Alzheimers Disease Therapeutics Approaches

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Alzheimer s Disease Therapeutics Approaches

• B.Vellas M.D, Ph.D
• Alzheimer s Disease Research Center, France

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MEDICAL TREATMENT

• Acethyl-cholinesterase Inhibitors
• Memantine.

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Cholinergic Pathways Implicated in Alzheimers
Disease
Medial Septum and Diagonal Band of Broca
Nucleus Basalis of Meynert
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Approved Cholinesterase Inhibitors
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Cholinergic Treatment of Alzheimers Disease

• Produces measurable improvement in cognition and
  caregivers and physicians impression
• Effect is modest equivalent to a 6-12 month
  delay
• Behavioral and functional effects
• Unclear if it alters the progression of
  neurodegeneration
• Long-term effects need to be clarified
• Effects also in severe dementia
• Switch Studies

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Mechanism of Actions
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I AchE
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Donepezyl
Inhibition maximale de lAChE à 10 mg / jour
5 mg/j 63,6 10 mg/j 77,3 (1)
Rogers SL et al. A 24-
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Donepezyl

• Efficacy on
• Cognitive functions
• global functioning
• Activities Daily Living
• For the patient
• Autonomy
• Quality of life
• delay to Institutionnalisation

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Cognitive Functions

Rogers S.L. et al.
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Functional Status
Un gain de 5 mois en moyenne sur 1 an
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Long-term effect
Rogers SL et al.. Long-term efficacy and safety
of donepezil in the treatment of Alzheimers
disease final analysis of a US multicentre
open-label
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If the treatment is stopped at 6 Months
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Neuro Psychiatry Inventory (NPI)

• 6 Months )
• Apaty and anxiety galantamine (p lt 0,0001)
• delusion placebo (p 0,048)

Cas observés LOCF à 6 mois Galantamine
placebo placebo galantamine
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Results at 3 years
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Résultats

• Survie
• Temps médian 77 mois tous patients confondus
• Temps médian 83 mois pour patients AD
• Temps médian 84 mois ayant reçu la Galantamine
  pendant au moins 1 ans (quelque soit la durée du
  traitement)
• Faiblesses
• Étude rétrospective, non contrôlée ? biais de
  sélection
• MAIS, analyse multivariée pour rendre résultats
  valides

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Schwalen, results at 48 months

• Results
• After 36 months
• After 48 months

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Glutamate and Alzheimer
hyperstimulation of NMDA receptors by the
glutamate
glutamate neurotoxic
Danysz W et al. Neuroprotective and
symptomatological action of memantine relevant
for Alzheimer s disease - A unified
glutamatergic hypothesis on the mechanismof
action. Neurotoxicity Research 2000 2
85-97. Cacabelos R. The glutamatergic system and
neurodegeneration in dementia preventive
strategies in Alzheimers disease.Int J Geriat
Psychiatry 1999 14 3-47.
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Mémantine First non competitive antagonist OF
NMDA receptors in Alzheimer

Mémantine un nouveau mode daction
Mémantine la restauration de la transmission
neuronale
Danysz W et al. Neuroprotective and
symptomatological action of memantine relevant
for Alzheimer s disease - A unified
glutamatergichypothesis on the mechanism of
action. Neurotoxicity Research 2000 2 85-97.
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Schéma de létude
Etude MRZ-9605 USA Ambulatoire.
Etude Reisberg

• Etude
• Nombre de patients(en intention de traiter)
• Diagnostic
• Age (moyenne)
• Severity
• Dose journalière
• Durée
• Critères primaires defficacité
• Critères secondaires defficacité

• Randomisée, multicentrique, double insu versus
  placebo
• n 252 patients à domicile
• Démence Alzheimer (DSM IV)
• ? 50 ans (76)
• MMSE 314 GDS 5-6
• 20 mg / jour
• 28 semaines
• CIBIC-plusADCS ADLsev
• SIB, RUD, FAST, MMSE, GDS et NPI

Reisberg et al, Memantine in moderate to severe
Alzheimers disease, NEJM, 2003, 34814
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CIBIC-PLUS
4,0
Mémantine
4,2
4,4
Aggravation
Score global CIBIC-plus
Placebo
4,6
4,8
5,0
0
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Fin d'étude LOCF
28 OC
Semaine
Mémantine
n 126
107
97
118
Placebo
n 126
105
84
118
p 0,03
p 0,06 (ns)
OC Observed cases LOCF Last Observation
Carried Forward
Reisberg et al, Memantine in moderate to severe
Alzheimers disease, NEJM, 2003, 34814
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ADCS-ADLsev
1
Amélioration
Mémantine
Aggravation
Différence de score ADCS-ADLsev
Placebo
- 4
- 5
- 6
- 7
4
0
12
Fin d'étude LOCF
28 OC
Semaine
Mémantine
n 126
107
97
124
119
Placebo
n 126
106
84
123
117
p 0,003
p 0,02
OC Observed cases LOCF Last Observation
Carried Forward
Reisberg et al, Memantine in moderate to severe
Alzheimers disease, NEJM, 2003, 34814
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SIB
2
Amélioration
Mémantine
Aggravation
Différence de score SIB
Placebo
- 12
0
12
Fin d'étude LOCF
28 OC
4
Semaine
Mémantine
n 126
107
96
124
119
Placebo
n 126
106
83
123
117
p 0,002
p lt 0,001
OC Observed cases LOCF Last Observation
Carried Forward
Reisberg et al, Memantine in moderate to severe
Alzheimers disease, NEJM, 2003, 34814
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Combination therapy

• Some improvment in patients with both AcheI and
  Memantine (JAMA 2004)
• Cost ?
• When to start ? When to stop ?

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Docosahexaenoic Acid (DHA) Epidemiological Studies

• Autopsy study - PUFA content, including DHA, was
  decreased in the hippocampus and frontal gray
  matter of AD brains (Söderberg et al. 1991)
• Framingham cohort - low DHA was a predictor of AD
• (Kyle et al. 1999)
• Rotterdam study - fish consumption, a marker of
  n-3 PUFAs including DHA, was associated with a
  lower risk of developing AD
• (Kalmijn et al. 1997)