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.

2. Outline of talk
This presentation will concentrate on AD, rather than Dementia in general:
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

3. Modifying disease processes in AD: Beta amyloid

4. Alzheimer’s Plaques – “Amyloid”

5. Anti-Amyloid Strategies
These include:
Preventing amyloid formation
Blocking its harmful effects
Removing it from the brain

6. Amyloid Precursor Protein Cleavage
b-amyloid peptide
b-secretase
-secretase
-secretase
Neuronal plasma membrane
Cytoplasm

7. 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 – phase 2

8. Activities of Daily Living — ADCS-ADL ITT Analysis – Mild AD
p=0.479
Preliminary analysis 8

9. 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 )

10. 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

11. 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

12. 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)

13. Evidence of extensive and/or patchy removal of plaques
Unimmunized AD
Temporal lobe
Immunised
Temporal lobe
Case 1
Prof. J Nicoll

14. Decreased Clearance of CNS ß-Amyloid in AD
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

15. 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?

16. Neurofibrillary Tangle Pathology

18. Neurofibrillary Tangles – Therapeutic Aspects
TAU
PHF
tau P P P P
TAU P
NFT
HYPER-PHOSPHORYLATION

19. 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)

20. Vascular Factors and Alzheimer’s disease

21. CVD and cerebral hypo-perfusion as risk factors for AD
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 yr olds in the presence of silent infarcts (Vermeer et al 2003)
“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)

22. Inflammation and AD

23. The role of systemic inflammation and cytokines (Holmes et al 2009)
Inflammatory markers associated with the pathology of AD
A number of pro-inflammatory cytokines have been implicated in the pathogenesis of AD, e.g. by activating microglia
300 community dwelling subjects with mild to severe AD
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:
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 TNF-alpha and the rate of cognitive decline

24. Clinical Implications

25. 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:
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

26. “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)

27. In Conclusion: 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:
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