Dementia Research

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Dementia Research Tony Bayer Cardiff University
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you can rearrange the deck chairs to make the
view more pleasant, even if you cant stop the
tide coming in
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Dementia UK Report (for the Alzheimers Society)
LSE Kings College London, 2007

• Total number of people in Wales with dementia is
  now 36,924, with forecast to rise to 50,766 by
  2021 and to 93,695 by 2051
• The estimated financial cost of late-onset
  dementia in Wales amounts to 910million
• Delaying onset of dementia by 5 years would halve
  the number of UK deaths attributable to dementia

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Caerphilly Prospective Study
Prevalence of dementia CIND in men aged 65-84
years by age group (screened population, n1209)
Prevalence of dementia by probable
aetiology (screened population, n1209)
Proportion of dementia cases known and newly
diagnosed
Fish, Bayer, Gallacher et al, 2007
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National Epidemiology Wales (John Gallacher,
Cardiff University)

• Development of Wales as an epidemiological
  laboratory
• Establishing the infrastructure for large scale
  epidemiological studies (research governance,
  sampling, national recruitment centre, data
  handling etc.)
• Pilot studies (web architecture, electronic
  consent, questionnaires, DNA sampling by post
  etc.)
• Proof of principle project - Feel good, age
  well (cognitive function, QoL, behaviour, health
  status)

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More than just a memory problem
Distractibility in early AD


Sign diff. from baseline, plt0.05
C1

C2
Figure 1 Mean response time per trial. AD
patients are slowed by the presence of an
irrelevant word (C3) whereas the control group
are not, suggesting they are distracted by
peripheral verbal stimuli.
C3
C4
Griffin, Maciewski Wright
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Combined analysis of donepezil trials in AD
(n10) and VaD (n2)
ADAS-Cog
CIBIC-plus
Bayer et al, 2006
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Memantine and rate of brain atrophy in AD - a
placebo controlled RCT

• Primary objective
• To evaluate effects of memantine on rate of brain
  atrophy in patients with moderate AD over the
  course of one years treatment, through the use
  of MRI technology
• Secondary objectives
• To evaluate effects of memantine on cognitive and
  behavioural outcomes over 1 year
• To explore associations between changes in
  clinical and MRI outcomes
• To evaluate safety and tolerability of memantine
  over 1 year

• Scan image provided by Professor Nick Fox

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The pathological cascade of AD
Clinical symptoms
Cholinergic glutamatergic dysfunction
Neurodegeneration
Neurofibrillary tangles
Genetic risk factors
?-amyloid
Apo-E
tau hyperphosphorylation
PS1,2
Environmental risk factors
Pathogenetic mutations
APP
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AD treatment - anti-amyloid drugs in clinical
trials in Wales

• Inhibition of amyloid production
• Flurizan (R-flurbiprofen) - inhibits breakdown of
  APP to beta amyloid by gamma secretase
• Alzhemed blocks fibrilization and aggregation of
  amyloid into plaques
• Immunotherapy
• Active or passive immunisation with beta amyloid
  (AN1792) or anti-amyloid antibodies

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Beta amyloid immunisation (AN1792) in AD
Anti-amyloid antibody titers
Temporal neocortex virtually devoid of plaques in
immunized cases (with unimmunized AD for
comparison above)
Functional outcome (DAD score) in patients given
active or placebo
Bayer et al. 2005
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Beta amyloid immunisation (AN1792) in AD
Specific histologic features of areas cleared of
plaques in patient first immunized 4 months
before death
Residual plaque core (arrow) in a plaque-free
area and persistence of cerebrovascular beta
amyloid
Plaques with a moth-eaten appearance associated
with abundant beta amyloid in microglia (arrows)
Nicoll et al. 2006
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Beta amyloid immunotherapy approaches
Active immunisation AN1792 (but T cell response
to C terminal can lead to encephalitis) ACC-001
(N terminal fragment) in Phase 1
Passive immunisation AAB-001 (bapineuzumab),
RN1219, RA1022 (Phase 1 studies underway)
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Dementia Research more than just moving
deckchairs