Develop Treatment Plan
 Treat Behavioural Symptoms
 Non-Pharmacological Treatment First
 Treat Co-Morbid Conditions
 Provide End-of-Life Care
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40.  Patient & family education & support
Integrate Medical Care & Support
Discuss Diagnosis & Treatment
Involve Early-Stage Patients
Discuss Stages
Discuss End-of-Life Decisions
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41.  Legal considerations
Planning
Capacity Evaluations
Elder Abuse
Driving
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44. NSAIDs & AD
 Past studies found patients who reported higher use of
NSAIDs were less likely to develop AD compared to
patients with less frequent NSAID use
 These findings suggested that NSAIDs may have
neuroprotective properties against development of AD
 Recent double blind, placebo controlled trials have
failed to demonstrate any therapeutic benefit in the
development of AD
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45. Statins in AD
 Statins inhibit β-secretase & activate α-secretase
thereby decreasing Aβ load
 Reduce the risk of dementia & cognitive impairment
by modifying the vascular risk factors that have been
implicated in both vascular dementia & Alzheimer’s
disease
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46. Antipsychotics use in AD
 Adverse effects offset advantages in the efficacy of atypical
antipsychotic drugs for the treatment of psychosis,
aggression, or agitation in AD patients
 REGULATORY ALERT June 17, 2008: The U.S. FDA
notified that both conventional & atypical antipsychotics
are associated with an increased risk of mortality in elderly
patients treated for dementia-related psychosis
 Prescribing information for all antipsychotic drugs will
now include information about the increased risk of death
in the BOXED WARNING & WARNING sections
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47. 10th February 2009 Pharmacotherapy of Alzheimer's disease 47
Novel targets

48. Strategies targeting τ-protein
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49. 1. Modulators of τ-kinases or phosphatases
 An imbalance in activity between kinases &
phosphatases results in abnormal phosphorylation of
microtubule-associated τ-protein
 Major kinases involved in this process are glycogen
synthase kinase(GSK)-3, cyclin-dependent protein
kinase-5, casein kinase-1, protein kinase A etc.
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50. Kinase Inhibitors
 Lithium: Inhibits GSK-3β activity results in decreased
levels of both Aβ & τ-phosphorylation τ-aggregation &
NFT formation (in transgenic mice)
 Other GSK-3β inhibitors are being developed, such as
AR-A014418 as well as other kinase inhibitors
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51. Problems with Kinase Inhibitors
 Ubiquitous expression of kinases
 Pleiotropic activities in countless cellular functions
 Low selectivity for specific kinases, isoforms of a
particular kinase, cellular compartment and/or
pathological, rather than physiological, activity of
the kinase
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52. 2. τ –aggregation Inhibitors (TAIs)
 AL-108 or NAP: An intra-nasal formulation, derived from
the biological activity-dependent neuroprotective
protein secreted by brain in response to various insults
 AL-108 interacts with microtubules, reduces τ-
hyperphosphorylation & increases soluble τ levels
leading to an improvement in cognition
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53.  AL-108 recently completed phase IIa trial in patients
with amnestic mild cognitive impairment
demonstrated that it is safe & well tolerated
 An IV formulation of NAP, known as AL-208, is also
under clinical investigation
 Rember™ proposed to prevent oligomerization & self-
aggregation of τ & dissolve pre-formed τ-oligomers
10th February 2009 Pharmacotherapy of Alzheimer's disease 53
Cont.

54. Strategies targeting Aβ
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55. Aims of therapy
 Stimulating α-secretase cleavage in order to direct APP
processing towards the non-amyloidogenic pathway
 Suppressing β- and/or γ-secretase cleavage in order to
reduce the amount of Aβ produced
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56. 1. Inhibitors or modulators of the secretases
 Numerous β- & γ–secretase inhibitors and/or
modulators have been designed
 But majority of these agents are not specific for the
secretase cleavage of APP & thus may prevent the
cleavage & processing of additional substrates, which
could result in various adverse effects
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57. 2. Aβ aggregation inhibitors
 Its found that soluble Aβ monomers assume a random
coil or α-helix conformation but in AD they undergo a
structural change into a pleated β–sheet
 This induces the peptide to form LMW oligomers, HMW
complexes, mature fibrils & amyloid plaques (APs)
 As our understanding of Aβ structure improves & with
advent of more advanced techniques, the development
of inhibitors of Aβ oligomers will improve
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58. 3. Amyloid-plaque degradation enhancers
 Aβ can be catabolized via enzymatic degradation
 Serine proteases plasmin, tissue plasminogen
activator, Neprilysin (NEP) & Insulin-degrading
enzyme (IDE) have been suggested as potential
methods of reducing Aβ levels
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59. Passive or active immunization
 Transgenic mouse when actively immunized with Aβ
or passively immunized with humanized anti-Aβ
antibodies showed reduced Aβ and τ-pathology,
neutralized soluble Aβ oligomers and improved
learning
 Following successful completion of the phase I trial, a
phase IIa trial with AN-1792 / Betabloc was initiated
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60.  Trial was terminated when 4 patients reported
autoimmune meningoencephalitis
 A subsequent autopsy analysis of a phase I study
patients indicated evidence of encephalitis
 A composite neuropsychological performance study
has shown that the patients developing Aβ antibodies
showed improvement in memory attention &
concentration
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Cont.

61.  Many patients developed anti-Aβ antibodies which
was consistent with a slowing in the rate of cognitive
decline 12 months after completion of the trial
 Long-term clinical follow-up of 80 patients
demonstrated a varied degree of Aβ plaque removal &
no prevention of progressive neurodegeneration with
no evidence for improved survival
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Cont.

62.  Development of IV recombinant humanized anti-Aβ
monoclonal immunoglobulins (IVIg) which avoid
induction of an immune response continues in parallel
 Examples of passive vaccines against Aβ in various stages
of research and development are:
Phase I (V950)
Completed phase II (LY2062430)
Ogoing parallel phase II & III (AAB-001/Bapineuzumab)
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Cont.

63. The metal hypothesis of AD
 It is found that cerebral concentrations of Zn, Cu & Fe
ions are significantly elevated in AD
 APs are rich in Zn, Cu & Fe
 Cu2+ alters τ-structure promoting its phosphorylation
& inducing its aggregation
 This suggests role of metals in AD
10th February 2009 Pharmacotherapy of Alzheimer's disease 63

64.  Age-related endogenous metal dyshomeostasis in
brain allows binding of metal ions (Cu2+ & Fe3+) to Aβ
 This can lead to neurotoxicity
 Metallated-Aβ produces reactive oxygen species
resulting in free radicals induced oxidative stress
damage of lipids proteins & DNA, ultimately leading
to synaptic & neuronal loss
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Cont.

65.  To restore metal homeostasis,
 Inhibit Aβ-metal interactions
 Inhibit metallated Aβ-catalysed oxidation
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Strategies targeting metal ions

66. Antioxidants
 Antioxidant are capable of neutralizing free or
incorrectly bound metals thereby interfering with
generation of ROS & other free radicals
 Antioxidants like Estrogen, melatonin, vitamin C & E,
ginkgo biloba extract, curcumin & flavonoids shown to
have neuroprotective effects against Aβ-induced
toxicity in cellbased experiments & animal models but
have conflicting results in clinical settings
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67. Metal chelators
 It binds strongly to 2 or more metal ions & form a
cyclic ring which converts metal ions into an inert
form & depletes total pool of bioavailable metals
 Desferrioxamine (DFO) an Fe chelator with high
binding affinities for Zn, Cu & Al was the 1st such agent
to enter clinical investigations for treatment of AD
 DP-109 reduced formation of CAA & deposition of APs
as well as it re-solubilized Aβ
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68. Metal complexes
 An alternative approach to chelation is to modulate
metals with metallo-complexes
 This serves to remove metals from biologically
deleterious sites & potentially deliver them to areas of
deficiency thereby maintaining overall metal
homeostasis
 Example: Complexes of pyrrolidine dithiocarbamate
(PDTC) & Cu
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69. Metal-protein attenuating compounds (MPACs)
 MPACs have weak, reversible affinity towards metals,
which enables them to compete with endogenous
ligands for metal ions & restore normal metal levels in
specific cellular compartments
 Example: Clioquinol
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70. Indian Medicinal Plants for Alzheimer’s disease /
Memory improvements
 Brahmi (Bacopa Monnieri)
 Amla (Phyllanthus Emblica)
 Guduchi (Tinospora Cordifolia)
 Tulsi (Ocimum Sanctum)
 Ashwagandha (Withania somnifera)
 Shankhapushpi (Convolvulus pluricaulis)
 Haritaki (Terminalia chebula)
Pharmacotherapy of Alzheimer's disease

71. Conclusion:
 AD pathogenesis is a complex process involving both
genetic & environmental factors
 Therefore development of effective disease-modifying
drugs is proving to be a difficult task
 Current pharmacotherapy is not sufficient to halt the
disease progression
 Aβ, τ & metals are some of the therapeutic targets
identified & compounds that modulate them represent
promising drug candidates
Pharmacotherapy of Alzheimer's disease 71

72. 10th February 2009 Pharmacotherapy of Alzheimer's disease 72
Thank you

73.  Fe-enriched environment upregulates APP translation
whereas it is down-regulated in response to an Fe-
deficient environment
 Increasing Cu levels in vitro can shift APP processing
towards non-amyloidogenic pathway & result in
decreased Aβ production
73
Cont.

74.  Metallated-Aβ also has an increased affinity for the
phospholipid heads of the membrane bilayer which
acts as a reductant in the production of reactive oxygen
species (ROS)
 Resulting radicals, such as hydrogen peroxide (H2O2)
and superoxide (OH), induce oxidative stress damage
of lipids, proteins and DNA, ultimately leading to
synaptic and neuronal loss
Pharmacotherapy of Alzheimer's disease 74

75. 10th February 2009 Pharmacotherapy of Alzheimer's disease 75

76.  In vitro studies have shown that amyloidogenesis &
fibrillogenesis can be affected by factors such as time,
concentration, temperature, pH and metal ion
concentration
 LMW, soluble, oligomeric forms of Aβ1–42 rather than
Aβ1–40 are more neurotoxic than the mature Aβ fibrils
 soluble Aβ monomers assume a random coil or α-helix
conformation; however, in AD they undergo a structural
change into a pleated β-sheet
10th February 2009 Pharmacotherapy of Alzheimer's disease 76
Cont.