Optimizing Neurotherapy and Emerging Paradigm for Alzheimer’s Disease

Optimizing Neurotherapy and Emerging Paradigm for Alzheimer’s Disease
Investigations • Innovation • Clinical Application Optimizing Neurotherapy and Emerging Paradigm for Alzheimer’s Disease The Current Foundation Role of Cholinergic Stimulation of Alzheimer’s Disease—Focus on Evidence-Based Management of Moderate and Severe AD Program Chairman MURRAY A. RASKIND, MD Professor and Vice-Chairman Department of Psychiatry and Behavioral Sciences University of Washington School of Medicine Director of the University of Washington Alzheimer’s Disease Research Center Director of the VA Northwest Network Mental Illness Research, Education and Clinical Center (MIRECC)

Program Faculty Program Chairman MURRAY A. RASKIND, MD
Professor and Vice-Chairman Department of Psychiatry and Behavioral Sciences University of Washington School of Medicine Director of the University of Washington Alzheimer’s Disease Research Center Director of the VA Northwest Network Mental Illness Research, Education and Clinical Center Seattle, WA SANDRA E. BLACK, MD, FRCPC Brill Chair in Neurology University of Toronto, Sunnybrook Health Sciences Centre Toronto, Ontario Canada JAMES E. GALVIN, MD, MPH Professor of Neurology and Psychiatry Director of Clinical Operations Center of Excellence on Brain Aging Director Pearl Barlow Center for Memory Evaluation and Treatment New York University Langone School of Medicine New York, NY SERGE GAUTHIER, MD Director of the Alzheimer’s Disease Research Unit McGill Centre for Studies in Aging Professor of Neurology and Neurosurgery, Psychiatry and Medicine McGill University Montreal, Quebec Canada

Optimizing Neurotherapy and Emerging Paradigms for
Alzheimer's Disease Advances in Alzheimer’s Disease Diagnostics and Therapeutics: A Clinician’s Perspective Program Chairman MURRAY A. RASKIND, MD Professor and Vice-Chairman Department of Psychiatry and Behavioral Sciences University of Washington School of Medicine Director of the University of Washington Alzheimer’s Disease Research Center Director of the VA Northwest Network Mental Illness Research, Education and Clinical Center (MIRECC)

Questions How can biomarkers help us diagnose AD and estimate treatment response? Do “disease modifying” anti-beta-amyloid (Aβ) therapeutics modify AD progression? Are cholinesterases “simply” symptomatic drugs? Can we find rational pharmacotherapies for AD agitation/aggression?

Keeping Expectations Modest
If your primary goal is cure, switch to ophthalmology or orthopedics. Maintain quality of life and function and relieving distress are important accomplishments. Slowing disease progression is a primary goal.

Why Biomarkers? Earlier diagnosis.
More precise monitor of the effect of anti-amyloid therapeutics. However, cognitive testing may still be most sensitive measure of disease progression.

AD Biomarkers PET imaging of brain beta-amyloid protein in aggregated form. Cerebrospinal fluid Aβ and tau concentrations.

“Promise Seen for Detection of Alzheimer’s”
Headline – New York Times June 23, 2010 This front page article discusses the development and potential of PET Aβ imaging

Beta Amyloid PET Imaging Ligands
[11C] Pittsburgh Compound B (PIB) Currently available, but short half-life (20 minutes), requires close proximity to cyclotron. [18F] –AV-45 Approaching availability. Longer half-life (10 minutes), enhances availability.

Alzheimer’s Disease Neuroimaging Initiative (ADNI)
PIB distinguishes AD from MCI from normals. PIB highly correlated with CSF Aβ42. But PIB and CSF Aβ42 not significantly correlated with MMSE cognitive measure. In 17 normal, 50 MCI, and 13 AD one-year follow-up subjects: small, nonsignificant changes in Aβ load. However, some individuals had apparently meaningful Aβ load increases. Jagust WJ et al, Alzheimer’s and Dementia 6: , 2010.

A Treatment Relevance Question
Does a drug that reduces [C-11] PIB-measured Aβ load slow cognitive decline? If so, do beneficial cognitive effects reflect Aβ load reductions?

The “Anti-Amyloid Antibody” Approach to the Treatment of Alzheimer’s Disease
Transgenic AD mice show marked reduction in amyloid plaque deposition when actively immunized against beta amyloid. Active beta amyloid immunization in humans produced apparent reduction of amyloid plaque density; but no clear cognitive benefits. 6% incidence of meningo-encephalitis.

Would Passive Monoclonal Anti-Amyloid Antibody Approaches be More Effective and Less Toxic?
Bapineuzumab: N terminus-directed beta amyloid monoclonal antibody in clinical trials. Primary efficacy outcomes in Phase 2 trial not significant. Significant effect on ADAS-Cog in completers. Signal for efficacy in E4 negative subjects. Solanezumab: Mid domain-directed beta amyloid monoclonal antibody in clinical trials. No human trial results available. Antibody design targets soluble beta amyloid.

Estimated Mean Change from Baseline on ADAS-COG
ADAS-COG mITT ADAS-COG Completers 2 -2 -4 -6 -8 -10 -12 2 -2 -4 -6 -8 -10 -12 Placebo Bapineuzumab Rx difference at week 78 = 2.3 P=0.078 Rx difference at week 78 = 4.3 P=0.003 Salloway S, et al. Neurology 2009; 73:

Bapineuzumab Decreases 11C-PIB Aβ Load
28 AD patients assigned to bapineuzumab (n=20) or placebo (n=8). Treatment with bapineuzumab for 78 weeks reduced cortical 11C-PIB amyloid load compared to baseline and placebo. But, in this small subsample, effects on clinical endpoints were disappointing and did not appear related to effects on Aβ binding.

Estimated Change from Baseline in Mean C-PiB PET
Week Estimated mean change from baseline in mean C-PiB Baseline 0.4 0.3 0.2 0.1 -0.1 -0.2 Placebo Bapineuzumab Rinne JO , et al. Lancet Neurol 2010;9:

Potential Utility of CSF Biomarkers
3/27/2017 Potential Utility of CSF Biomarkers A, Total Tau, and Phosphorylated Tau - in Alzheimer’s Disease Improving diagnostic accuracy. Predictive value. Monitoring treatment: Alzheimer’s disease (AD) Mild cognitive impairment (MCI) Primary prevention CSF biomarkers/EP 1-07

Neurochemical Changes in Alzheimer’s Disease
3/27/2017 tau Axonal damage phospho-tau Neurofibrillary tangles oxidation? isoprostanes inflammation?? Amyloid A42 A deposition/metabolism/clearance? CSF biomarkers/EP 1-07

3/27/2017 A42 is the Initiator and Main Culprit in Amyloid Deposition, and Implicated in AD Pathogenesis A42 is the initial amyloid species deposited in brain. A42 exceeds A40 in amyloid deposits. Toxicity and amyloid fibril formation: A42>A 40.  in trisomy 21 and almost all APP mutations. Selectively  in presenilin mutations. CSF biomarkers/EP 1-07

What Does Decreased CSF A42 Mean?
3/27/2017 What Does Decreased CSF A42 Mean? In Tg 2576 (APP-Swedish mutation) mice, decreases in CSF A42 parallel increases in brain A421. In humans, inverse relation between in vivo brain amyloid load (PIB binding) and CSF A42, even in cognitively normal subjects2. 1Kawarabayashi et al., J Neurosci 21: , 2001. 2Fagan et al., Ann Neurol 59: , 2006. CSF biomarkers/EP 1-07

Mean Cortical PIB Binding
Inverse Relation Between in vivo Amyloid Imaging Load and CSF A42 in Humans 1000 750 500 250 CSF Aß42 (pg/mL) Mean Cortical PIB Binding (Binding Potential) Fagan AM, et al., Ann Neurol 59: , 2006.

CSF Total Tau in the Diagnosis of AD
3/27/2017 CSF Total Tau in the Diagnosis of AD CSF total tau is measured by a sensitive ELISA. Meta-analysis of AD versus controls:1 35 studies, 2315 AD; 1126 controls In all studies, CSF T-tau in AD > normal controls 2-3 fold increase in AD Effect size = 1.31 (95% CI ) No correlation with age, dementia duration or severity Increases slightly with aging in normals 1Sunderland T, et al., JAMA 289: , 2003. CSF biomarkers/EP 1-07

Summary of CSF Biomarkers
3/27/2017 Summary of CSF Biomarkers CSF A42 is decreased and CSF tau increased in 75-85% of patients with AD. Changes in CSF A42 and tau are present, but are less marked, in MCI than AD. CSF biomarkers/EP 1-07

Use of CSF Biomarkers for Preclinical Diagnosis: Where Do We Stand
3/27/2017 Optimizing Neurotherapy and Emerging Paradigms for Alzheimer's Disease Use of CSF Biomarkers for Preclinical Diagnosis: Where Do We Stand CSF biomarkers/EP 1-07

3/27/2017 Optimizing Neurotherapy and Emerging Paradigms for Alzheimer's Disease CSF Tau: A42 Ratio for Increased Risk of Mild Cognitive Impairment: A Follow-up Study Li G, et al., Neurology 69: , 2007. CSF biomarkers/EP 1-07

3/27/2017 Methods Subjects: 129 controls aged 12 MCI 21 probable AD 12 other neurodegenerative disease CSF collected between hours after overnight fast. Li G, et al., Neurology 69: , 2007. CSF biomarkers/EP 1-07

Subject Characteristics and CSF Biomarker Concentrations
Controls < 65 yr ≥ 65 yr MCI AD Other n 81 48 12 21 M:F 41:40 22:26 8:4 10:11 7:5 Age 40 ± 15* (21 – 64) 73 ± 7 (65 – 100) 71 ± 13 (49 – 82) 69±9 (52 – 87) 63 ± 11 % APOE*4+ 18 14 50 72 --- RBC/l 7 ± 22 (0 – 176) 10 ± 28 (0 – 163) 10 ± 21 (0 – 58) 14 ± 39 (0 – 180) 8 ± 18 (0 – 83) CSF A42 (pg/ml) 313 ± 14 386 ± 34 245 ± 41 225 ± 27* 332 ± 35 CSF tau 487 ± 24* 784 ± 49 1117 ± 115 1535 ± 131 769 ± 111 CSF P-tau181 (pg/ml) 97 ± 16* 248 ± 33 676 ± 125 936 ± 120 Li G, et al., Neurology 69: , 2007.

High CSF T/A42 Ratio and Conversion to MCI in 42 month F/U
3/27/2017 Conversion to MCI over 42-months of follow-up in: 4/17 persons with high CSF T/A42 ratio 0/26 persons with normal CSF T/A42 ratio Logrank test for survival curve, p<0.05 Li G, et al., Neurology 69: , 2007. CSF biomarkers/EP 1-07

Implications of High CSF T/A42 Ratio
3/27/2017 Implications of High CSF T/A42 Ratio The high CSF T/A42 subgroup of controls had significantly increased risk of conversion to MCI during 42 months of follow-up. Suggests that high CSF T/A42 individuals had “latent” AD at time of CSF collection. Li G, et al., Neurology 69: , 2007. CSF biomarkers/EP 1-07

3/27/2017 Optimizing Neurotherapy and Emerging Paradigms for Alzheimer's Disease Cross-sectional Lifespan Study Suggests CSF A42 Concentration is Altered in APOE*4 Carriers. Peskind ER, et al., Arch Neurol 63: , 2006. CSF biomarkers/EP 1-07

CSF A42 and A40 in 184 Normal Controls Aged 21-88
3/27/2017 Peskind ER, et al., Arch Neurol 63: , 2006. CSF biomarkers/EP 1-07

3/27/2017 A Sobering Finding CSF A42 findings consistent with acceleration by the APOE*4 allele of pathogenic A42 deposition starting in later middle life in persons with normal cognition. Peskind ER, et al., Arch Neurol 63: , 2006. CSF biomarkers/EP 1-07

Persistent treatment slows clinical progression.
Cholinesterase Inhibitor Clinical Experience and Clinical Trials Support Reduction of AD Progression Persistent treatment slows clinical progression. Delayed start design: persons first on placebo than switched to a cholinesterase inhibitor do not “catch up.” Increasingly divergent clinical status in long-term trials favoring cholinesterase inhibitors. Sounds like disease modification to me.

Persistent Treatment with Cholinesterase Inhibitors and/or Memantine Slows Progression of AD
641 AD patients followed at Baylor College of Medicine for over 20 years. Persistent treatment with donepezil, other cholinesterase inhibitors, and memantine slowed AD progression assessed by multiple cognitive, functional and global measures. Rountree SD, et al. Alzheimers Res Ther 1(2):7, 2009

Galantamine Shows Sustained Cognitive Benefits in AD Over 12 months
(including a delayed start time) Double-blind Open-extension - 4 - 3 - 2 - 1 1 2 3 4 5 6 7 *p < 0.05 vs placebo/ Galantamine 24 mg/day # not significantly different from baseline * # in ADAS-Cog from baseline Mean ( SE) change Galantamine 24 mg/day Placebo/ Galantamine 24 mg/day Data from historical placebo group Baseline 3 6 9 12 Raskind M et al., Neurology 54:2261–8, 2000

Long-term Data: Change from Baseline in ADAS-Cog/11 scores
Clinical Improvement -4 4 Mean change from baseline ± SE in ADAS-Cog/11 8 12 16 Placebo comparison Estimation of decline – Stern Equation Clinical Decline 20 Galantamine 24–32 / 24 mg 24 Baseline 3 6 9 12 18 24 30 36 Months of Treatment Raskind MA et al. Arch Neurology 61: , 2004.

Donepezil Significantly Better Compared to Calculated Change by Stern Equation over 3 Years
Wallin AK, et al. Dement Geriatr Disord 2007:23:

36-Month Galantamine Trial
Does a greater rate of cognitive decline in “dropouts” than 36 month “completers” explain results? No! Rate of decline prior to galantamine discontinuation in “dropouts” was the same as in “completers.”

We Compared Slopes of ADAS-cog Decline Between Dropouts and Completers
-1 1 2 3 4 Change from baseline in ADAS-Cog/11 5 6 7 8 9 Galantamine patients who completed treatment 10 Galantamine patients who discontinued 11 10 20 30 40 Time (months) Raskind MA, et al., Arch Neurol 61: , 2004.

If ChEIs Delay Disease Progression, What are the Candidate Mechanisms?
Nicotinic cholinergic stimulation in vitro: Protects against A-induced neuronal death1 Muscarinic cholinergic stimulation in vitro: Inhibits A production from amyloid precursor protein (APP)2 Reduces phosphorylation of tau2 1Arias E et al., Neuropharmacology 46: , 2004. 2Fisher A et al., J Mol Neurosci 20: , 2003.

Mechanisms of Neuroprotective Effects of Nicotine and Acetylcholinesterase Inhibitors
Role of Alpha-4 and Alpha-7 Receptors in Neuroprotection An excellent review Highlights: Stimulation of nicotinic receptors (particularly alpha-7) by nicotine or galantamine or donepezil prevents glutamate neurotoxicity. These effects of cholinesterase inhibitors appear independent of their inhibition of cholinesterase activity. Akaike A, et al. J Mol Neurosci 40: , 2010

Loss of Alpha-7 Nicotinic Receptors Enhances Beta-amyloid Oligomer Accumulation in a Mouse Model of Alzheimer’s Disease “Alzheimer’s” transgenic mice with deletion of the alpha-7 nicotinic receptor have increased: Learning and memory deficits Hippocampal and cholinergic neurodegeneration Soluble oligomer (neurotoxic) beta-amyloid Hernandez CM, et al. J Neuroscience 30: , 2010.

Disruptive Agitation: What is it?
Distressing behaviors that often cluster together Irritability Anger outbursts, aggression Sleep disruption Pressured pacing and restlessness Uncooperativeness with necessary care Major cause of long-term care placement.

Commonly Used Psychotropic Medications for Disruptive Agitation in AD
Antipsychotics: haloperidol, risperidone, olanzapine, aripiprazole, quetiapine. All show modest efficacy in some placebo-controlled trials. Frequent non-responders Adverse effects: pseudoparkinsonism, sedation Increased risk of stroke and death caused FDA to issue “Black Box Warning.” All antipsychotics are antagonists of the Alpha-1 Adrenoreceptor: Does this contribute to efficacy for agitation?

The Brain Noradrenergic System
The noradrenergic system is the brain “adrenaline” system for attention and arousal. Excessive noradrenergic reactivity produces anxiety and agitation. Does excessive noradrenergic activity contribute to agitation in AD?

Noradrenergic System Pathology in Alzheimer’s Disease
Despite loss of noradrenergic locus coeruleus neurons there is: Increased cerebrospinal fluid (CSF) norepinephrine (NE) in AD1 Increased agitation response to NE in AD2 Compensatory upregulation of surviving LC neurons3 Increased alpha-1 adrenoreceptors in locus ceruleus target areas4 1Elrod et al., Am J Psychiatry 154:25-30, 1997. 2Peskind, et al., Arch Gen Psychiatry, 1995. 3Szot, et al., J Neuroscience, 2006. 4Szot, et al., J Neuroscience, 2007.

CSF Norepinephrine: Effects of Aging and AD
*significantly higher than young subjects **significantly higher than all other subject groups 500 Advanced AD (n=25) ** 400 Old (n=42) * 300 Mild-Moderate AD (n=49) * CSF norepinephrine (pg/ml) 200 Young (n=54) 100 Elrod et al., Am J Psychiatry 154:25-30,

Postsynaptic Adrenergic Receptor Antagonists in AD
Would reducing brain responsiveness to NE by blocking adrenergic receptors reduce agitation in AD? Alpha-1 receptor antagonist: prazosin. Long lasting benefits in posttraumatic stress disorder Would prazosin be helpful in AD? Raskind MA, et al., Am J Psychiatry 160: , 2003.

Prazosin as a Novel Pharmacologic Approach to Agitation in AD
Prazosin is an alpha-1 receptor antagonist. Only one that crosses from the blood into the brain Inexpensive, generic, used for BPH and hypertension by millions of older persons for decades. Clinically effective for AD agitation in open label pilot study. 50

Placebo-Controlled Trial of Prazosin for Disruptive Agitation in Dementia
Twenty-one persons (mean age 80 years) with DSM-IV dementia (possible or probable AD) and frequent disruptive agitation. Randomized to prazosin (n = 10) or placebo (n = 11) for 8 weeks. Prazosin dose range 2-6 mg/day (mean dose 5.6 ± 1.2 mg/day). Primary outcome measures: BPRS, NPI, CGIC.

Placebo-Controlled Trial of Prazosin for Disruptive Agitation in Dementia: NPI
Wang L, et al., Am J Geriatr Psych 17:744-75, 2009.

Where Are We Now? AD biomarkers will be increasingly valuable, but do not under-estimate the importance of a careful history and longitudinal cognitive/ functional assessment. The primacy of Aβ in AD pathogenesis and therapeutics remains in question. Improving treatments for behavioral disturbances in AD will have major impacts on patients and caregiver quality of life and health care costs.

Alzheimer's Disease Pathophysiology of AD: Foundation Role of Cholinergic Dysregulation and Emerging Perspectives on the Pathobiology of AD JAMES E. GALVIN, MD, MPH Professor of Neurology and Psychiatry Director of Clinical Operations Center of Excellence on Brain Aging Director Pearl Barlow Center for Memory Evaluation and Treatment New York University Langone School of Medicine New York, NY

Objectives Pathophysiology of AD Beta-amlyoid hypothesis
Cholinergic Hypothesis Clinical and therapeutic implications of Cholinergic hypothesis Intersection of cholinergic and amyloid-based pathobiology Approaches to therapy Implications for multi-modal therapies for AD

Pathophysiology of AD Neuropathologic hallmarks of AD
Senile plaques – Amyloid b-protein (Ab) Neurofibrillary tangle – tau protein Largely a sporadic, late-life cause of dementia, early-onset and familial forms exist Mutations in APP, PS-1 and PS-2 Mutations increase production of Ab Late-onset disease is associated with presence of the e4 allele of Apolipoprotein E More than 40 other genes have been associated with AD

Amyloid Hypothesis First proposed in 1991
Initiating molecule in AD, ultimately leading to AD Mutations in familial AD encode substrate (APP) and enzyme (Presenilin) for Ab production Infusions of Ab cause neuronal degeneration and cognitive deficits Harmful form of Ab is small, diffusable aggregates or oligomers Pakasi and Kalman 2008, Hardy and Allsop 1991, Kowall et al 1991, McDonald et al 1994, Dahlgren et al 2002

A is Derived After Cleavage of APP
Plaque b C99 (b-stub) sAPP a C83 (a-stub) sAPP APP g Ab AICD g p3 AICD (Ab50-Cter) Lumen/ Extracellular A Cytosol APP = amyloid precursor protein; sAPP = soluble form of APP; AICD = APP intracellular domain

Acetylcholine ACh activity known since turn of 20th century
Nobel prize to Henry Dales and Otto Loewi Synthesized de novo by the brain Two types of receptors Muscaric Nicotinic In the CNS, largely produced in collection of neurons in basal forebrain and pons with wide-range projections

Cholinergic Projections
From: Cooper, Roth and Bloom, Biochemical Basis of Neuropharmacology, 7th Ed, 1996

Cholinergic Hypothesis
Dysfunction of cholinergic system contributes to memory decline Drachman and Leavitt (1974) Link between cholinergic dysfunction and memory impairment Scopolamine in young adults caused impairment Corroborated by primate, canine and rodent studies Reduced choline acetyl transferase (ChAT) activity in cortex, hippocampus and amygdala of AD patients Activity correlated with level of cognitive impairment Selective loss of cholinergic cells in basal forebrain Davies and Maloney, 1976, Perry et al 1978, Wilcock et al 1982, Whitehouse et al 1981.

Neuropathological Signaling: Cholinergic Hypothesis
Acetyl CoA + Choline Glial Cell Presynaptic Neuron Choline ChAT BuChE ACh BuChE Synaptic Cleft ACh Choline + Acetate Postsynaptic Neuron AChE AChE Purpose: To review the schematic of the cholinergic hypothesis Key Points: If you’re going to try to boost function in a system as demonstrated above, you can do it in 3 ways: You can give a building block or a precursor like choline. You could block the breakdown of the neurotransmitter once it’s left the presynaptic neuron; use a cholinesterase inhibitor (ChEI) to delay the breakdown and prolong its physiological effect. Or you could use a false messenger or agonist to tickle the postsynaptic receptor and give a message. Cholinergic Receptor ACh = acetylcholine; AChE = acetylcholinesterase; BuChE = butyrylcholinesterase; ChAT = choline acetyltransferase; CoA = coenzyme A. Adapted from Adem A. Acta Neurol Scand. 1992;85(suppl 139):69-74.

Cholinergic Hypothesis
Basal forebrain and rostral brainstem cholinergic pathways converge to serve important functional rolls in awareness, attention, working memory and mnemonic processes Loss of cholinergic function contributes to cognitive decline associated with AD Perry et al 1999, Bartus 2000,

Cholinergic Receptors and AD
Two classes Nicotinic ionic channels Responsible for fast transmission Reduction in a4 nAChR in AD Up-regulation of a7 nAChR in AD compared with MCI and controls a7 receptors down-regulated in DLB Possible compensatory response to maintain basal forebrain-cortical cholinergic activity a7 nAChR interacts with APP and Ab peptides which could lead to aberrant function Muscarinic G protein-coupled receptors Preserved during progression of AD In triple transgenic mice, M1 agonists improved cognitive and reduced Ab and tau pathology Hypothesis: activation of TACE/ADAM17, decreased BACE1 levels and/or inhibition of GSK3b Mufson et al 2009, Nagele et al 2002, Counts et al, 2007, Caccamo et al 2006

Role of Cholinergic Deficits in Behavioral Symptoms of AD
Temporal and frontal lobe dysfunction implicated in psychosis of AD Regional cholinergic deficits—apathy and indifference Cholinergic-monoaminergic imbalance hypothesized in mood disorders Cholinesterase inhibitors (ChEIs) have shown behavioral benefits in several clinical trials Lanari A, et al 2006; Cummings JL. 2000

Clinical and Therapeutic Implications of Cholinergic hypothesis
Recent functional MRI study demonstrated MCI treated with donepezil demonstrated increased frontal cortex activation relative to untreated control Correlated with task performance AChE does not show decline until late stages of disease Only mild losses in MCI and mild AD Vesicular Ach transporter is not severely altered in AD Cholinergic neurons appear then to shrink and become dysfunctional rather than degenerate early in disease Suggest cholinergic neurons may be viable, however dysfunctional early in disease and thus amenable to manipulations Changes in neurotrophic gene expression may provide targets of intervention for dysregulation of cholinergic neurons NGF (trk) receptors down-regulation may be a molecular marker for transition from MCI to frank AD Saykin et al, 2004, Bierer et al 1995, Rinne et al, 2003, Gilmor et al, 1999, Rinne et al 1987, Mufson et al, 2009

Challenges to Cholinergic Hypothesis
Studies of post-mortem tissue Levels of AChE and ChAT are not reduced in very mild AD Levels of ChAT may be upregulated in MCI and very mild AD Since neither ChAT nor AChE are rate-limiting cholinergic enzymes, they are unlikely to accurately reflect cholinergic function in a living patient Other factors may be involved Alterations in high-affinity choline transport (rate-limiting step) Deficits in nicotinic and muscarinic receptors Dysfunctional neurotrophic support Neurochemical analyses of autopsy tissue maybe unreliable Dependent on length of agonal state and post-mortem interval More recent in vivo imaging studies support amyloid hypothesis 11C N-methylpiperidine-4-yl proprianate (AChE activity) Nicotine-based ligands Non-selective muscarinic ligands 123I Benzovesamacol (vesicular Ach transporter) Terry and Buccafusco 2003, Slotkin 1990, Auld et al 2002, Kuhl et al 1999, Norberg 2001, Zubieta et al 2001, Kuhl et al 1996

Recent Developments Extension of studies to early, prodromal stages
Religious Orders Study Very mild cases did not show decreases in ChAT but actually increases Immunochemistry of brain with very mild AD/MCI ChAT or vesicular ACh transporter not reduced Markers of NGF receptors markedly reduced Possible that other pre- or post-synaptic mechanisms may be compromised Perhaps down-regulation of retrograde transmission of NGF from hippocampus/frontal cortex to basal forebrain Altered neurotrophic receptors may mark early stage of disease with initial increases in ChAT activity Decreased connectivity between hippocampus and entorhinal cortex Davis et al, 1999, Dekosky et al, 2002, Gilmor et al, 2000, Mufson et al, 2002, Terry et al, 2003, Counts and Mufson, 2005, Ikonomovic et al, 2003, Kordower et al, 2001

Interactions Between Amyloid and Cholinergic Hypotheses
Regulation of Ab by stimulation of muscarinic or nicotinic receptors Partial M1 agonists increase aAPPs, decrease Ab and decrease tau phosphorylation Nicotine may increase downstream synthesis of neurotropins Cholinergic deficits could be secondary to amyloid toxicity Bidirectional interaction between cholinergic function and processing of amyloid precursor protein High affinitity a7 receptors can serve as high affinity binding sites for Ab peptides Amyloid peptides inhibit uptake of choline and decrease endogenous Ach release without exhibiting effects on ChAT activity Ab block functional interaction between nicotinic agonists and receptors on hippocampal neurons Court et al, 1998, Muller et al 1997, Genis et al 1999, Jonnala et al 2002, Roberson et al, 1997, Wang et al 2000, Pakaski and Kalman, 2008, Liu 2001

Interactions Between Ab and ACh
Toxicity of Ab on the cholinergic system Ach synthesis and release reduced by solubilized Ab Loss of cholinergic fibers without loss of cholinergic neurons Reduction of binding to vesicular Ach transporter Inhibition of fast axonal transport Ab 42 binds with higher affinity to a7 nAChR than Ab 40 Ab 42 reduced downstream events in mAChR signal transduction Cholinergic system and APP processing via a-secretase mAChR a7nAChR agonists AChEI Auld et al 1998, Boncristiano et al 2002, Ikeda et al 2000, Kasa et al 2000, Qi et al 2005, Kelly et al 1996, Buxbaum et al 1992, Zimmerman et al 2004

Mechanisms of AChE Inhibitors on the Release of sAPPα
Change Cholinergic mechanism Other mechanism Reference Tacrine Decrease − ? Lahiri et al. (1994); Lahiri et al. (1996) Metrifonate Increase + (Pakaski et al., 2000) and (Pakaski et al., 2001); Racchi et al. (2001) Ambenonium Pakaski et al. (2001) Ganstigmine Mazzucchelli et al. (2003) Ladostigil MAP-kinase or tyrosin kinase-dependent pathway Yogev-Falach et al. (2002) Donepezil Enhancing trafficking and activity of ADAM 10 Zimmermann et al. (2004) Phenserine Inhibition of APP mRNA translation Lahiri et al. (2000); Shaw et al. (2001) Galantamine Lenzken et al. (2007) Pakaski and Kalman 2008

Linking Ab and ACh Pakaski and Kalman 2008

Disease-modifying effect Disease-modifying effect
Discrimination Between Disease Modification and Symptomatic Benefit Withdrawal design Staggered-start design Randomized phase Placebo phase Randomized phase Placebo phase Active Active Disease-modifying effect Performance Performance Placebo Placebo Symptomatic effect Symptomatic effect Disease-modifying effect Time Time

Is There Evidence of Disease-Modifying Effects?
From clinical trials, functional imaging and basic science studies, anti-cholinesterase drugs may: Reduce circulating Ab Alter APP processing Prevent Ab deposition in cholinergic projection sites Promote non-amyloidogenic APP processing If changes in cholinergic transmission alters APP processing, appropriate cholimimetic therapeutics might provide both symptomatic benefit and modify AD pathogenesis Lopez et al 2002, Krishman et al 2003, Francis et al 2005, Nordberg 2006, Inestrosa et al 1996, Rogers et al 2000

Amyloid-Based Approaches
Barten and Albright 2008

Immunization Reduces Ab burden
Holmes et al 2008

Immunization Does not rRduce Disease Burden
Time to severe dementia Time to death Holmes et al 2008

Neurotransmitter-Based Approaches
Barten and Albright 2008

Model of Multi-Modal Approach
Mild Moderate Severe Disease-modifying Rx Performance Combining Symptomatic and Disease-modifying RX Symptomatic Rx Time

Summary Ab as the likely culprit leading to AD is a logical target for anti-AD therapies but to date, Phase III trials have not been successful Ach provides targets for symptomatic benefit Dysfunction/degeneration of the cholinergic projection neurons is a later stage event in AD Dysregulation of the cholinergic system is an early event Mufson et al 2009,Davis et al 1999, DeKosky et al 2002, Mufson et al 200, Mufson et al 2002

Summary (cont.) There is a bidirectional relationship between the amyloid and cholinergic hypotheses Disease-modifying therapies will likely be more effective when used earlier in disease process Clear need for improve detection of AD at earliest, even preclinical stages Multi-modal approaches offer the best potential to provide treatment throughout the spectrum of disease Mufson et al 2009,Davis et al 1999, DeKosky et al 2002, Mufson et al 200, Mufson et al 2002

Alzheimer's Disease Evidence-based Role of Cholinesterase Inhibition Across the Severity Spectrum in AD SANDRA E. BLACK, MD, FRCPC Brill Chair in Neurology University of Toronto, Sunnybrook Health Sciences Centre Toronto, Ontario Canada

Learning Objectives Review evidence for cholinesterase inhibitors as cognitive enhancers in mild-moderate Alzheimer’s Disease Summarize evidence for utility in earlier and later stages of AD Consider evidence for longer term use See Canadian Consensus on Dementia Diagnosis and Treatment: Hogan et al, CMAJ 2008; Alzheimer’s and Dementia special issue 2007

The Cholinergic Deficit in AD
Progressive loss of cholinergic neurons Progressive decrease in available ACh Impairment in ADL, behavior and cognition N. basalis Meynert Hippocampus Cortex Slide 9: The cholinergic deficit in AD underlies the clinical symptomatology Acetylcholine (ACh) is needed in sufficient amounts for maintaining proper neurotransmission. Reduction in ACh is the most predominant neurotransmitter deficit found in AD. The progressive loss of ACh available for neurotransmission has been correlated with the cognitive deficits found in AD patients (Perry et al.,1978). These findings have led to the formulation of the cholinergic hypothesis of AD (Bartus et al., 1982), which proposes that the cognitive deficits of AD are related to the observed decrease in central cholinergic activity and that increasing intrasynaptic ACh could enhance cognitive function and clinical well being. Furthermore, cholinergic deficits in the limbic and paralimbic structures may contribute to the development of certain behavioral abnormalities seen in AD (Cummings and Back, 1998). Bartus et al., 1982; Cummings and Back, 1998, Perry et al., 1978

Cholinesterase Inhibitors: Mechanisms of Action
N = nicotinic M = muscarinic ACh = acetylcholine Presynaptic nerve terminal ACh Astrocyte BuChE N receptor Galantamine M receptor ACh Donepezil Rivastigmine Galantamine Rivastigmine In the normal human brain, an electrical nerve impulse travels to the end of the pre-synaptic neuron. This triggers acetylcholine (ACh)-containing vesicles to fuse with the synaptic knob. ACh is released into the synaptic cleft and diffuses towards the post-synaptic neuron. ACh is hydrolyzed by the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) to acetic acid and choline. Choline is taken up into the pre-synaptic neuron and used as a substrate for ACh re-synthesis, which is finally stored again in the pre-synaptic vesicles. The pre-synaptic neuron is then ready for further transmitter release. This cycle ensures normal cholinergic transmission, normal development of the central nervous system (CNS), and survival. The biological role of AChE and BuChE in this cycle is the termination of impulse transmissions at cholinergic synapses by rapid hydrolysis of the neurotransmitter ACh. Donepezil is a selective AChE inhibitor, while rivastigmine is a dual AChE and BuChE inhibitor. Studies have shown that galantamine is a weak AChE inhibitor but it is also an allosteric nicotinic receptor modulator. Reference: Adem A: Putative mechanisms of action of tacrine in Alzheimer's disease. Acta Neurol Scand 1992; 85(suppl 139):69-74. Butyrylcholinesterase Acetylcholinesterase Postsynaptic nerve terminal Increased availability of ACh at synapse (AChE and BuChE inhibition)

Efficacy-Cognitive Improvement
benefit no benefit heterogeneous Based on 2419 subjects Responders defined as >/=4 points on ADAS 10% [4%, 17%] of patients show significant benefit over placebo Lanctot et al, CMAJ, 2003

Efficacy Clinical Global Impression
benefit no benefit Homogeneous Based 4468 subjects Responder defined as improved on CGIC or CIBIC 9% [6%, 12%] of patients show significant benefit over placebo Lanctot et al, CMAJ, 2003

Number Needed to Treat for Benefit
Numbers needed to treat to benefit 7 (CI95%: 6, 9) for stabilization or better 12 (CI95%: 9, 16) for minimal improvement or better 42 (CI95%: 26, 114) for marked improvement NNT for clinically benefit are low. Homogeneous-all 3 ChEI similar Lanctot et al, CMAJ, 2003

Tolerability Caveat Galantamine above recommended doses, heterogeneity
8% [5,11] 8% [5,12] 7% [3,10] Lanctot et al CMAJ, 2003

Safety Number needed to harm (ie to cause AE in 1 patient) = (Lanctot et al CMAJ 2003 ) Recent study of community-dwelling dementia patients using healthcare database in Ontario, Canada (2002-4) 19,803 treated with cholinesterase inhibitors vs 61,499 not on CHEI’s Syncope vs 18.6/ HR 1.76 Bradycardia 6.9 vs 4-4/ HR 1.69 Pacemaker needed 4.7 vs 3.3/1000 HR 1.49 Hip fracture 22.4 vs 19.8/ HR 1.18 Gill et al Arch Int Med 2009

Limitations of Drug Trials to Date
Benefits in cognition, behavior and function have been for 6 months- only a few 1-year placebo-controlled studies Longer term benefits derived from open label extensions, limited by large dropouts and bias from self-selection Most clinical trials have been pharma-sponsored without independent analyses, except for AD 2000 Differential treatment effects on specific cognitive domains are not known as they have not been studied; the tools used may not have sampled the most sensitive domains Placebo trials may no longer be feasible or ethical Recent review of RCTs highlight methodological flaws (e.g., no corrections for multiple comparisons, LOCF method) and questions utility of drugs in clinical practice Kaduszkiewicz et al., BMJ, 2005

Use in Early and Later Disease Stages
Optimizing Neurotherapy and Emerging Paradigms for Alzheimer's Disease Use in Early and Later Disease Stages

Nursing home placement
Natural History of AD: early 5 10 15 20 25 30 1 2 3 4 6 7 8 9 MMSE Years Early Cognitive symptoms Loss of functional independence Mild-moderate Behavioural problems Nursing home placement Severe Death Feldman H and Gracon S in: Clinical Diagnosis and Management of Alzheimer’s Disease 1998.

Conversion of Normal and MCI Subjects to Dementia (AD Cooperative Study)
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 10 20 30 40 50 60 70 80 90 100 Follow-up Time (Years) Proportion Free of Dementia (%) Normals MCI 45% Key Points This graph demonstrates the conversion rate from MCI to dementia next to the conversion rate of normal (non-MCI) to dementia. The conversion to dementia is much more common in patients with MCI than in normals. In fact, by the 3.5-year mark, >50% of MCI sufferers will have converted to dementia. References DeKosky ST. Pathology and pathways of Alzheimer's disease with an update on new developments in treatment. J Am Geriatr Soc 2003;51(5 Suppl):S314-S320. Grundman M et al. Rate of dementia of Alzheimer type (DAT) in subjects with mild cognitive impairment? The Alzheimer's Disease Cooperative Study. Neurology 1996;46:A403. Retrospective analysis of 687 subjects with MCI Mean age 72.2 yrs DeKosky ST. J Am Geriatr Soc, 2003; Adapted from Grundman M et al, Abstract in Neurology, 1996.

ADCS: MCI Study Design Objectives
To determine whether daily doses of vitamin E or donepezil given over a 3-year period can: 1) delay or prevent the onset of AD in people who have MCI 2) slow the decline of symptoms Design: 3-year, randomized, double-blind, placebo-controlled, parallel group study 60 sites in the US and 9 sites in Canada Patients were randomized to receive donepezil 10 mg/day, vitamin E 1,000 IU b.i.d., or placebo Subjects: 769 patients with MCI Outcome measures: Primary: Conversion to AD Secondary: MMSE, ADAS-cog, CDR, CDR-SB, ADCS, GDS, Neuropsychological battery Key Points The objective of this study was to determine whether daily doses of vitamin E or donepezil given over a 3-year period can: delay or prevent the onset of AD in people who have MCI slow the decline of symptoms This long-term, randomized, double-blind, placebo-controlled parallel group study included 769 patients with MCI from 60 sites in the US and 9 sites in Canada. Patients received donepezil 10 mg/day, vitamin E 1,000 IU b.i.d., or placebo. The primary outcome measures used to evaluate this population of patients was the rate of conversion to AD, based on the clinical criteria of the National Institute of Neurological and Communicative Diseases and Stroke and the Alzheimer’s Disease and related Disorders Association (NINCDS-ARDRA). The secondary outcome measures used to evaluate the symptoms of AD included the MMSE, ADAS-cog, CDR, CDR-SB, ADCS, GDS, and a neuropsychological battery. Reference Petersen RC et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 2005;352. Petersen et al. N Engl J Med, 2005

Survival Analysis: Donepezil vs. Placebo
6 mo 1 yr 18 mo 1.0 0.9 0.8 Probability of not converting to AD 0.7 0.6 Donepezil Placebo Key Points: Survival with P-Value Reference from Pointwise Z-Test: Donepezil vs. Placebo At study endpoint (3 years) the risk of progression was the same in all three treatment groups Donepezil reduced the risk of progressing from MCI to AD vs. placebo for up to 12 months The effects of donepezil treatment lasted longer (up to 2-3 years) in patients with the Apo E4 genotype The mean difference in time to conversion between donepezil and placebo-treated patients was 6 months, with mean times of 661 days and 484 days, respectively Vitamin E had no effect on progression to AD Donepezil had an effect on overall function, memory and language for up to 18 months Vitamin E had a minor effect on secondary outcomes Amnestic MCI strongly predicted progression to AD – 99% of converters converted to AD Reference Petersen RC et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 2005;352. p<0.001 0.5 p<0.009 p<0.035 0.4 200 400 600 800 1,000 1,200 Time on MCI study (days) Petersen RC et al. N Engl J Med, 2005

Summary of MCI Studies NIH MCI study with donepezil failed statistical significance on primary endpoint, but decline delayed by up to 12 months, and was slower in APOE e4 participants (Petersen et al NEJM 2005) Recent 48 wk study of donepezil in 821 aMCI patients likewise found nsd in 1o and 2o outcomes, though patients felt better subjectively (Doody et al Neurol 2009) Other MCI trials with galantamine (Winblad et al Neurol 2008) rivastigmine (Feldman et al Lancet Neurol 2007) also did not delay conversion More deaths noted with galantamine 1.4% vs 0.3% in placebo MCI subjects leading to product label warning See Raschetti et al Cochrane Review PLoS Med 2007 Key Points Although the symptomatic MCI studies with donepezil failed to reach statistical significance on their primary endpoints, results were promising and warrant further investigation. As such, there are other currently ongoing trials are examining the role of donepezil treatment in MCI further. Further investigation using longer study duration, flexible dosing, and other efficacy measures is also warranted, and is currently underway with donepezil.

Safety and Tolerability of Donepezil (10mg/d) in aMCI
Study Design Safety and tolerability of donepezil (10mg) was evaluated in 145 aMCI patients as an open label 28-week extension study after a 48-week RCT of 821 aMCI Key Results 57.4% in the donepezil/donepezil group and 62.3% in the placebo/donepezil group experienced an AE Most frequent treatment related AEs were diarrhea, muscle spasms, insomnia, and nausea (more common early on & mild-moderate in severity) 22.1% in the placebo/donepezil group discontinued donepezil due to an AE compared with 10.3% in the donepezil/donepezil group Background It has been suggested that aMCI may be an early clinical manifestation of AD in many individuals Thus, treatments for AD may be expected to benefit patients with aMCI and possibly delay the progression to AD To this date, studies have not demonstrated a delay to onset and there are significant safety risks associated with use in this population. Conclusions Donepezil in aMCI appeared to be safe, but patients with AD seem to tolerate it better than patients with MCI Doody, et al., Am J of AD & Other Dem. 2010

Higher Rate of Progression to AD in Patients with aMCI and Depressive Symptoms
Study Design 756 aMCI from the three year NIH study drug trial of donepezil and vitamin E Depressive symptoms assessed at baseline using the Beck Depression Inventory (BDI) Key Results On regression analysis higher BDI scores were associated with progression to AD Depressive subjects: proportion progressing to AD was lower in donepezil group than combined vitamin E and placebo groups at 1.7 years, 2.2 years, and marginally lower at 2.7 years Nondepressive subjects: no difference between the three treatment groups Study Design Patients were followed either to the end of the study or to the endpoint of progression to probable or possible AD. Conclusions The study suggests that donepezil modulates the increased risk of progressing to AD by the presence of depressive symptoms Conclusions Depressive symptoms may be predictive of progression from aMCI to AD Treatment with donepezil delayed progression to AD in depressive subjects with aMCI Lu, et al., Neurology 2009

Survival Lu, et al., Neurology 2009 Conclusions
- The study suggests that donepezil modulates the increased risk of progressing to AD by the presence of depressive symptoms Lu, et al., Neurology 2009

Nursing home placement
Natural History of AD: Moderate to severe stage 5 10 15 20 25 30 1 2 3 4 6 7 8 9 MMSE Years Early Cognitive symptoms Loss of functional independence Mild-moderate Behavioural problems Nursing home placement Severe Death Feldman H and Gracon S in: Clinical Diagnosis and Management of Alzheimer’s Disease 1998.

Mean Change From Baseline
Donepezil vs Placebo in Nursing Home Study in Severe AD (MMSE 1-10): Cognition (SIB) SIB p=0.003* 6 p=0.008† Clinical improvement p=0.008* 4 2 Mean Change From Baseline in SIB Score Baseline -2 Donepezil -4 Placebo Clinical decline -6 3 6 ITT LOCF *OC analysis; †LOCF analysis. Months Winblad et al. Lancet, 2006.

Functional Abilities Also Showed Less Decline
Clinical Improvement P = 0.086* P = 0.031* P = 0.029† Mean Change From Baseline in ADCS-ADL Baseline Multicenter, randomized, double-blind, parallel-group trial of ARICEPT versus placebo Patients residing in assisted-care facilities in Sweden (equivalent to skilled nursing facilities) 248 subjects with severe AD Baseline MMSE = 5.8 for ARICEPT; 6.3 for placebo Diagnosis Patients with severe AD consistent with DSM-IV and NINCDS-ADRDA criteria Main criteria for inclusion MMSE 1-10 Functional Assessment Staging (FAST) 5-7c Clinical Decline 3 6 ITT LOCF Months *OC analysis; †LOCF analysis. Winblad et al Lancet, 2006

Less Cognitive Decline in Community Dwelling Severe AD (MMSE1-12)
-8 -6 -4 -2 2 4 6 8 p = Clinical improvement SIB scores: LS mean change from baseline (SE) Raw data required to complete d Clinical decline 10mg/d Donepezil Placebo 8 16 24 ITT LOCF Study week Black et al Neur 2007

Cholinesterase Inhibitor Use in Other Dementias
Level 1 evidence for different compounds according to studies undertaken Donepezil in vascular dementia Rivastigmine in parkinson/diffuse lewy body dementia Galantamine in mixed vascular dementia (Memantine also shows efficacy in moderate to severe AD)

Use of Higher Doses, New Formulations
Optimizing Neurotherapy and Emerging Paradigms for Alzheimer's Disease Use of Higher Doses, New Formulations

Once Daily Formulations
Galantamine extended release 8mg od –16mg od– 24mg od Rivastigmine patch 4.6-mg od –9.5mg od GI tolerability better than oral formulation (eg nausea: oral 23 vs patch 7% vs placebo 5%) Skin sensitivity (erythema, edema, pruritus, pain) Recent caution due to additive dose effects if patch not removed daily before new one applied Exposure levels and Cmax are highest when the patch is applied to the upper back, chest or upper arm (Lefevre et al. J Clin Pharmacol 2007;47:471-8). Taking the upper back as the reference point, the relative bioavailabilities with other body sites are 100% for the chest, 92% for the upper arm, 80% for the abdomen, and 71% for the thigh. It is recommended that the Patch be applied to the upper or lower back, chest or upper arm. The patch is kept on for 24 hrs and should be applied to a new site every day. It is recommended that the patch not be applied to the same site for 14 days to minimize the risk of any skin irritation. Winblad et al. Int J Geri Psych. 2007 107

Safety & Tolerability of Higher Dose Donepezil (20mg)
Purpose To evaluate the safety and tolerability of donepezil at doses of 15 and 20mg/day Study Design A 24-week, randomized, double-blind, placebo controlled, pilot study 31 patients (male and female) aged years All patients had been treated with 10mg/day donepezil for months prior to enrollment Primary outcome measures: Tolerability (discontinuations, dose modifications, and adverse events) Safety (monitored by adverse events, physical examinations, clinical lab tests, and ECGs) Secondary outcome measures: Psychometric measures: ADAS-Cog, MMSE, CIBIC+, pharmacokinetic/pharmacodynamic parameters Study Design - diagnosed mild to moderate probable AD (MMSE 10-26) Doody, et al., Drugs Aging 2008

Safety & Tolerability of higher dose Donepezil (20mg)
Key Results Higher-dose group: 15 of 16 patients tolerated the maximum 20 mg/day dose by week 24 Standard-dose group: 14 of 15 patients tolerated donepezil 10 mg/day plus placebo 10 mg/day by the end of the study Adverse events possibly related to treatment were reported by 3 patients in the standard-dose group and 6 patients in the higher-dose group No difference between groups on psychometric measures Results No patients withdrew from the study and there were no serious adverse events or deaths 1 patient in the higher-dose group had a permanent dose reduction to donepezil 15 mg/day 1 patient in the standard-dose group had a permanent dose reduction to donepezil 10 mg/plus placebo 5 mg/day Temporary dose reductions occurred in two patients (one in each group) Adverse events were mild to moderate as expected Increased donepezil dose was associated with an increase in donepezil plasma concentrations Conclusions Doses of 15 and 20 mg/day of donepezil appeared to be safe and well tolerated May justify larger clinical trials for the safety and efficacy of donepezil at higher doses in patients with AD. Doody, et al., Drugs Aging 2008

Purpose Design Results
High Dose (23mg/d) vs Standard 10mg Dose Donepezil in Moderate to Severe Stage AD Purpose To determine effectiveness, safety and tolerability of 23 mg vs 10mg donepezil in mod-severe AD already on 10 mg donepezil Design 1467 patients (465 US) in 209 sites randomized to 23mg (n=972) vs 10mg (n= 479) MMSE: 76%: 0-16; 34%: 17-20 Approx 36% also on memantine (75% in US) Results Discontinuation higher for 23 mg vs 10mg: 30% (18% for AE’s vs 18% (8% for AE’s)

Effectiveness analysis:Cognition
Severe Impairment Battery MMSE Less decline from baseline on SIB P<0.001 Farlow et al. Clinical Therapeutics 2010.

Frequency Distribution of CIBIC
Scores at Week 24 No difference in ADL scores Adverse Events: vs 10 Nausea % vs 3.4 Vomiting % vs 2.5 Diarrhea % vs 5.3 Anorexia % SAE % vs 9.6 Farlow et al. Clinical Therapeutics2010.

Alzheimer's Disease Is There Any Evidence for Longer Term Use of Cholinesterase Inhibitors?

Rivastigmine-Placebo Group Does not Catch Up to Treated Group
6–12 mg/day rivastigmine 1–4 mg/day rivastigmine Placebo Proj. placebo Dose optimization with rivastigmine (6-12 mg/day) * 2 –2 –4 –6 –8 ADAS-Cog mean change from baseline Slide 38: Rivastigmine on Cognition: greater long-term benefits when therapy starts earlier These results represent the first evidence showing that rivastigmine is effective in the long-term treatment of mild to moderately-severe AD patients. Furthermore, they suggest rivastigmine treatment should be started as early as possible in order to gain the maximum benefit (Messina et al., 2000). Patients who participated in Study B352 were followed through week 52 in the open-label extension Study B353. This figure illustrates the mean change in ADAS-Cog scores over time, from baseline through the end of the double-blind study (week 26), and through a total of 52 weeks in the study. At week 26, all patients were restarted on rivastigmine and adjusted to their optimal dose (up to 6 mg b.i.d.). Due to the open-label design of Study B353, a placebo-control group was no longer available after week 26. Therefore, a model was created based on data from the first 26 weeks for the original placebo group, to estimate the expected change in cognition in the placebo group through 52 weeks. The change in this projected placebo group is depicted by the dashed line. The decline of 7 points in the projected placebo group is consistent with the cognitive decline observed after 1 year in untreated community-based patients with AD (Stern et al., 1994). In the extension study, the original 6–12 mg/day group remained above baseline on the ADAS-Cog through 38 weeks. The original 1–4 mg/day and placebo groups improved after restarted on rivastigmine, but did not reach the level of cognitive improvement observed in the original 6–12 mg/day group. Compared with the projected placebo group, all three randomization groups showed a statistically significant improvement in cognition at week 52 versus projected placebo. Although all patients were re-adjusted to their optimal rivastigmine dose (up to 6 mg b.i.d.) in the extension phase, patients originally randomized to placebo did not catch up to the original rivastigmine groups. Of interest, the decline seen in the original 6–12 mg/day group after 52 weeks was less than the decline seen in the placebo group after 26 weeks. The results suggest that although patients who start treatment later demonstrate cognitive improvement, they may not attain the level of cognitive benefit seen in patients who begin therapy earlier. All patients restarted on rivastigmine 26 Study week B352 patients in Study B353 (OC) at week 52 *p<0.05 vs projected placebo Messina et al., 2000

Mean change from baseline
Mean Change in ADAS-Cog Score from Baseline: Open Label Galantamine Over 4 Years –4 4 8 Mean change from baseline (±SE) in ADAS-Cog/11 12 12-month placebo Expected decline in untreated patients of 6–9 points/year 16 20 24 Galantamine 24–32/24 mg 28 Baseline 3 6 9 12 24 36 48 (n) (322) (309) (310) (233) (298) (228) (140) (103) Time (months) Database and from Raskind et al Arch Neurol 2004.

1-year Preservation of Function Study with Donepezil
Design 1-year, randomized, placebo-controlled, double-blind Subjects 431 patients with mild-to-moderate AD Aged 49-94, mean MMSE 17.1 Primary Outcome Time to clinically evident functional decline’, defined by: Decline in  1 basic ADL present at baseline Decline of  20% of the instrumental ADL present at baseline Increase  1 point from baseline in global CDR score (Clinical Dementia Rating scale) Mohs et al. Neurology. 2001

Time to Clinically Evident
Functional Decline* 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 6 12 18 24 30 36 42 48 54 Duration of treatment (weeks) Probability of survival Donepezil 10 mg/day Placebo Kaplan-Meier survival estimates The probability of survival (maintaining functional ability) at 48 weeks was: 51% for donepezil 35% for placebo Survival curve comparison: p=0.002 (log-rank test) p=0.005 (Wilcoxon test) *As judged by investigator, ITT population Mohs et al. Neurology. 2001

Longer-Term Effects: Non-Pharmaceutical
Sponsored Study Two-year, double blind, RCT in AD of donepezil versus placebo in a family practice setting in the UK sponsored by local health authority (AD2000) Small improvements shown but not considered clinically significant since no delay in NHP, loss of milestones or decrease in caregiver costs (AD 2000, Courtney et al., Lancet, 2004) Issues: a) Large dropout (40% 1-year, 77% 2-year) b) Not clear if samples used for analyses were matched after run in; also used washout c) 51% of total sample had CVD

Other Studies Suggesting Symptomatic Stabilization over Longer Periods
Potential for symptom stabilization – 50% of patients with no change or improvement on SIB after 1 year, and 35% after 2 years in head to head trial of rivastigmine and donepezil1 Compared with placebo or untreated populations,2–7 ChE-I therapy may delay cognitive and functional decline and the progression of neuropsychiatric symptoms by up to a year In this general Alzheimer’s disease population, symptomatic benefits were observed in cognition, activities of daily living and behaviour for up to 2 years in both treatment groups.1 No placebo group was used for ethical reasons, but historical data for all outcome measures suggest that untreated patients would have shown a more marked decline than that observed with cholinesterase inhibitor-treated patients in this study. When compared with data on placebo or untreated AD populations,2,3 the decline on SIB in the study population (9 points over 2 years) suggests that cholinesterase inhibitor treatment might have delayed decline on this measure by about a year. In addition, the current study indicates that cholinesterase inhibition has the potential for stabilization of symptoms, as performance on the SIB was stable (no change or improvement) in approximately 50% of patients after 1 year and 35% of patients after 2 years. Similarly, compared with historical data on MMSE decline,4–6 ADCS-ADL decline,7 and NPI decline,7 the results of this study suggest that cholinesterase inhibitor therapy may delay the advance of cognitive and functional decline and the progression or emergence of neuropsychiatric symptoms by up to a year. 1Bullock R et al. CMRO 2005;21:1317–27; 2Schmitt FA et al. Alzheimer Dis Assoc Disord 1997;11(Suppl 2):S51–6; 3Feldman H et al. Neurology 2001;57:613–20; 4Winblad B et al. Neurology 2001;57:489–95; 5Klatte ET et al. Alzheimer Dis Assoc Disord 2003;17:113–6; 6Small G et al. Int J Clin Pract 2005;59:473–7; 7Aisen PS et al. JAMA 2003;289:2819–26. 1Bullock R et al. CMRO 2005 2Schmitt et al. Alzheimer Dis Assoc Disord 1997 3 Feldman et al. Neurology 2001 4Winblad et al. Neurology 2001; 5Klatte et al. Alzheimer Dis Assoc Disord 2003 6Small et al Int J Clin Pract 2005 7Aisen et al. JAMA 2003

Patients on ChEI’s Had Less Decline in
Multiple Cognitive Domains over 1 Year N= 65 in each of treated vs untreated group, well-matched on age, edcuation, severity, comorbidities, vasc risk factors and medications Less decline in: Overall cognition Naming Visuospatial and visuoconstructive skills Executive functions Dementia Rating Scale p<0.0001 Effect size d = 0.7 Behl et al Dem Ger Cog Dis 2006

Treated patients showed less decline on:
Patients on ChEI’s Continued to Show Less Decline on Select Cognitive Domains at Two Years Verbal Memory Treated patients showed less decline on: Overall cognition Memory Naming Executive functions p=0.007 ES: d1 =0.8; d2 = 0.4 Behl et al Dem Ger Cog Dis 2006

Instrumental Basic Overall DAD
Patients on ChEI’s also showed less decline in functional abilities over 2 years, especially in initiation (DAD) Instrumental Basic Overall DAD Pyear1=0.04; Pyear2=0.001 ES 1 =0.6; ES 2= 0.9 Pyear1=0.08 ; Pyear2=0.001 ES 1= 0.4; ES 2 = 0.7 Pyear1=0.036; Pyear2=0.001 ES 1= 0.5; ES 2= 0.8 Behl et al, Int Psychoger 2008

Also Planning and Organization
Basic Overall DAD Pyear1=0.039; Pyear2=0.001 ES 1 = 0.7; ES = 1.0 Pyear1= 0.038; Pyear2=0.006 ES 1=0.8; ES 2 =1.0 Behl et al, Int Psychoger 2008

Does Persistent Use of Antidementia Drugs Slow Clinical Progression of AD over 20 Years?
Study Design 641 probable AD patients were followed for 20 years in a single centre Cumulative drug exposure was expressed as a persistency index (PI) reflecting total years of drug use divided by total years of disease symptoms Measures: annual change in slope of neuropsychological and functional tests as predicted by follow up time, PI, and the interaction between these variables Key Results PI was associated with significantly slower rates of decline on MMSE, Physical Self-Maintenance Scale (PSMS), IADL, CDR-SB Results suggest that PI (cumulative drug exposure) slowed ADAS-Cog decline for 3.3 years, with effect then lost Background Observational studies suggest that antidementia drugs may benefit cognition in AD patients for a year and/or slow time to dementia related nursing home placement. No studies have evaluated the optimal duration of treatment, or whether greater persistency of antidementia drug therapy affects patient outcomes. The authors hypothesize that greater cumulative exposure to the Cholinesterase Inhibitors (ChEIs) or memantine or both would be associated with slower rates of decline on cognitive and functional measures in AD patients over the long term. Study Design The authors did not quantify dosage or distinguish between outcomes on monotherapy with ChEI or combination therapy with a ChEI and glutamate modulator. Results 43% of patients had been exposed to drug before the initial visit and 43% began treatment within 2 years following the new patient visit 12% never used medication over the entire period of follow up Including all visits, there were equal proportions of patients on a ChEI alone (n=1623) or combination therapy of a ChEI and memantine (n=1627), but only few taking memantine alone (n=169) Greater antidementia drug use was associated with slower rate of decline on the ADAS-Cog for the first 3.3 years, followed by a diminished positive effect. The treatment effect was clinically significant in magnitude Conclusions Persistent drug treatment had a positive impact on AD progression in terms of cognitive, functional, and global outcome measures Positive treatment effects extended to those at more advanced stages of disease Rountree, et al., Alzheimer’s Res. & Ther. 2009

Conclusions Cholinesterase inhibitors have modest symptomatic benefits in cognition, function, and behavior in mild-moderate AD and remain the only proven therapy for these disease stages after 20 years. They may be associated with increase risk of syncope and falls Their benefits are also seen in more advanced stages, but are not evident in MCI though some MCI subgroups may be more responsive Duration of benefits may go beyond the 6 months used in the pivotal trials but Level 1 evidence for this is scarce and ethically difficult to obtain Cognitive benefits are likely selective to the processes most affected by acetylcholine (attention/executive, initiation and social engagement)

Alzheimer's Disease Translating Advances in Biomarker-based Detection into Clinical Practice Implications for Current Therapies and Beyond SERGE GAUTHIER, MD Director of the Alzheimer’s Disease Research Unit McGill Centre for Studies in Aging Professor of Neurology and Neurosurgery, Psychiatry and Medicine McGill University Montreal, Quebec Canada

Outline Case histories of persons at risk Case history of person with MCI Case histories of persons with AD Conclusions

Young Person with Strong Family History of AD
Age: 40 Cognitive symptoms: none Family history of AD: mother d55, sister d53 Biomarkers: genetic (PS, APP); neuro-imaging (FDG-PET) Current Rx: enroll in DIAN Future Rx: anti-amyloid

FDG-PET IN AD

Middle-age Person with Concern About Family History of AD
Cognitive symptoms: none Family history of AD: mother d85 Biomarkers: genetic (apoE); neuro-imaging (MRI) Current Rx: assess risk using mid-life risk score Future Rx: enhance protective factors

CAIDE Dementia Risk Score
Age < 47 years 47-53 years >53 years 0 3 4 Formal education ≥10 years 7-9 years 0-6 years 0 2 3 Sex Women Men 0 1 Systolic BP  140 mm Hg > 140 mm Hg 0 2 BMI  30 kg/m2 > 30 kg/m2 Total cholesterol  6.5 mmol/l > 6.5 mmol/l Physical activity Active Inactive 1 The Dementia Risk Score was composed as the sum of the individual score; can vary between 0-15. Kivipelto et al., Lancet Neurol 2006 131

The overall occurrence of dementia 4.4%
Probability of Dementia in Late-life According to the Risk Score Category in Middle Age The overall occurrence of dementia 4.4% SCORE All /Demented, n % Risk (95% CI) 0-5 401 / 4 1.0 ( ) 6-7 270 / 5 1.9 ( ) 8-9 312 / 13 4.2 ( ) 10-11 245 / 18 7.4 ( ) 12-15 122 / 20 16.4 ( ) The probability of dementia increased as the risk score became greater. The increase was especially clear in the highest categories. Kivipelto et al., Lancet Neurology 2006 132

Older Person with Concern About
Family History of AD Age: 76 Cognitive symptoms: none Family history of AD: mother d93 Biomarkers: genetic (apoE); neuro-imaging (MRI) Current Rx: assess risk using late-life dementia risk index Future Rx: enhance protective factors, reduce risk factors

The Late-Life Dementia Risk Index
Barnes DE, et al. Neurology 2009;73; ;

Older Person with MCI Age: 70 Cognitive symptoms: mild
Family history of AD: mother d87 Biomarkers: genetic (apoE); CSF (ß42, total tau, phospho tau); neuro-imaging (MRI, FDG-PET) Current Rx: follow over time Future Rx: anti-amyloid

Dubois et al., Lancet Neurology 2007

Alzheimer's Disease Dubois et al., Lancet Neurology 2007

Slope Analyses According to AD CSF Profile at Baseline
Visser PJ, et al. Lancet Neurol 2009; 8: 619–27

Older Person with Mild AD
Age: 75 Cognitive symptoms: mild dementia Family history of AD: none Biomarkers: neuro-imaging (MRI) Current Rx: ChEI Future Rx: anti-amyloid

Older Person with AD and
High Tau Levels in CSF Age: 75 Cognitive symptoms: early dementia Family history of AD: none Biomarkers: Neuro-imagimg (MRI); CSF low ß42, very high phospho tau Current Rx: ChEI Future Rx: anti-amyloid and anti-tau

Distribution of CSF total tau, phosphorylated tau (P-tau), and ß-amyloid 1-42 (Aß42) levels
Wallin AK, et al. Neurology 2010;74;

Five-Year Survival in the Three Clusters
Wallin AK, et al. Neurology 2010;74;

Pathology by Clinical Status
Proximate to Death Schneider JA, et al. Ann Neurol 2009;66:200–208

Biomarkers for the Diagnosis and Management of AD
Assessment of risk is possible using mid-life and late-life risk profiles, including apoE genotyping Earlier diagnosis of AD is now possible using neuro-imaging and CSF analysis Better selection of disease-modifying treatments may be possible using CSF analysis and neuro-imaging, knowing the relative weight of each pathological component

Optimizing Neurotherapy and Emerging Paradigm for Alzheimer’s Disease

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Optimizing Neurotherapy and Emerging Paradigm for Alzheimer’s Disease

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Presentation on theme: "Optimizing Neurotherapy and Emerging Paradigm for Alzheimer’s Disease"— Presentation transcript:

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