Transcript Slide 1

Alzheimer’s disease: Changing
views of Pathophysiology
Gordon Wilcock
Professor of Clinical Geratology
University of Oxford
CoI statement: GW has received research support and honoraria from
companies developing Rx for AD and other dementias, and has led or
participated in many clinical trials of anti-dementia drugs.
Outline of talk
This presentation will concentrate on AD, rather
than Dementia in general:
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Where is the amyloid hypothesis taking us?
Are Tangle related strategies a therapeutic option?
The role of vascular factors
The role of systemic inflammation and cytokines
Modifying disease processes in AD:
Beta amyloid
Alzheimer’s Plaques – “Amyloid”
Anti-Amyloid Strategies
These include:
• Preventing amyloid formation
• Blocking its harmful effects
• Removing it from the brain
Amyloid Precursor Protein
Cleavage
b-amyloid peptide
b-secretase
-secretase
-secretase
Cytoplasm
Neuronal
plasma
membrane
Anti-amyloid strategies
Gamma-secretase modulators and
inhibitors
• Modulation v. inhibition
• Modulation
– Tarenflurbil – only secretase compound with
completed Phase III data – Trials negative
• Inhibition – many compounds in development
or evaluation
– Lilly: Semagacestat – Ph 3 Trials halted Aug 2010.
• Treated group did worse than those on placebo
• AE’s worse, e.g. skin cancer
– Bristol-Myers Squibb: BMS-708163 – phase 2
Activities of Daily Living — ADCS-ADL
ITT Analysis – Mild AD
Change from Baseline
ADCS-ADL
(Mean±SE)
0
-3
-6
Tarenflurbil
Placebo
-9
p=0.479
-12
0
3
6
9
12
15
18
Month
Preliminary analysis
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tarenflurbil
Anti-amyloid strategies:
β-Secretase (BACE-1*) Inhibition
• CoMentis
– Phase I study of CTS-21166
– reduced plasma Aβ levels by up to 80%
– no CSF data
• Other companies
– e.g. Merck, Eli Lilly and Co., Takeda
(* β-site of APP cleaving enzyme )
Anti-amyloid strategies
Alpha-secretase stimulation
e.g. EHT 0202: Phase IIa in France
– Inhibitor of cyclic 3'5-nucleotide phosphodiesterase
and subtype-selective GABAA receptor modulator
– stimulates α-secretase pathway.
– 159 mild/moderate AD; 3 months;
– 40 & 80 mg doses bd; ChEIs allowed
– Safe and well tolerated
– Efficacy: ADAS-cog encouraging
– ApoE e4 +ve patients responded better (strange!)
– Moving to Phase IIb for dose finding/efficacy
Anti-amyloid strategies
Anti-aggregants
• Tramiprosate (Alzhemed) trials negative:
– Binds to soluble Aß, reducing production of fibrillar
form
– Mild to moderate AD
– Inadequate phase II evaluation
– US phase III negative and European phase III
discontinued
• PBT2 phase 2 study:
– Affects Cu and Zn mediated toxic oligomerisation
of Aß
– More promising
Immunotherapy: Autopsy and clinical findings in
the AN1792 trial
• 8 autopsies from treated group and an aged matched control
group of non-immunised AD brains
• Aß load measured (= % of cortical area with Aß) and scored for
specific evidence of plaque removal
• Aß load was compared with mean antibody response, survival
time, and MMSE score before death
• Plaque removal correlated to some extent with antibody
response
• No clinical benefits observed with plaque clearance
This concept still under evaluation, mainly with more specific
monoclonal antibodies
(Holmes et al 2008)
Evidence of extensive and/or patchy removal of plaques
Unimmunized
AD
Temporal
lobe
Immunised
Temporal
lobe
Case 1
Prof. J Nicoll
Decreased Clearance of CNS ß-Amyloid in AD
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12 late onset AD and 12 control
subjects
Production/clearance of Aß40 & Aß42
Intravenous 13C6 - Leucine – crosses BBB
and labels proteins, then measured in
CSF
Reported a 30% impairment in clearance
rate of both Aß40 & Aß42
Estimates based on this 30% decrease in
clearance suggest that brain Aß
accumulates over 10 years in AD
Controversial at present:
• No control protein
• Only 12 subjects
• CSF not brain measurements
• Is the mathematical modelling method
correct?
• ? Over-interpreted
But if correct, has implications for
understanding pathology and therapeutic
strategies
Mawuenyega et al 2010 Science
Future questions:
– Is “plaque amyloid” harmful?
– Is “plaque amyloid” helpful?
– Is it loss of APP function rather than a gain
of pathological function that is important?
– Do we need to rethink trial design?
– Do we need a basic rethink e.g.
• Are tangles a more relevant target?
• Is there a vascular factor contribution?
Neurofibrillary Tangle Pathology
Neurofibrillary Tangles –
Therapeutic Aspects
P
TAU
P
P
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PHF
tau
TAU
P
HYPER-PHOSPHORYLATION
NFT
P
Tau targeted strategies:
Methylthioninium (MTC)
• Dissolves PHF from AD brain and prevents tau aggregation in
cellular models
• Dose ranging phase 2 RCT in 332 mild/moderate AD
• At 24 weeks:
– Mild subjects: no placebo decline, so no analysis
– Moderate subjects on 60 mg: ADAS-cog score 5.4 points better
than placebo
• At 50 weeks:
– Mild and moderate AD: -6.8 ADAS cog points cf 7.8 in placebo
– secondary outcomes also positive
• Supported by nested SPECT and PET scan data, and further
extension to 84 weeks
• Justifies further evaluation, but limited data published so far
(Wischik et al ICAD 2008)
Vascular Factors and
Alzheimer’s disease
CVD and cerebral hypo-perfusion as risk
factors for AD
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Cortical micro-infarcts occur in 32% of people with AD,
but only in 2.5% of controls (Suter et al 2002)
AD was more likely to develop in a cohort (1015) of non
demented 60-90 yr olds in the presence of silent infarcts
(Vermeer et al 2003)
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“MCI” patients with hypoperfusion (SPECT) in:
 hippocampal-amygdaloid structures more likely to
convert to AD within 3 years cf those with normal
perfusion patterns (Johnson & Albert, 2000)
 Others have reported similarly, e.g. posterior
cingulate hypoperfusion
(Rodriguez et al 2000)
Inflammation and AD
The role of systemic inflammation and
cytokines
(Holmes et al 2009)
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Inflammatory markers associated with the pathology of AD
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A number of pro-inflammatory cytokines have been implicated in the
pathogenesis of AD, e.g. by activating microglia
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300 community dwelling subjects with mild to severe AD
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Assessed at 2, 4 and 6 months with ADAS-cog
Acute systemic inflammatory events, e.g. infections, surgery, MI, occurred in
about 50%
Inflammatory events associated with:
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increased serum TNF-alpha
2 fold increase in rate of cognitive decline over 6 months
High baseline TNF–alpha associated with a 4 fold increase in rate of cognitive
decline
Subjects with low levels of TNF–alpha throughout the study did not decline
cognitively
Thus both acute and chronic systemic inflammation increased serum TNFalpha and the rate of cognitive decline
Clinical Implications
Revised diagnostic criteria for AD - 1
(Dubois et al., 2007)
Diagnosing AD before Dementia onset:
Presence of an early and significant episodic memory
impairment that includes the following features:
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Gradual and progressive change in memory function
reported by patients or informants over more than 6
months
Objective evidence of significantly impaired episodic
memory on testing:
generally consists of a recall deficit that does not improve
significantly or does not normalise with cueing or recognition
testing
AND other supportive features and exclusion criteria
“Biomarkers” to identify those with
predementia AD :
• Psychometric
– traditional and computer based
• Imaging
– Structural and functional
• CSF (and Blood based)
– Abeta 42, tau and phospho-tau, and many others
(see review by Hampel et al 2010)
• (Also needed as outcome measures in trials and
clinical practice)
In Conclusion:
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Traditional views of pathophysiology are under
review
Especially the role of Amyloid
Tangle pathology now being targeted as a potential
therapeutic strategy
Newer concepts include:
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Vascular disease (really an old concept!)
Inflammation
And others not covered, e.g Cu, Zn, oxidative damage etc
This has implications for day to day practice