2. Medication Therapies in the Treatment of Alzheimer’s Disease
Majid Barekatain, M.D.,
Associate Professor of Psychiatry
Neuropsychiatrist
Isfahan University of Medical Sciences
27-28 Ordibehesht 1392
April 16-17, 2013

3. LET’S HAVE LOOK! 1. Cholinergic hypothesis and
cholinesterase inhibitors in the treatment of dementias
2. Glutamate hypothesis and memantine
3. Treatment of behavioral symptoms
4. Prevention
5. Future Directions

4. The Cholinergic Hypothesis
Depletion of acetylcholine and nicotinic receptors thought to occur early and relate to memory impairment with AD
Focus on AD treatment with Acetylcholinesterase inhibitors: Recommended as first line treatment for patients with mild to moderate AD

5. Cholinesterase Inhibitors
Trials in patients with mild to moderate disease (10-24 on MMSE)
On average these drugs seem to stabilize cognitive function and activities of daily living and may have benefits with QOL and behavioral disturbances for at least one year
Side Effects: GI problems

6. Characteristics of Drugs for the Treatment of AD
Donepezil Galantamine Rivastigmine Memantine
Indication Mild to moderate AD Mild to moderate AD Mild to moderate AD Moderate to severe AD
Mode of action Selective AChE inhibition Selective AChE inhibition & Slowly reversible AChE and BuChE Non-competitive NMDA-
allosteric nictotine receptor modulation inhibition receptor antagonist
CYP450 metabolism Yes (CYP2D6 & CYP3A4) Yes (CYP2D6 & CYP3A4) No, hydrolysed by esterases No
Half-life Long (70 hours) Short (7- 8 hours) Very short (~1 hour) Long (60 to 100 hours)
Doses per day One Two IR or One ER Two Two
Given with food Irrelevant Recommended Yes (increased bio-availability) Irrelevant
Initial Dose mg/day mg/day mg/day mg/day
Dose escalation weeks every 4 weeks every 2-4 weeks every week
Recommended clinically mg/day mg/day mg/day mg/day
efficient dose
Adapted from Blennow, et al. Alzheimer’s Disease. Lancet 2006; 368:

7. Donepezil (Aricept)
Three large RCT demonstrate modest effectiveness in stabilizing cognitive function
Well tolerated (no difference in adverse events compared to placebo)
Not hepatoxic, no significant drug-drug interactions
Single bedtime dose: start 5 mg, increase to 10 mg after 4-6 weeks
Most common side effects: sleep disturbance, GI

8. Rivastigmine
May have increased selectivity for hippocampus and neocortex (areas affected by AD)
Modestly effective in treatment of mild to moderate AD (but only at high doses of 6-12 mg/day)
Recommended starting dose: 1.5 mg BID with breakfast and dinner
Minimize GI side effects with 4-6 week titration, increasing to 3 mg BID, 4.5 mg BID, 6 mg BID
More GI side effects, weight loss (dose dependent)

9. Galantamine
Potential second mechanism: modulator at nicotinic cholinergic receptor
Three large RCTs indicate effectiveness in mild to moderate AD (same degree as other agents) at doses of 16, 24, 32 mg/day
Open label 6 month extension of US trial: Possible disease modifying effect
Starting dose: 4mg BID with meals, increase by 4mg BID every 4-6 weeks

10. Cholinesterase inhibitors in moderate to severe dementia
RCT of donepezil vs placebo: 24 week international trial of 290 patients (MMSE 5-18)
63 % of donepezil treated patients were stable/better vs 42% in placebo group

11. Comparison of Cholinesterase Inhibitors…
Cochrane Dementia Group: 3 systematic reviews on efficacy of donepezil, rivastigmine, and galantamine
Each drug seems to have similar treatment effect at 6 months on global and cognitive rating scales
No double blind head to head trial

12. Galantamine: Mean Change From Baseline in ADAS-cog
Open-Extension
Double-blind
galantamine 24 mg/galantamine 24 mg (n = 212/116)
Historical placebo group
*P < .05 vs placebo/galantamine
and not statistically different from baseline.
Improvement
Deterioration 3 6 9 12
Mean (± SE) Change From Baseline in ADAS-cog Score –4 –3 –2 –1 1 2 4 5 7
Months
Placebo/galantamine 24 mg (n = 213/135) *
Raskind et al. Neurology

13. Cholinesterase Inhibitors and AD:
Approved for treatment of mild to moderate AD
Probably effective in treatment of more severe AD
Goal: stabilization (not miracle drugs)
Delay in nursing home placement, decline in ADLS
Probably benefits behavioral and functional status as well
Data suggest no big difference in efficacy among the 3 agents, although donepezil is easier to titrate and better tolerated

14. Cholinesterase Inhibitors and Other Dementias…
Vascular dementia and Dementia with Lewy Bodies each account for 10-15% cases
Prominence of mixed pathology (especially vascular and AD in older population)

15. Galantamine: Vascular and AD/Vascular Dementia
Placebo controlled trial, 6 months, 592 patients
50% in study had AD plus radiological evidence of CVD, 41% had probable vascular dementia, 9% indeterminant
Results for the whole group were similar to previous trials in typical AD : 74% galantamine groupwere improved/stable vs 59% in placebo group
AD-CVD subgroup similar effects to prior trials with AD patients

16. Galantamine and Vascular Dementia
Patients with typical features of AD mixed with features of CVD or evidence of CVD on radiological tests seem to respond similarly to patients with AD alone
Subgroup with CVD alone does better over long term (even with placebo)
Surprise: patients with what appears to be only CVD also seem to have some benefit (these patients not traditionally felt to have specific degeneration of cortical cholinergic pathways)

17. Cholinesterase Inhibitors and Other dementias
Lewy Body Dementia: may respond even more than AD patients
Frontal Lobe Dementia: often respond adversely to cholinesterase inhibitors with increased agitation and insomnia

18. Memantine
NMDA (glutamate) receptor activation thought to be involved in neurodegeneration
Memantine: NMDA antagonist aimed at protecting neurons from glutamate mediated excitotoxicity
Approved in Europe in 2002 for treatment of severe AD (MMSE 3-14)

19. Memantine
Randomized, double blind, placebo controlled study: 166 patients with severe dementia (AD and vascular, MMSE <10)
Cognitive and Behavioral Rating Scale significantly better with treatment, regardless of dementia type
Other European studies have looked at treatment for moderate-severe Vascular Dementia, demonstrating similar efficacy

20. Memantine
28 week RCT of 252 patients with severe AD (MMSE 3-14) in NEJM: memantine associated with less deterioration in cognitive and functional measures than placebo
Problem: small numbers, high drop out rate
Preliminary study: 400 patients with severe AD, 6 months RCT of memantine plus donepezil vs placebo plus donepezil: memantine group had significant benefit in comparison

21. Cognitive Rx in AD Efficacy of Cholinesterase Inhibitors
Donepezil, Rivastigmine, Galantamine
All of them work
Up to 80% of patients show no decline after 6 months of Rx and 50% no decline after 1 year
Need to give for at least 6 to 12 months to determine utility
Side effects: weight loss, diarrhea, nausea
Always titrate to highest dose

22. Cognitive Rx in AD NMDA Antagonists: Memantine
N-methyl-D-aspartate (NMDA) antagonists potentially prevent neuronal injury by reducing excitatory amino acid toxicity by glutamate
Side effects include headache, dizziness, fatigue, confusion
Titrate to 10 mg bid

23. Treatment of behavioral Symptoms & Nonpharmacological Treatment
Oh! Sorry!
This not the case in this lecture!

24. Future directions to AD treatment

25. Normal Mild Cognitive Impairment Dementia

26. Early diagnosis: Impact on treatment
Amyloid plaques probably start 20 years before clinical symptoms of AD
16 million Americans projected to have AD by 2050
Current AD meds work better if started earlier
Disease modifying agents are coming
Preventing or delaying AD could save billions of dollars and lead to improved quality of life for patients and families

27. Proteolytic Cleavages of Amyloid Precursor Protein (APP) That Produce A Peptide
-secretase
A peptide
-secretase
Extracellular space TM
Cytoplasm
COOH
NH2
Selkoe DJ et al. JAMA. 2000;283:

28. Clinical Criteria for Definite, Probable, and Possible Alzheimer’s Diaease
Definite Alzheimer’s Disease:
1. Clinical criteria for probable AD
2. Histopathological evidence of AD (autopsy or biopsy)

29. Probable Alzheimer’s Disease:
1. Dementia established by clinical examination and documented by mental status exam
2. Dementia confirmed by neuropsychological testing
3. Deficits in two or more areas of cognition
4. Progressive worsening of memory and other cognitive functions
5. No disturbance of consciousness
6. Absence of systemic disorders or other brain diseases capable of producing a dementia

30. Possible Alzheimer’s Disease:
1. Presence of a systemic disorder or other brain disease capable of producing dementia but not thought to be the cause of the dementia
2. Gradually progressive decline in a single intellectual function in the absence of any other identifiable cause

31. Unlikely Alzheimer’s Disease
1. Sudden or apoplectic onset
2. Focal neurologic signs
3. Seizures or gait disturbance early in the course of the illness

32. Immunization: Bapineuzumab (Phase III)
Passive immunotherapy
Monoclonal antibody against beta-amyloid peptide administered intravenously (IV)
Binds and removes beta-amyloid peptide that accumulates in plaques

33. Future Rx Strategies Anti-amyloid strategies Combined drug treatments
Tau interventions (methylene blue:
Phase II trials - disrupts tau aggregation)
Gene therapy
Brain transplants

34. Treatment Strategies to Lower AB/Plaque Load in DAT
Mechanism of Action
Secretase modulation
[OM00-3]DR9
DAPT
Bryostatin
Beta secretase inhibitor
Gamma secretase inhibitor
PKC activator, alpha-secretase stimulator
AB immunotherapy
Pre-aggregated AB1-42+adjuvant
Anti-AB antibodies
Active immunization
Passive immunization
Neurotransmitter modulation
Nicotine
AF267B
PEC
Huperzine A
Cholinergic stimulation
Selective M1 receptor agonist
Butyrylcholinesterase inhibitor
Cholinesterase inhibition

35. Treatment Strategies to Lower AB/Plaque Load in DAT
Mechanism of Action
Anti-inflammatory
NSAIDS
Vitamin E
Lipopolysaccharide
Anti-inflammatory, gamma secretase inhibition?
Anti-oxidative
Immune system activation
Miscellaneous
Cerebrolysin
Insulin-like growth factor 1 (IGF-1)
Epigallocatechin-3-gallate (green tea)
Rosiglitazone
Neurotrophic
Increased AB clearance
Possible alpha-secretase stimulation
Increased insulin sensitivity? Cortisol lowering?
Treatment Strategies to Lower AB/Plaque Load in DAT
Treatment
Mechanism of Action
Secretase modulation
[OM00-3]DR9
DAPT
Bryostatin
Beta secretase inhibitor
Gamma secretase inhibitor
PKC activator, alpha-secretase stimulator
AB immunotherapy
Pre-aggregated AB1-42+adjuvant
Anti-AB antibodies
Active immunization
Passive immunization
Neurotransmitter modulation
Nicotine
AF267B
PEC
Huperzine A
Cholinergic stimulation
Selective M1 receptor agonist
Butyrylcholinesterase inhibitor
Cholinesterase inhibition
Anti-inflammatory
NSAIDS
Vitamin E
Lipopolysaccharide
Anti-inflammatory, gamma secretase inhibition?
Anti-oxidative
Immune system activation
Miscellaneous
Cerebrolysin
insulin-like growth factor 1 (IGF-1)
Epigallocatechin-3-gallate (green tea)
Rosiglitazone
Neurotrophic
Increased AB clearance
Possible alpha-secretase stimulation
Increased insulin sensitivity? Cortisol lowering?

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