optimizing neurotherapy and emerging paradigm for alzheimers disease the current foundation role of...

Optimizing Neurotherapy and Emerging Optimizing Neurotherapy and Emerging ParadigmParadigm

forfor Alzheimer’s Disease Alzheimer’s Disease

The Current Foundation Role of Cholinergic The Current Foundation Role of Cholinergic Stimulation of Alzheimer’s Disease—Focus on Stimulation of Alzheimer’s Disease—Focus on Evidence-Based Management of Moderate and Evidence-Based Management of Moderate and

Severe AD Severe AD

Program ChairmanProgram ChairmanMURRAY A. RASKIND, MDMURRAY A. RASKIND, MD

Professor and Vice-Chairman Professor and Vice-Chairman Department of Psychiatry and Behavioral Sciences Department of Psychiatry and Behavioral Sciences

University of Washington School of Medicine University of Washington School of Medicine Director of the University of Washington Alzheimer’s Disease Research Center Director of the University of Washington Alzheimer’s Disease Research Center

Director of the VA Northwest Network Mental Illness Director of the VA Northwest Network Mental Illness Research, Education and Clinical Center (MIRECC) Research, Education and Clinical Center (MIRECC)

Investigations • Innovation • Clinical ApplicationInvestigations • Innovation • Clinical Application

Program FacultyProgram Faculty

Program ChairmanProgram ChairmanMURRAY A. RASKIND, MDMURRAY A. RASKIND, MDProfessor and Vice-Chairman Professor and Vice-Chairman Department of Psychiatry and Behavioral Department of Psychiatry and Behavioral Sciences Sciences University of Washington School of University of Washington School of Medicine Medicine Director of the University of Washington Director of the University of Washington Alzheimer’s Disease Research Center Alzheimer’s Disease Research Center Director of the VA Northwest Network Director of the VA Northwest Network Mental Illness Mental Illness Research, Education and Clinical CenterResearch, Education and Clinical CenterSeattle, WASeattle, WA SANDRA E. BLACK, MD, FRCPCSANDRA E. BLACK, MD, FRCPCBrill Chair in Neurology Brill Chair in Neurology University of Toronto, Sunnybrook University of Toronto, Sunnybrook Health Sciences Centre Health Sciences Centre Toronto, Ontario CanadaToronto, Ontario Canada

JAMES E. GALVIN, MD, MPHJAMES E. GALVIN, MD, MPHProfessor of Neurology and Psychiatry Professor of Neurology and Psychiatry Director of Clinical Operations Director of Clinical Operations Center of Excellence on Brain Aging Center of Excellence on Brain Aging Director Pearl Barlow Center for Director Pearl Barlow Center for Memory Evaluation and Treatment Memory Evaluation and Treatment New York University Langone School of New York University Langone School of Medicine Medicine New York, NYNew York, NY SERGE GAUTHIER, MDSERGE GAUTHIER, MDDirector of the Alzheimer’s Disease Director of the Alzheimer’s Disease Research Unit Research Unit McGill Centre for Studies in Aging McGill Centre for Studies in Aging Professor of Neurology and Neurosurgery, Professor of Neurology and Neurosurgery, Psychiatry and Medicine Psychiatry and Medicine McGill University McGill University Montreal, Quebec CanadaMontreal, Quebec Canada

Advances in Alzheimer’s Disease Advances in Alzheimer’s Disease Diagnostics and Therapeutics:Diagnostics and Therapeutics:

A Clinician’s PerspectiveA Clinician’s Perspective

Program ChairmanProgram ChairmanMURRAY A. RASKIND, MDMURRAY A. RASKIND, MD

Professor and Vice-Chairman Professor and Vice-Chairman Department of Psychiatry and Behavioral Sciences Department of Psychiatry and Behavioral Sciences

University of Washington School of Medicine University of Washington School of Medicine Director of the University of Washington Alzheimer’s Disease Research Center Director of the University of Washington Alzheimer’s Disease Research Center

Director of the VA Northwest Network Mental Illness Director of the VA Northwest Network Mental Illness Research, Education and Clinical Center (MIRECC) Research, Education and Clinical Center (MIRECC)

Optimizing Neurotherapy Optimizing Neurotherapy andand Emerging Paradigms Emerging Paradigms forfor

Alzheimer's DiseaseAlzheimer's Disease

QuestionsQuestions

► How can biomarkers help us diagnose How can biomarkers help us diagnose AD and estimate treatment response?AD and estimate treatment response?

► Do “disease modifying” anti-beta-Do “disease modifying” anti-beta-amyloid (Aamyloid (Aββ) therapeutics modify AD ) therapeutics modify AD progression?progression?

► Are cholinesterases “simply” Are cholinesterases “simply” symptomatic drugs?symptomatic drugs?

► Can we find rational pharmacotherapies Can we find rational pharmacotherapies for AD agitation/aggression?for AD agitation/aggression?

Keeping Expectations ModestKeeping Expectations Modest

► If your primary goal is cure, If your primary goal is cure, switch to ophthalmology or switch to ophthalmology or orthopedics.orthopedics.

► Maintain quality of life and Maintain quality of life and function and relieving distress function and relieving distress are important accomplishments.are important accomplishments.

► Slowing disease progression is a Slowing disease progression is a primary goal.primary goal.

Why Biomarkers?Why Biomarkers?

► Earlier diagnosis.Earlier diagnosis.

► More precise monitor of the More precise monitor of the effect of anti-amyloid effect of anti-amyloid therapeutics.therapeutics.

► However, cognitive testing may However, cognitive testing may still be most sensitive measure of still be most sensitive measure of disease progression.disease progression.

AD BiomarkersAD Biomarkers

► PET imaging of brain beta-amyloid PET imaging of brain beta-amyloid protein in aggregated form.protein in aggregated form.

► Cerebrospinal fluid ACerebrospinal fluid Aββ and tau and tau concentrations.concentrations.

““Promise Seen for DetectionPromise Seen for Detectionof Alzheimer’s”of Alzheimer’s”

Headline – Headline – New York Times New York Times June 23, 2010June 23, 2010

This front page article discusses the This front page article discusses the development and potential of PET Adevelopment and potential of PET Aββ

imagingimaging

Beta Amyloid PET Imaging LigandsBeta Amyloid PET Imaging Ligands

[[1111C] Pittsburgh Compound B (PIB)C] Pittsburgh Compound B (PIB)

Currently available, but short Currently available, but short half-life (20 minutes), requires half-life (20 minutes), requires close proximity to cyclotron.close proximity to cyclotron.

[[1818F] –AV-45F] –AV-45

Approaching availability. Longer Approaching availability. Longer half-life (10 minutes), half-life (10 minutes), enhances availability.enhances availability.

Alzheimer’s Disease Alzheimer’s Disease Neuroimaging Initiative (ADNI)Neuroimaging Initiative (ADNI)

► PIB distinguishes AD from MCI from PIB distinguishes AD from MCI from normals.normals.

► PIB highly correlated with CSF APIB highly correlated with CSF Aββ4242..

► But PIB and CSF ABut PIB and CSF Aββ4242 not not significantly significantly correlated with MMSE cognitive correlated with MMSE cognitive measure.measure.

► In 17 normal, 50 MCI, and 13 AD one-In 17 normal, 50 MCI, and 13 AD one-year follow-up subjects: small, year follow-up subjects: small, nonsignificant changes in Anonsignificant changes in Aββ load. load.

► However, some individuals had However, some individuals had apparently meaningful Aapparently meaningful Aββ load load increases.increases.

Jagust WJ et al, Alzheimer’s and Dementia 6:221-229, 2010.Jagust WJ et al, Alzheimer’s and Dementia 6:221-229, 2010.

A Treatment Relevance QuestionA Treatment Relevance Question

► Does a drug that reduces [C-11] Does a drug that reduces [C-11] PIB-measured APIB-measured Aββ load slow load slow cognitive decline?cognitive decline?

► If so, do beneficial cognitive If so, do beneficial cognitive effects reflect Aeffects reflect Aββ load load reductions?reductions?

The “Anti-Amyloid Antibody” Approach toThe “Anti-Amyloid Antibody” Approach tothe Treatment of Alzheimer’s Diseasethe Treatment of Alzheimer’s Disease

► Transgenic AD mice show marked Transgenic AD mice show marked reduction in amyloid plaque reduction in amyloid plaque deposition when actively deposition when actively immunized against beta amyloid.immunized against beta amyloid.

► Active beta amyloid Active beta amyloid immunization in humans immunization in humans produced apparent reduction of produced apparent reduction of amyloid plaque density; but no amyloid plaque density; but no clear cognitive benefits. 6% clear cognitive benefits. 6% incidence of meningo-incidence of meningo-encephalitis.encephalitis.

Would Passive Monoclonal Anti-Amyloid Antibody Would Passive Monoclonal Anti-Amyloid Antibody Approaches be More Effective and Less Toxic?Approaches be More Effective and Less Toxic?

BapineuzumabBapineuzumab: : N terminus-directed beta amyloid N terminus-directed beta amyloid monoclonal antibody in clinical trials.monoclonal antibody in clinical trials.Primary efficacy outcomes in Phase 2 trial not significant.Primary efficacy outcomes in Phase 2 trial not significant.

Significant effect on ADAS-Cog in completers.Significant effect on ADAS-Cog in completers.

Signal for efficacy in E4 negative subjects.Signal for efficacy in E4 negative subjects.

Solanezumab: Solanezumab: Mid domain-directed beta amyloid Mid domain-directed beta amyloid monoclonal antibody in clinical trials.monoclonal antibody in clinical trials.No human trial results available.No human trial results available.

Antibody design targets soluble beta amyloid.Antibody design targets soluble beta amyloid.

Estimated Mean Change from Baseline on Estimated Mean Change from Baseline on ADAS-COG ADAS-COG

22

00

-2-2

-4-4

-6-6

-8-8

-10-10

-12-12

22

00

-2-2

-4-4

-6-6

-8-8

-10-10

-12-120 11 24 37 50 63 780 11 24 37 50 63 78 0 11 24 37 50 63 780 11 24 37 50 63 78

Salloway S, et al. Neurology 2009; 73:2061-2070Salloway S, et al. Neurology 2009; 73:2061-2070

ADAS-COG mITTADAS-COG mITT ADAS-COG CompletersADAS-COG Completers

Rx difference at week 78 = 2.3Rx difference at week 78 = 2.3P=0.078P=0.078 Rx difference at week 78 = 4.3Rx difference at week 78 = 4.3

P=0.003P=0.003

PlaceboPlaceboBapineuzumabBapineuzumab

Bapineuzumab Decreases Bapineuzumab Decreases 1111C-PIB AC-PIB Aββ Load Load

► 28 AD patients assigned to 28 AD patients assigned to bapineuzumab (n=20) or placebo (n=8).bapineuzumab (n=20) or placebo (n=8).

► Treatment with bapineuzumab for 78 Treatment with bapineuzumab for 78 weeks reduced cortical weeks reduced cortical 1111C-PIB amyloid C-PIB amyloid load compared to baseline and placebo.load compared to baseline and placebo.

► But, in this small subsample, effects on But, in this small subsample, effects on clinical endpoints were disappointing clinical endpoints were disappointing and did not appear related to effects on and did not appear related to effects on AAββ binding. binding.

Estimated Change from Baseline in Estimated Change from Baseline in Mean C-PiB PETMean C-PiB PET

Rinne JO , et al. Rinne JO , et al. Lancet NeurolLancet Neurol 2010;9:363-72. 2010;9:363-72.

WeekWeek

Est

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ean

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BaselineBaseline 20 45 20 45 78 78

0.40.4

0.30.3

0.20.2

0.10.1

00

-0.1-0.1

-0.2-0.2

PlaceboPlaceboBapineuzumabBapineuzumab

Potential Utility of CSF Biomarkers Potential Utility of CSF Biomarkers

► Improving diagnostic accuracy.Improving diagnostic accuracy.► Predictive value.Predictive value.► Monitoring treatment:Monitoring treatment:

● Alzheimer’s disease (AD)Alzheimer’s disease (AD)● Mild cognitive impairment Mild cognitive impairment

(MCI)(MCI)● Primary preventionPrimary prevention

AA, Total Tau, and Phosphorylated Tau - , Total Tau, and Phosphorylated Tau - in Alzheimer’s Diseasein Alzheimer’s Disease

tauAxonal damagephospho-tau

Neurofibrillary tangles

Amyloid A42 A deposition/metabolism/clearance?

oxidation? isoprostanes

inflammation??

Neurochemical Changes inNeurochemical Changes in Alzheimer’s DiseaseAlzheimer’s Disease

AA4242 is the Initiator and Main Culprit in Amyloid is the Initiator and Main Culprit in Amyloid Deposition, and Implicated in AD PathogenesisDeposition, and Implicated in AD Pathogenesis

► AA4242 is the initial is the initial amyloid species amyloid species deposited in brain.deposited in brain.

► AA4242 exceeds A exceeds A4040 in in amyloid deposits.amyloid deposits.

► Toxicity and amyloid Toxicity and amyloid fibril formation: Afibril formation: A4242>A>A

4040..► in trisomy 21 and in trisomy 21 and

almost all APP almost all APP mutations. mutations.

► Selectively Selectively in in presenilin mutations.presenilin mutations.

What Does Decreased CSF AWhat Does Decreased CSF A4242 Mean?Mean?

► In Tg 2576 (APP-Swedish mutation) mice, In Tg 2576 (APP-Swedish mutation) mice, decreases in CSF Adecreases in CSF A4242 parallel increases in parallel increases in brain Abrain A4242

11..

► In humans, inverse relation between In humans, inverse relation between in in vivovivo brain amyloid load (PIB binding) and brain amyloid load (PIB binding) and CSF ACSF A4242, even in cognitively normal , even in cognitively normal subjectssubjects22..

1Kawarabayashi et al., J Neurosci 21:372-381, 2001.2Fagan et al., Ann Neurol 59:512-519, 2006.

Inverse Relation Between Inverse Relation Between in vivoin vivo Amyloid Amyloid Imaging Load and CSF AImaging Load and CSF A42 42 in Humansin Humans

Fagan AM, et al., Ann Neurol 59:512-519, 2006.

Mean Cortical PIB BindingMean Cortical PIB Binding(Binding Potential)(Binding Potential)

CS

F A

ßC

SF

Aß

4242 (

pg/m

L) (

pg/m

L)

0.00.0 0.50.5 1.01.0

10001000

750750

500500

250250

00

CSF Total Tau in the Diagnosis of ADCSF Total Tau in the Diagnosis of AD

► CSF total tau is measured by a sensitive CSF total tau is measured by a sensitive ELISA.ELISA.

► Meta-analysis of AD versus controls:Meta-analysis of AD versus controls:11

● 35 studies, 2315 AD; 1126 controls35 studies, 2315 AD; 1126 controls► In all studies, CSF T-tau in AD > normal In all studies, CSF T-tau in AD > normal

controlscontrols● 2-3 fold increase in AD2-3 fold increase in AD● Effect size = 1.31 (95% CI 1.23-1.39) Effect size = 1.31 (95% CI 1.23-1.39) ● No correlation with age, dementia duration No correlation with age, dementia duration

or severityor severity● Increases slightly with aging in normalsIncreases slightly with aging in normals

1Sunderland T, et al., JAMA 289:2094-2103, 2003.

Summary of CSF BiomarkersSummary of CSF Biomarkers

► CSF ACSF A4242 is decreased and CSF tau is decreased and CSF tau increased in 75-85% of patients with increased in 75-85% of patients with AD.AD.

► Changes in CSF AChanges in CSF A4242 and tau are and tau are present, but are less marked, in MCI present, but are less marked, in MCI than AD.than AD.

Use of CSF Biomarkers for Use of CSF Biomarkers for PreclinicalPreclinical Diagnosis: Diagnosis: Where Do We StandWhere Do We Stand



CSF Tau: ACSF Tau: A4242 Ratio for Ratio for Increased Risk of Mild Increased Risk of Mild Cognitive Impairment: Cognitive Impairment:

A Follow-up StudyA Follow-up Study

Li G, et al., Neurology 69:631-639, 2007.



MethodsMethods

► Subjects:Subjects:● 129 controls aged 21-100129 controls aged 21-100● 12 MCI12 MCI● 21 probable AD21 probable AD● 12 other neurodegenerative 12 other neurodegenerative

diseasedisease

► CSF collected between 0900-1100 CSF collected between 0900-1100 hours after overnight fast.hours after overnight fast.

Li G, et al., Li G, et al., NeurologyNeurology 69:631-639, 2007. 69:631-639, 2007.

Subject Characteristics and CSF Subject Characteristics and CSF Biomarker Concentrations Biomarker Concentrations

ControlsControls < 65 yr< 65 yr

Controls Controls ≥ ≥ 65 yr65 yr MCIMCI ADAD OtherOther

n 81 48 12 21 12

M:F 41:40 22:26 8:4 10:11 7:5

Age40 ± 15*(21 – 64)

73 ± 7(65 – 100)

71 ± 13(49 – 82)

69±9(52 – 87)

63 ± 11

% APOE*4+ 18 14 50 72 ---

RBC/l7 ± 22

(0 – 176)10 ± 28

(0 – 163)10 ± 21(0 – 58)

14 ± 39(0 – 180)

8 ± 18(0 – 83)

CSF A42

(pg/ml)313 ± 14 386 ± 34 245 ± 41 225 ± 27* 332 ± 35

CSF tau(pg/ml)

487 ± 24* 784 ± 49 1117 ± 115 1535 ± 131 769 ± 111

CSF P-tau181 (pg/ml)

97 ± 16* 248 ± 33 676 ± 125 936 ± 120 ---


High High CSF T/ACSF T/A4242 Ratio and Ratio and Conversion to MCI in 42 month F/UConversion to MCI in 42 month F/U

► Conversion to MCI over 42-months of Conversion to MCI over 42-months of follow-up in:follow-up in:● 4/17 persons with high CSF T/A4/17 persons with high CSF T/A4242 ratio ratio● 0/26 persons with normal CSF T/A0/26 persons with normal CSF T/A4242

ratio ratio ● Logrank test for survival curve, p<0.05Logrank test for survival curve, p<0.05


Implications of High CSF Implications of High CSF T/AT/A42 42 Ratio Ratio

► The high CSF T/AThe high CSF T/A4242 subgroup of controls subgroup of controls had significantly increased risk of had significantly increased risk of conversion to MCI during 42 months of conversion to MCI during 42 months of follow-up.follow-up.

► Suggests that high CSF T/ASuggests that high CSF T/A4242 individuals had “latent” AD at time of individuals had “latent” AD at time of CSF collection.CSF collection.


Peskind ER, et al., Arch Neurol 63:936-939, 2006.

Cross-sectional Cross-sectional Lifespan Study Lifespan Study

Suggests CSF ASuggests CSF A4242 Concentration is Concentration is

Altered in APOE*4 Altered in APOE*4 Carriers.Carriers.



CSF ACSF A42 42 andand AA4040 in 184 Normal in 184 Normal Controls Aged 21-88Controls Aged 21-88

Peskind ER, et al., Peskind ER, et al., Arch NeurolArch Neurol 63:936-939, 2006. 63:936-939, 2006.

A Sobering FindingA Sobering Finding

► CSF ACSF A42 42 findings consistent with findings consistent with acceleration by theacceleration by the APOE*4 allele of APOE*4 allele of pathogenicpathogenic AA42 42 deposition starting in deposition starting in later middle life in persons with normal later middle life in persons with normal cognition.cognition.

Peskind ER, et al., Peskind ER, et al., Arch NeurolArch Neurol 63:936-939, 2006. 63:936-939, 2006.

Cholinesterase Inhibitor Clinical Experience and Cholinesterase Inhibitor Clinical Experience and Clinical Trials Support Reduction of AD ProgressionClinical Trials Support Reduction of AD Progression

► Persistent treatment slows clinical Persistent treatment slows clinical progression.progression.

► Delayed start design: persons first on Delayed start design: persons first on placebo than switched to a cholinesterase placebo than switched to a cholinesterase inhibitor do not “catch up.” inhibitor do not “catch up.”

► Increasingly divergent clinical status in Increasingly divergent clinical status in long-term trials favoring cholinesterase long-term trials favoring cholinesterase inhibitors.inhibitors.

► Sounds like disease modification to me.Sounds like disease modification to me.

Persistent Treatment with Cholinesterase Persistent Treatment with Cholinesterase Inhibitors and/or Memantine Slows Progression of Inhibitors and/or Memantine Slows Progression of

ADAD

► 641 AD patients followed at Baylor 641 AD patients followed at Baylor College of Medicine for over 20 years.College of Medicine for over 20 years.

► Persistent treatment with donepezil, Persistent treatment with donepezil, other cholinesterase inhibitors, and other cholinesterase inhibitors, and memantine slowed AD progression memantine slowed AD progression assessed by multiple cognitive, assessed by multiple cognitive, functional and global measures.functional and global measures.

Rountree SD, et al. Alzheimers Res Ther 1(2):7, 2009Rountree SD, et al. Alzheimers Res Ther 1(2):7, 2009

**##

Data from historical placebo group

Raskind M et al., Neurology 54:2261–8, 2000

*p < 0.05 vs placebo/ Galantamine 24 mg/day

# not significantly different from baseline

Galantamine 24 mg/day

Placebo/ Galantamine 24 mg/day

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11

22

33

44

55

66

779933BaselineBaseline 121266

Double-blind Open-extension

Galantamine Shows Sustained Galantamine Shows Sustained Cognitive Benefits in AD Over 12 monthsCognitive Benefits in AD Over 12 months

(including a delayed start time)

Long-term Data: Change from Long-term Data: Change from Baseline in ADAS-Cog/11 scoresBaseline in ADAS-Cog/11 scores

Mea

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Raskind MA et al. Arch Neurology 61:252-246, 2004.Raskind MA et al. Arch Neurology 61:252-246, 2004.

-4

0

4

8

12

16

BaselineBaseline

Months of TreatmentMonths of Treatment3 6 9 12 18 24 30 36

20

24

Placebo comparison

Galantamine 24–32 / 24 mg

Estimation of decline – Stern Equation

Clinical Improvement

Clinical Decline

Donepezil Significantly Better Compared to Donepezil Significantly Better Compared to Calculated Change by Stern Equation over 3 Calculated Change by Stern Equation over 3

YearsYears

Wallin AK, et al. Dement Geriatr Disord 2007:23:150-160Wallin AK, et al. Dement Geriatr Disord 2007:23:150-160

36-Month Galantamine Trial36-Month Galantamine Trial

► Does a greater rate of cognitive Does a greater rate of cognitive decline in “dropouts” than 36 decline in “dropouts” than 36 month “completers” explain month “completers” explain results?results?

► No! No! Rate of decline prior to Rate of decline prior to galantamine discontinuation in galantamine discontinuation in “dropouts” was the same as in “dropouts” was the same as in “completers.”“completers.”

We Compared Slopes of ADAS-cog Decline We Compared Slopes of ADAS-cog Decline Between Dropouts and CompletersBetween Dropouts and Completers

Time (months)Time (months)

-1

Galantamine patients who completed treatmentGalantamine patients who discontinued

Cha

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Cha

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AS

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/11

0

1

2

3

4

5

6

7

8

9

10

110 10 20 30 40

Raskind MA, et al.,Raskind MA, et al., Arch Neurol Arch Neurol 61:252-256, 2004. 61:252-256, 2004.

If ChEIs Delay Disease Progression, If ChEIs Delay Disease Progression, What are the Candidate What are the Candidate

Mechanisms?Mechanisms?► Nicotinic cholinergic stimulation Nicotinic cholinergic stimulation in in

vitrovitro::● Protects against AProtects against A-induced -induced

neuronal deathneuronal death11

► Muscarinic cholinergic stimulation Muscarinic cholinergic stimulation in in vitrovitro::● Inhibits AInhibits A production from amyloid production from amyloid

precursor protein (APP)precursor protein (APP)22

● Reduces phosphorylation of tauReduces phosphorylation of tau22

1Arias E et al., Neuropharmacology 46:103-114, 2004.

2Fisher A et al., J Mol Neurosci 20:349-356, 2003.

Mechanisms of Neuroprotective Effects of Mechanisms of Neuroprotective Effects of Nicotine and Acetylcholinesterase Nicotine and Acetylcholinesterase

Inhibitors Inhibitors

► An excellent reviewAn excellent review► Highlights:Highlights:

● Stimulation of nicotinic receptors Stimulation of nicotinic receptors (particularly alpha-7) by nicotine or (particularly alpha-7) by nicotine or galantamine or donepezil prevents galantamine or donepezil prevents glutamate neurotoxicity.glutamate neurotoxicity.

● These effects of cholinesterase These effects of cholinesterase inhibitors appear independent of their inhibitors appear independent of their inhibition of cholinesterase activity.inhibition of cholinesterase activity.

Akaike A, et al. J Mol Neurosci 40:211-216, 2010Akaike A, et al. J Mol Neurosci 40:211-216, 2010

Role of Alpha-4 and Alpha-7 Receptors in NeuroprotectionRole of Alpha-4 and Alpha-7 Receptors in Neuroprotection

Loss of Alpha-7 Nicotinic Receptors Enhances Loss of Alpha-7 Nicotinic Receptors Enhances Beta-amyloid Oligomer Accumulation in a Beta-amyloid Oligomer Accumulation in a

Mouse Model of Alzheimer’s DiseaseMouse Model of Alzheimer’s Disease

► ““Alzheimer’s” transgenic mice with Alzheimer’s” transgenic mice with deletion of the alpha-7 nicotinic receptor deletion of the alpha-7 nicotinic receptor have increased:have increased:● Learning and memory deficitsLearning and memory deficits● Hippocampal and cholinergic Hippocampal and cholinergic

neurodegenerationneurodegeneration● Soluble oligomer (neurotoxic) beta-Soluble oligomer (neurotoxic) beta-

amyloidamyloid

Hernandez CM, et al. J Neuroscience 30:2442-2453, 2010. Hernandez CM, et al. J Neuroscience 30:2442-2453, 2010.

Disruptive Agitation: What is it?Disruptive Agitation: What is it?

Distressing behaviors that often cluster Distressing behaviors that often cluster togethertogether• IrritabilityIrritability• Anger outbursts, aggressionAnger outbursts, aggression• Sleep disruptionSleep disruption• Pressured pacing and restlessnessPressured pacing and restlessness• Uncooperativeness with necessary careUncooperativeness with necessary care

Major cause of long-term care placement.Major cause of long-term care placement.

Commonly Used Psychotropic Medications Commonly Used Psychotropic Medications for Disruptive Agitation in ADfor Disruptive Agitation in AD

► Antipsychotics: haloperidol, risperidone, Antipsychotics: haloperidol, risperidone, olanzapine, aripiprazole, quetiapine. All olanzapine, aripiprazole, quetiapine. All show modest efficacy in some placebo-show modest efficacy in some placebo-controlled trials.controlled trials.

● Frequent non-respondersFrequent non-responders● Adverse effects: pseudoparkinsonism, sedationAdverse effects: pseudoparkinsonism, sedation● Increased risk of stroke and death caused FDA to issue Increased risk of stroke and death caused FDA to issue

“Black Box Warning.”“Black Box Warning.”

All antipsychotics are antagonists of the All antipsychotics are antagonists of the Alpha-1 Adrenoreceptor: Does this Alpha-1 Adrenoreceptor: Does this contribute to efficacy for agitation?contribute to efficacy for agitation?

The Brain Noradrenergic SystemThe Brain Noradrenergic System

► The noradrenergic system is the The noradrenergic system is the brain “adrenaline” system for brain “adrenaline” system for attention and arousal.attention and arousal.

► Excessive noradrenergic reactivity Excessive noradrenergic reactivity produces anxiety and agitation.produces anxiety and agitation.

► Does excessive noradrenergic Does excessive noradrenergic activity contribute to agitation in activity contribute to agitation in AD?AD?

Noradrenergic System Pathology in Noradrenergic System Pathology in Alzheimer’s DiseaseAlzheimer’s Disease

► Despite loss of noradrenergic Despite loss of noradrenergic locus coeruleus neurons there is:locus coeruleus neurons there is:● Increased cerebrospinal fluid (CSF) Increased cerebrospinal fluid (CSF)

norepinephrine (NE) in ADnorepinephrine (NE) in AD11

● Increased agitation response to NE in Increased agitation response to NE in ADAD22

● Compensatory upregulation of surviving Compensatory upregulation of surviving LC neuronsLC neurons33

● Increased alpha-1 adrenoreceptors in Increased alpha-1 adrenoreceptors in locus ceruleus target areaslocus ceruleus target areas44

11Elrod et al., Elrod et al., Am J PsychiatryAm J Psychiatry 154:25-30, 1997. 154:25-30, 1997.22Peskind, et al., Peskind, et al., Arch Gen Psychiatry, Arch Gen Psychiatry, 1995.1995.33Szot, et al., Szot, et al., J NeuroscienceJ Neuroscience, 2006., 2006.44Szot, et al., Szot, et al., J NeuroscienceJ Neuroscience, 2007., 2007.

0

100

200

300

400

500

Young Young (n=54)(n=54)

CS

F n

ore

pin

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rine

(p

g/m

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SF

no

rep

ine

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ne (

pg/

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Old Old (n=42)(n=42)

**

Mild-Moderate Mild-Moderate AD (n=49)AD (n=49)

**

Advanced Advanced AD (n=25)AD (n=25)

****

*significantly higher than young subjects**significantly higher than all other subject groups

Elrod et al., Am J Psychiatry 154:25-30, 1997.4

CSF Norepinephrine: CSF Norepinephrine: Effects of Aging and ADEffects of Aging and AD

Postsynaptic Adrenergic Receptor Postsynaptic Adrenergic Receptor Antagonists in ADAntagonists in AD

► Would reducing brain Would reducing brain responsiveness to NE by blocking responsiveness to NE by blocking adrenergic receptors reduce adrenergic receptors reduce agitation in AD?agitation in AD?

► Alpha-1 receptor antagonist: Alpha-1 receptor antagonist: prazosin.prazosin.● Long lasting benefits in Long lasting benefits in

posttraumatic stress disorderposttraumatic stress disorder● Would prazosin be helpful in AD?Would prazosin be helpful in AD?

Raskind MA, et al.,Raskind MA, et al., Am J Psychiatry Am J Psychiatry 160:371-373, 2003. 160:371-373, 2003.

Prazosin as a Novel Pharmacologic Prazosin as a Novel Pharmacologic Approach to Agitation in ADApproach to Agitation in AD

► Prazosin is an alpha-1 receptor Prazosin is an alpha-1 receptor antagonist.antagonist.● Only one that crosses from the blood Only one that crosses from the blood

into the braininto the brain

► Inexpensive, generic, used for BPH and Inexpensive, generic, used for BPH and hypertension by millions of older hypertension by millions of older persons for decades.persons for decades.

► Clinically effective for AD agitation in Clinically effective for AD agitation in open label pilot study.open label pilot study.

Placebo-Controlled Trial of Prazosin Placebo-Controlled Trial of Prazosin for Disruptive Agitation in Dementiafor Disruptive Agitation in Dementia

► Twenty-one persons (mean age 80 years) Twenty-one persons (mean age 80 years) with DSM-IV dementia (possible or with DSM-IV dementia (possible or probable AD) and frequent disruptive probable AD) and frequent disruptive agitation.agitation.

► Randomized to prazosin (n = 10) or Randomized to prazosin (n = 10) or placebo (n = 11) for 8 weeks.placebo (n = 11) for 8 weeks.

► Prazosin dose range 2-6 mg/day (mean Prazosin dose range 2-6 mg/day (mean dose 5.6 ± 1.2 mg/day).dose 5.6 ± 1.2 mg/day).

► Primary outcome measures: BPRS, NPI, Primary outcome measures: BPRS, NPI, CGIC.CGIC.

Placebo-Controlled Trial of Prazosin for Placebo-Controlled Trial of Prazosin for Disruptive Agitation in Dementia: NPIDisruptive Agitation in Dementia: NPI

Wang L, et al., Wang L, et al., Am J Geriatr PsychAm J Geriatr Psych 17:744-75, 2009. 17:744-75, 2009.

Where Are We Now?Where Are We Now?

► AD biomarkers will be increasingly AD biomarkers will be increasingly valuable, but do not under-estimate the valuable, but do not under-estimate the importance of a careful history and importance of a careful history and longitudinal cognitive/ functional longitudinal cognitive/ functional assessment.assessment.

► The primacy of AThe primacy of Aββ in AD pathogenesis in AD pathogenesis and therapeutics remains in question.and therapeutics remains in question.

► Improving treatments for behavioral Improving treatments for behavioral disturbances in AD will have major disturbances in AD will have major impacts on patients and caregiver quality impacts on patients and caregiver quality of life and health care costs.of life and health care costs.

Pathophysiology of AD: Pathophysiology of AD: Foundation Role of Cholinergic Foundation Role of Cholinergic Dysregulation and Emerging Dysregulation and Emerging

Perspectives on the Pathobiology of Perspectives on the Pathobiology of AD AD

JAMES E. GALVIN, MD, MPHJAMES E. GALVIN, MD, MPHProfessor of Neurology and Psychiatry Professor of Neurology and Psychiatry

Director of Clinical Operations Director of Clinical Operations Center of Excellence on Brain Aging Center of Excellence on Brain Aging

Director Pearl Barlow Center for Memory Evaluation and Director Pearl Barlow Center for Memory Evaluation and Treatment Treatment

New York University Langone School of Medicine New York University Langone School of Medicine New York, NYNew York, NY



ObjectivesObjectives

► Pathophysiology of ADPathophysiology of AD► Beta-amlyoid hypothesisBeta-amlyoid hypothesis► Cholinergic HypothesisCholinergic Hypothesis► Clinical and therapeutic Clinical and therapeutic

implications of Cholinergic implications of Cholinergic hypothesishypothesis

► Intersection of cholinergic and Intersection of cholinergic and amyloid-based pathobiologyamyloid-based pathobiology

► Approaches to therapyApproaches to therapy► Implications for multi-modal Implications for multi-modal

therapies for ADtherapies for AD

Pathophysiology of ADPathophysiology of AD

► Neuropathologic hallmarks of ADNeuropathologic hallmarks of AD● Senile plaques – Amyloid b-protein (Ab)Senile plaques – Amyloid b-protein (Ab)● Neurofibrillary tangle – tau proteinNeurofibrillary tangle – tau protein

► Largely a sporadic, late-life cause of Largely a sporadic, late-life cause of dementia, early-onset and familial forms dementia, early-onset and familial forms existexist● Mutations in APP, PS-1 and PS-2Mutations in APP, PS-1 and PS-2● Mutations increase production of AbMutations increase production of Ab

► Late-onset disease is associated with Late-onset disease is associated with presence of the e4 allele of Apolipoprotein presence of the e4 allele of Apolipoprotein EE● More than 40 other genes have been More than 40 other genes have been

associated with AD associated with AD

Amyloid HypothesisAmyloid Hypothesis

► First proposed in 1991First proposed in 1991► Initiating molecule in AD, Initiating molecule in AD,

ultimately leading to ADultimately leading to AD► Mutations in familial AD encode Mutations in familial AD encode

substrate (APP) and enzyme substrate (APP) and enzyme (Presenilin) for A(Presenilin) for A production production

► Infusions of AInfusions of A cause neuronal cause neuronal degeneration and cognitive degeneration and cognitive deficitsdeficits

► Harmful form of AHarmful form of A is small, is small, diffusable aggregates or diffusable aggregates or oligomersoligomersPakasi and Kalman 2008, Hardy and Allsop 1991, Kowall et al 1991, McDonald et al 1994, Dahlgren et al 2002

AA is Derived After Cleavage of APP is Derived After Cleavage of APP

Lumen/Lumen/Extracellular Extracellular

CytosolCytosol

C83C83((-stub)-stub)

sAPPsAPP

p3p3

AICD AICD (A(A5050-Cter)-Cter)

C99C99((-stub)-stub)

sAPPsAPP

APPAPP

AbAb

AICDAICD

A

PlaquePlaque

APP = amyloid precursor protein; sAPP = soluble form of APP; AICD = APP intracellular domain

AcetylcholineAcetylcholine

► ACh activity known since turn of 20ACh activity known since turn of 20thth century century● Nobel prize to Henry Dales and Otto LoewiNobel prize to Henry Dales and Otto Loewi

► Synthesized Synthesized de novode novo by the brain by the brain► Two types of receptorsTwo types of receptors

● MuscaricMuscaric● NicotinicNicotinic

► In the CNS, largely produced in collection of In the CNS, largely produced in collection of neurons in basal forebrain and pons with neurons in basal forebrain and pons with wide-range projectionswide-range projections

Cholinergic ProjectionsCholinergic Projections

From: Cooper, Roth and Bloom, Biochemical Basis of Neuropharmacology, 7From: Cooper, Roth and Bloom, Biochemical Basis of Neuropharmacology, 7 thth Ed, 1996 Ed, 1996

Cholinergic HypothesisCholinergic Hypothesis

► Dysfunction of cholinergic system contributes Dysfunction of cholinergic system contributes to memory declineto memory decline

► Drachman and Leavitt (1974) Drachman and Leavitt (1974) ● Link between cholinergic dysfunction and Link between cholinergic dysfunction and

memory impairmentmemory impairment● Scopolamine in young adults caused Scopolamine in young adults caused

impairmentimpairment● Corroborated by primate, canine and rodent Corroborated by primate, canine and rodent

studiesstudies► Reduced choline acetyl transferase (ChAT) Reduced choline acetyl transferase (ChAT)

activity in cortex, hippocampus and amygdala activity in cortex, hippocampus and amygdala of AD patientsof AD patients● Activity correlated with level of cognitive Activity correlated with level of cognitive

impairment impairment ● Selective loss of cholinergic cells in basal Selective loss of cholinergic cells in basal

forebrainforebrain

Davies and Maloney, 1976, Perry et al 1978, Wilcock et al 1982, Whitehouse et al 1981.Davies and Maloney, 1976, Perry et al 1978, Wilcock et al 1982, Whitehouse et al 1981.

AChEAChEAChEAChE

AcetylAcetylCoACoA

+ +CholineCholine

CholineCholine++

AcetateAcetate

AChACh

Presynaptic Presynaptic NeuronNeuron

Synaptic CleftSynaptic Cleft

PostsynapticPostsynapticNeuronNeuron

Cholinergic ReceptorCholinergic Receptor

CholineCholine

AChEAChEAChEAChE

ChATChATChATChAT

Glial CellGlial Cell

BuChEBuChEBuChEBuChE

BuChEBuChEBuChEBuChE

Neuropathological Signaling:Neuropathological Signaling:Cholinergic HypothesisCholinergic Hypothesis

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.

AChACh

Cholinergic HypothesisCholinergic Hypothesis

► Basal forebrain and rostral brainstem Basal forebrain and rostral brainstem cholinergic pathways converge to cholinergic pathways converge to serve important functional rolls in serve important functional rolls in awareness, attention, working memory awareness, attention, working memory and mnemonic processes and mnemonic processes

► Loss of cholinergic function contributes Loss of cholinergic function contributes to cognitive decline associated with to cognitive decline associated with ADAD

Perry et al 1999, Bartus 2000,

Cholinergic Receptors and ADCholinergic Receptors and AD

► Two classesTwo classes● Nicotinic ionic channelsNicotinic ionic channels

• Responsible for fast transmissionResponsible for fast transmission• Reduction in Reduction in 4 nAChR in AD4 nAChR in AD• Up-regulation of Up-regulation of 7 nAChR in AD compared with 7 nAChR in AD compared with

MCI and controlsMCI and controls– 7 receptors down-regulated in DLB7 receptors down-regulated in DLB

• Possible compensatory response to maintain basal Possible compensatory response to maintain basal forebrain-cortical cholinergic activityforebrain-cortical cholinergic activity

• 7 nAChR interacts with APP and 7 nAChR interacts with APP and AA peptides which peptides which could lead to aberrant functioncould lead to aberrant function

● Muscarinic G protein-coupled receptorsMuscarinic G protein-coupled receptors• Preserved during progression of ADPreserved during progression of AD• In triple transgenic mice, M1 agonists improved In triple transgenic mice, M1 agonists improved

cognitive and reduced Acognitive and reduced A and tau pathology and tau pathology• Hypothesis: activation of TACE/ADAM17, Hypothesis: activation of TACE/ADAM17,

decreased BACE1 levels and/or inhibition of GSK3decreased BACE1 levels and/or inhibition of GSK3

Mufson et al 2009, Nagele et al 2002, Counts et al, 2007, Caccamo et al 2006Mufson et al 2009, Nagele et al 2002, Counts et al, 2007, Caccamo et al 2006

Role of Cholinergic Deficits in Role of Cholinergic Deficits in Behavioral Symptoms of ADBehavioral Symptoms of AD

► Temporal and frontal lobe dysfunction Temporal and frontal lobe dysfunction implicated in psychosis of ADimplicated in psychosis of AD

► Regional cholinergic deficitsRegional cholinergic deficits—apathy and —apathy and indifferenceindifference

► Cholinergic-monoaminergic imbalance Cholinergic-monoaminergic imbalance hypothesized in mood disordershypothesized in mood disorders

► Cholinesterase inhibitors (ChEIs) have shown Cholinesterase inhibitors (ChEIs) have shown behavioral benefits in several clinical trials behavioral benefits in several clinical trials

Lanari A, et al Lanari A, et al 2006; 2006; Cummings JL. Cummings JL. 20002000

Clinical and Therapeutic Implications Clinical and Therapeutic Implications of Cholinergic hypothesis of Cholinergic hypothesis

► Recent functional MRI study demonstrated MCI treated Recent functional MRI study demonstrated MCI treated with donepezil demonstrated increased frontal cortex with donepezil demonstrated increased frontal cortex activation relative to untreated controlactivation relative to untreated control

● Correlated with task performanceCorrelated with task performance► AChE does not show decline until late stages of diseaseAChE does not show decline until late stages of disease

● Only mild losses in MCI and mild ADOnly mild losses in MCI and mild AD► Vesicular Ach transporter is not severely altered in ADVesicular Ach transporter is not severely altered in AD

● Cholinergic neurons appear then to shrink and become Cholinergic neurons appear then to shrink and become dysfunctional rather than degenerate early in diseasedysfunctional rather than degenerate early in disease

● Suggest cholinergic neurons may be viable, however Suggest cholinergic neurons may be viable, however dysfunctional early in disease and thus amenable to dysfunctional early in disease and thus amenable to manipulationsmanipulations

► Changes in neurotrophic gene expression may provide Changes in neurotrophic gene expression may provide targets of intervention for dysregulation of cholinergic targets of intervention for dysregulation of cholinergic neuronsneurons

● NGF (NGF (trktrk) receptors down-regulation may be a molecular ) receptors down-regulation may be a molecular marker for transition from MCI to frank AD 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, 2009Saykin 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 HypothesisChallenges to Cholinergic Hypothesis

► Studies of post-mortem tissueStudies of post-mortem tissue● Levels of AChE and ChAT are not reduced in very mild ADLevels of AChE and ChAT are not reduced in very mild AD● Levels of ChAT may be upregulated in MCI and very mild ADLevels of ChAT may be upregulated in MCI and very mild AD

► Since neither ChAT nor AChE are rate-limiting cholinergic Since neither ChAT nor AChE are rate-limiting cholinergic enzymes, they are unlikely to accurately reflect cholinergic enzymes, they are unlikely to accurately reflect cholinergic function in a living patientfunction in a living patient

► Other factors may be involvedOther factors may be involved● Alterations in high-affinity choline transport (rate-limiting step)Alterations in high-affinity choline transport (rate-limiting step)● Deficits in nicotinic and muscarinic receptorsDeficits in nicotinic and muscarinic receptors● Dysfunctional neurotrophic supportDysfunctional neurotrophic support

► Neurochemical analyses of autopsy tissue maybe unreliableNeurochemical analyses of autopsy tissue maybe unreliable● Dependent on length of agonal state and post-mortem intervalDependent on length of agonal state and post-mortem interval● More recent More recent in vivoin vivo imaging studies support amyloid hypothesis imaging studies support amyloid hypothesis

• 1111C N-methylpiperidine-4-yl proprianate (AChE activity)C N-methylpiperidine-4-yl proprianate (AChE activity)• Nicotine-based ligandsNicotine-based ligands• Non-selective muscarinic ligandsNon-selective muscarinic ligands• 123123I Benzovesamacol (vesicular Ach transporter)I 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 DevelopmentsRecent Developments

► Extension of studies to early, prodromal stagesExtension of studies to early, prodromal stages● Religious Orders StudyReligious Orders Study● Very mild cases did not show decreases in ChAT but Very mild cases did not show decreases in ChAT but

actually increasesactually increases● Immunochemistry of brain with very mild AD/MCIImmunochemistry of brain with very mild AD/MCI

• ChAT or vesicular ACh transporter not reducedChAT or vesicular ACh transporter not reduced• Markers of NGF receptors markedly reducedMarkers of NGF receptors markedly reduced• Possible that other pre- or post-synaptic Possible that other pre- or post-synaptic

mechanisms may be compromisedmechanisms may be compromised• Perhaps down-regulation of retrograde Perhaps down-regulation of retrograde

transmission of NGF from hippocampus/frontal transmission of NGF from hippocampus/frontal cortex to basal forebraincortex to basal forebrain

• Altered neurotrophic receptors may mark early Altered neurotrophic receptors may mark early stage of disease with initial increases in ChAT stage of disease with initial increases in ChAT activityactivity

• Decreased connectivity between hippocampus Decreased connectivity between hippocampus and entorhinal cortexand 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 Interactions Between Amyloid and Cholinergic HypothesesCholinergic Hypotheses

► Regulation of ARegulation of A by stimulation of muscarinic or nicotinic by stimulation of muscarinic or nicotinic receptorsreceptors

● Partial M1 agonists increase Partial M1 agonists increase APPs, decrease AAPPs, decrease A and decrease and decrease tau phosphorylationtau phosphorylation

● Nicotine may increase downstream synthesis of neurotropinsNicotine may increase downstream synthesis of neurotropins

► Cholinergic deficits could be secondary to amyloid toxicityCholinergic deficits could be secondary to amyloid toxicity

► Bidirectional interaction between cholinergic function and Bidirectional interaction between cholinergic function and processing of amyloid precursor proteinprocessing of amyloid precursor protein

● High affinitity High affinitity 7 receptors can serve as high affinity binding 7 receptors can serve as high affinity binding sites for Asites for A peptides peptides

● Amyloid peptides inhibit uptake of choline and decrease Amyloid peptides inhibit uptake of choline and decrease endogenous Ach release without exhibiting effects on ChAT endogenous Ach release without exhibiting effects on ChAT activityactivity

● AA block functional interaction between nicotinic agonists and block functional interaction between nicotinic agonists and receptors on hippocampal neuronsreceptors 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 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 20012000, Pakaski and Kalman, 2008, Liu 2001

Interactions Between Ab and AChInteractions Between Ab and ACh

► Toxicity of AToxicity of A on the cholinergic system on the cholinergic system● Ach synthesis and release reduced by solubilized AbAch synthesis and release reduced by solubilized Ab● Loss of cholinergic fibers without loss of cholinergic Loss of cholinergic fibers without loss of cholinergic

neuronsneurons● Reduction of binding to vesicular Ach transporterReduction of binding to vesicular Ach transporter● Inhibition of fast axonal transportInhibition of fast axonal transport● AA42 binds with higher affinity to 42 binds with higher affinity to 7 nAChR than A7 nAChR than A4040● AA42 reduced downstream events in mAChR signal 42 reduced downstream events in mAChR signal

transductiontransduction

► Cholinergic system and APP processing via Cholinergic system and APP processing via --secretasesecretase

● mAChRmAChR● 7nAChR agonists7nAChR agonists● AChEIAChEI

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 Mechanisms of AChE Inhibitors on the Release of sAPPαthe Release of sAPPα

AchE inhibitor

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 Increase + ? Pakaski et al. (2001)

Ganstigmine Increase + ? Mazzucchelli et al. (2003)

Ladostigil Increase +MAP-kinase or tyrosin kinase-dependent pathway

Yogev-Falach et al. (2002)

Donepezil Increase +Enhancing trafficking and activity of ADAM 10

Zimmermann et al. (2004)

Phenserine Decrease −Inhibition of APP mRNA translation

Lahiri et al. (2000); Shaw et al. (2001)

Galantamine Increase + ? Lenzken et al. (2007)

Pakaski and Kalman 2008

Linking Ab and AChLinking Ab and ACh

Pakaski and Kalman 2008

Withdrawal designWithdrawal design Staggered-start designStaggered-start design

Time

Per

form

ance

Time

Per

form

ance

RandomizedRandomizedphasephase

RandomizedRandomizedphasephase

PlaceboPlacebophasephase

PlaceboPlacebophasephase

Placebo

Active

Placebo

Active

Symptomatic effect

Disease-modifyingeffect

Disease-modifyingeffect

Symptomatic effect

Discrimination Between Disease Discrimination Between Disease Modification and Symptomatic Modification and Symptomatic

BenefitBenefit

Is There Evidence of Disease-Is There Evidence of Disease-Modifying Effects?Modifying Effects?

► From clinical trials, functional imaging and From clinical trials, functional imaging and basic science studies, anti-cholinesterase basic science studies, anti-cholinesterase drugs may:drugs may:● Reduce circulating AReduce circulating A● Alter APP processingAlter APP processing● Prevent APrevent A deposition in cholinergic projection sites deposition in cholinergic projection sites● Promote non-amyloidogenic APP processingPromote non-amyloidogenic APP processing

► If changes in cholinergic transmission If changes in cholinergic transmission alters APP processing, appropriate alters APP processing, appropriate cholimimetic therapeutics might provide cholimimetic therapeutics might provide both symptomatic benefit and modify AD both symptomatic benefit and modify AD pathogenesispathogenesisLopez et al 2002, Krishman et al 2003, Francis et al 2005, Nordberg 2006, Inestrosa et al 1996, Rogers et al 2000Lopez et al 2002, Krishman et al 2003, Francis et al 2005, Nordberg 2006, Inestrosa et al 1996, Rogers et al 2000

Amyloid-Based ApproachesAmyloid-Based Approaches

Barten and Albright 2008Barten and Albright 2008

Immunization Reduces Ab burdenImmunization Reduces Ab burden

Holmes et al 2008Holmes et al 2008

Immunization Does not rRduce Immunization Does not rRduce Disease BurdenDisease Burden

Time to severe dementiaTime to severe dementia Time to deathTime to death

Holmes et al 2008Holmes et al 2008

Neurotransmitter-Based ApproachesNeurotransmitter-Based Approaches

Barten and Albright 2008

TimeTime

Per

form

ance

Per

form

ance

Mild

Combining Combining Symptomatic and Symptomatic and Disease-modifying RXDisease-modifying RX

Disease-modifying Disease-modifying RxRx

Symptomatic RxSymptomatic Rx

Model of Multi-Modal Approach Model of Multi-Modal Approach

Moderate Severe

Summary Summary

► Ab as the likely culprit leading to AD is a Ab as the likely culprit leading to AD is a logical target for anti-AD therapies but to logical target for anti-AD therapies but to date, Phase III trials have not been date, Phase III trials have not been successfulsuccessful

► Ach provides targets for symptomatic Ach provides targets for symptomatic benefitbenefit● Dysfunction/degeneration of the cholinergic Dysfunction/degeneration of the cholinergic

projection neurons is a later stage event in ADprojection neurons is a later stage event in AD● Dysregulation of the cholinergic system is an Dysregulation of the cholinergic system is an

early eventearly event

Mufson et al 2009,Davis et al 1999, DeKosky et al 2002, Mufson et al 200, Mufson et al 2002

Summary (cont.) Summary (cont.)

► There is a bidirectional relationship There is a bidirectional relationship between the amyloid and cholinergic between the amyloid and cholinergic hypotheseshypotheses

► Disease-modifying therapies will likely be Disease-modifying therapies will likely be more effective when used earlier in disease more effective when used earlier in disease processprocess● Clear need for improve detection of AD at earliest, Clear need for improve detection of AD at earliest,

even preclinical stageseven preclinical stages

► Multi-modal approaches offer the best Multi-modal approaches offer the best potential to provide treatment throughout potential to provide treatment throughout the spectrum of disease the spectrum of disease Mufson et al 2009,Davis et al 1999, DeKosky et al 2002, Mufson et al 200, Mufson et al 2002

SANDRA E. BLACK, MD, FRCPCSANDRA E. BLACK, MD, FRCPCBrill Chair in Neurology Brill Chair in Neurology

University of Toronto, Sunnybrook University of Toronto, Sunnybrook Health Sciences Centre Health Sciences Centre Toronto, Ontario CanadaToronto, Ontario Canada

Evidence-based Role of Evidence-based Role of Cholinesterase Inhibition Cholinesterase Inhibition

Across the Severity Across the Severity Spectrum in ADSpectrum in AD



► 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

Learning ObjectivesLearning ObjectivesLearning ObjectivesLearning Objectives

See Canadian Consensus on Dementia Diagnosis and Treatment: Hogan et al, CMAJ 2008; Alzheimer’s and Dementia special issue 2007

– Progressive loss of Progressive loss of cholinergic neuronscholinergic neurons

– Progressive decrease in Progressive decrease in available AChavailable ACh

– Impairment in ADL, Impairment in ADL, behavior and cognitionbehavior and cognition

HippocampusCortex

N. basalis Meynert

Bartus et al., 1982; Cummings and Back, 1998, Perry et al., 1978

The Cholinergic Deficit in ADThe Cholinergic Deficit in ADThe Cholinergic Deficit in ADThe Cholinergic Deficit in AD

ButyrylcholinesteraseButyrylcholinesterase

N = nicotinic N = nicotinic M = muscarinic M = muscarinic ACh = acetylcholineACh = acetylcholine

Postsynaptic Postsynaptic nerve nerve terminalterminal

M receptorM receptor

N receptorN receptor

Presynaptic Presynaptic nerve terminalnerve terminal

AChACh

AcetylcholinesteraseAcetylcholinesterase

Increased availability of ACh at synapse (AChE and BuChE inhibition)Increased availability of ACh at synapse (AChE and BuChE inhibition)

AChACh

AstrocyteAstrocyte

BuChE

GalantamineGalantamine

Donepezil Donepezil Rivastigmine Rivastigmine GalantamineGalantamine

RivastigmineRivastigmine

Cholinesterase Inhibitors:Cholinesterase Inhibitors:Mechanisms of ActionMechanisms of Action

Cholinesterase Inhibitors:Cholinesterase Inhibitors:Mechanisms of ActionMechanisms of Action

-10%0%10%20%30%

Rogers, 1998b

Rosler, 1999

Wilcock, 2000

Rockwood,2001Wilkinson, 2001

Meta-analyticdifference

benefit no benefit

heterogeneous

Efficacy-Cognitive ImprovementEfficacy-Cognitive ImprovementEfficacy-Cognitive ImprovementEfficacy-Cognitive Improvement

10% [4%, 17%] of patients show significant benefit over placebo

Lanctot et al, CMAJ, 2003

-10%0%10%20%30%

Rogers, 1998aRogers, 1998bBurns, 1999Rosler, 1999Raskind, 2000Wilcock, 2000Rockwood, 2001Wilkinson, 2001Meta-analytic difference

benefit no benefit

9% [6%, 12%] of patients show significant benefit over placebo

Homogeneous

Lanctot et al, CMAJ, 2003Lanctot et al, CMAJ, 2003

Efficacy Clinical Global ImpressionEfficacy Clinical Global ImpressionEfficacy Clinical Global ImpressionEfficacy Clinical Global Impression

► Numbers needed to treat to Numbers needed to treat to benefitbenefit● 7 7 (CI(CI95%95%:: 6, 9) for stabilization or 6, 9) for stabilization or

better better ● 1212 (CI (CI95%95%:: 9, 16) for minimal 9, 16) for minimal

improvement or better improvement or better ● 42 42 (CI(CI95%95%:: 26, 114) for marked 26, 114) for marked

improvementimprovement

► NNT for clinically benefit are NNT for clinically benefit are low. low.

► Homogeneous-all 3 ChEI Homogeneous-all 3 ChEI similarsimilar

Lanctot et al, CMAJ, 2003Lanctot et al, CMAJ, 2003

Number Needed to Treat for BenefitNumber Needed to Treat for BenefitNumber Needed to Treat for BenefitNumber Needed to Treat for Benefit

0

2

4

6

8

10

12

14

ChE

I pla

cebo

diff

DO AE DO d/t AE

donepezil

rivastigminegalantamine

CaveatCaveat

Galantamine above recommended doses, heterogeneity

8% [5,11]8% [5,11] 7% [3,10]7% [3,10]8% [5,12]8% [5,12]

Lanctot et al CMAJ, 2003

TolerabilityTolerabilityTolerabilityTolerability

SafetySafety

► Number needed to harm Number needed to harm ((ie to cause AE in 1 ie to cause AE in 1 patientpatient)) = = 12 12 ((Lanctot et al CMAJ 2003Lanctot et al CMAJ 2003 ) )

► Recent study of community-dwelling Recent study of community-dwelling dementia patients using healthcare dementia patients using healthcare database in Ontario, Canada (2002-4)database in Ontario, Canada (2002-4)

► 19,803 treated with cholinesterase 19,803 treated with cholinesterase inhibitors vs 61,499 not on CHEI’sinhibitors vs 61,499 not on CHEI’s● Syncope Syncope 31.5 vs 18.6/1000 31.5 vs 18.6/1000 HR 1.76HR 1.76● Bradycardia Bradycardia 6.9 vs 4-4/1000 6.9 vs 4-4/1000 HR 1.69HR 1.69● Pacemaker needed Pacemaker needed 4.7 vs 3.3/1000 4.7 vs 3.3/1000 HR 1.49HR 1.49● Hip fracture Hip fracture 22.4 vs 19.8/1000 22.4 vs 19.8/1000 HR 1.18HR 1.18

Gill et al Arch Int Med 2009Gill et al Arch Int Med 2009

► Benefits in cognition, behavior and function have been for 6 Benefits in cognition, behavior and function have been for 6 months- only a few 1-year placebo-controlled studies months- only a few 1-year placebo-controlled studies

► Longer term benefits derived from open label extensions, Longer term benefits derived from open label extensions, limited by large dropouts and bias from self-selectionlimited by large dropouts and bias from self-selection

► Most clinical trials have been pharma-sponsored without Most clinical trials have been pharma-sponsored without independent analyses, except for AD 2000 independent analyses, except for AD 2000

► Differential treatment effects on specific cognitive domains Differential treatment effects on specific cognitive domains are not known as they have not been studied; the tools used are not known as they have not been studied; the tools used may not have sampled the most sensitive domainsmay not have sampled the most sensitive domains

► Placebo trials may no longer be feasible or ethicalPlacebo trials may no longer be feasible or ethical

► Recent review of RCTs highlight methodological flaws (e.g., Recent review of RCTs highlight methodological flaws (e.g., no corrections for multiple comparisons, LOCF method) and no corrections for multiple comparisons, LOCF method) and questions utility of drugs in clinical practicequestions utility of drugs in clinical practice

Limitations of Drug Trials to DateLimitations of Drug Trials to DateLimitations of Drug Trials to DateLimitations of Drug Trials to Date

Kaduszkiewicz et al., BMJ, 2005Kaduszkiewicz et al., BMJ, 2005

Use in Early and Later Use in Early and Later Disease StagesDisease Stages



0

5

10

15

20

25

30

1 2 3 4 5 6 7 8 9

MM

SE

Years

Early

Mild-moderate

Severe

Cognitive symptoms

Loss of functionalindependence

Behavioural problems

Nursing home placement

Death

Feldman H and Gracon S in: Clinical Diagnosis and Management of Alzheimer’s Disease 1998.

Natural History of AD: earlyNatural History of AD: earlyNatural History of AD: earlyNatural History of AD: early

0.00.0 0.50.5 1.01.0 1.51.5 2.02.0 2.52.5 3.03.0 3.53.500

101020203030404050506060707080809090

100100

Follow-up Time (Years)Follow-up Time (Years)

Pro

port

ion

Fre

e o

f D

em

en

tia (

%)

Pro

port

ion

Fre

e o

f D

em

en

tia (

%)

NormalsNormals

MCIMCI

Retrospective analysis of 687 subjects with MCI Mean age 72.2 yrs

45%

DeKosky ST. J Am Geriatr Soc, 2003; Adapted from Grundman M et al, Abstract in Neurology, 1996.

Conversion of Normal and MCI SubjectsConversion of Normal and MCI Subjectsto Dementia (AD Cooperative Study)to Dementia (AD Cooperative Study)

Conversion of Normal and MCI SubjectsConversion of Normal and MCI Subjectsto Dementia (AD Cooperative Study)to Dementia (AD Cooperative Study)

ObjectivesObjectives► To determine whether daily doses of vitamin E or donepezil To determine whether daily doses of vitamin E or donepezil

given over a 3-year period can:given over a 3-year period can:

1) delay or prevent the onset of AD in people who have MCI 1) delay or prevent the onset of AD in people who have MCI

2) slow the decline of symptoms2) slow the decline of symptoms

Design: Design: 3-year, randomized, double-blind, placebo-controlled,3-year, randomized, double-blind, placebo-controlled,parallel group studyparallel group study

► 60 sites in the US and 9 sites in Canada60 sites in the US and 9 sites in Canada► Patients were randomized to receive donepezil 10 mg/day, Patients were randomized to receive donepezil 10 mg/day,

vitamin E 1,000 IU b.i.d., or placebovitamin E 1,000 IU b.i.d., or placebo

Subjects: Subjects: 769 patients with MCI769 patients with MCI

Outcome measures:Outcome measures:► Primary: Primary: Conversion to ADConversion to AD► Secondary:Secondary: MMSE, ADAS-cog, CDR, CDR-SB, ADCS, GDS, MMSE, ADAS-cog, CDR, CDR-SB, ADCS, GDS,

Neuropsychological batteryNeuropsychological battery

ADCS: MCI Study DesignADCS: MCI Study Design

Petersen et al. N Engl J Med, 2005

Survival Analysis: Donepezil vs. PlaceboSurvival Analysis: Donepezil vs. PlaceboP

roba

bili

ty o

f not

Pro

bab

ility

of n

otco

nve

rtin

g to

AD

con

vert

ing

to A

DP

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bili

ty o

f not

Pro

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ility

of n

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g to

AD

con

vert

ing

to A

D

Time on MCI study (days)Time on MCI study (days)Time on MCI study (days)Time on MCI study (days)

4002000 600 800 1,000 1,200

0.5

0.8

0.7

0.6

0.9

1.0

0.4

DonepezilPlaceboDonepezilPlacebo

1 yr6 mo 18 mo

pp<0.001<0.001pp<0.009<0.009

pp<0.035<0.035

Petersen RC et al. N Engl J Med, 2005

Summary of MCI StudiesSummary of MCI Studies

► NIH MCI study with donepezil failed statistical NIH MCI study with donepezil failed statistical significance on primary endpoint, but decline significance on primary endpoint, but decline delayed by up to 12 months, and was slower in delayed by up to 12 months, and was slower in APOE e4 participants APOE e4 participants (Petersen et al NEJM 2005)(Petersen et al NEJM 2005)

► Recent 48 wk study of donepezil in 821 aMCI Recent 48 wk study of donepezil in 821 aMCI patients likewise found nsd in 1patients likewise found nsd in 1oo and 2 and 2o o outcomes, outcomes, though patients felt better subjectively (though patients felt better subjectively (Doody et al Doody et al

Neurol 2009)Neurol 2009)

► Other MCI trials with galantamine Other MCI trials with galantamine (Winblad et al(Winblad et al Neurol Neurol

2008)2008) rivastigmine ( rivastigmine (Feldman et al Lancet Neurol 2007Feldman et al Lancet Neurol 2007) )

also did not delay conversionalso did not delay conversion

► More deaths noted with galantamine 1.4% vs 0.3% More deaths noted with galantamine 1.4% vs 0.3% in placebo MCI subjects leading to product label in placebo MCI subjects leading to product label warning warning

See Raschetti et al Cochrane Review PLoS Med 2007See Raschetti et al Cochrane Review PLoS Med 2007

Doody, et al., Am J of AD & Other Dem. 2010Doody, et al., Am J of AD & Other Dem. 2010

Safety and Tolerability of Donepezil Safety and Tolerability of Donepezil (10mg/d) in aMCI(10mg/d) in aMCI

Study DesignStudy Design

• Safety and tolerability of donepezil (10mg) was evaluated in 145 aMCI patients as 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 aMCIan open label 28-week extension study after a 48-week RCT of 821 aMCI

Key ResultsKey Results

• 57.4% in the donepezil/donepezil group and 62.3% in the placebo/donepezil group 57.4% in the donepezil/donepezil group and 62.3% in the placebo/donepezil group experienced an AEexperienced an AE

• Most frequent treatment related AEs were diarrhea, muscle spasms, insomnia, and Most frequent treatment related AEs were diarrhea, muscle spasms, insomnia, and nausea (more common early on & mild-moderate in severity)nausea (more common early on & mild-moderate in severity)

• 22.1% in the placebo/donepezil group discontinued donepezil due to an AE 22.1% in the placebo/donepezil group discontinued donepezil due to an AE compared with 10.3% in the donepezil/donepezil groupcompared with 10.3% in the donepezil/donepezil group

ConclusionsConclusions

• Donepezil in aMCI appeared to be safe, but patients with AD seem to tolerate it Donepezil in aMCI appeared to be safe, but patients with AD seem to tolerate it better than patients with MCIbetter than patients with MCI

Lu, et al., Neurology 2009 Lu, et al., Neurology 2009

Higher Rate of Progression to AD in Higher Rate of Progression to AD in Patients with aMCI and Depressive Patients with aMCI and Depressive

SymptomsSymptomsStudy DesignStudy Design• 756 aMCI from the three year NIH study drug trial of donepezil and vitamin 756 aMCI from the three year NIH study drug trial of donepezil and vitamin EE• Depressive symptoms assessed at baseline using the Beck Depression Depressive symptoms assessed at baseline using the Beck Depression Inventory (BDI)Inventory (BDI)

Key ResultsKey Results• On regression analysis higher BDI scores were associated with progression to ADOn regression analysis higher BDI scores were associated with progression to AD• Depressive subjectsDepressive subjects: proportion progressing to AD was lower in donepezil group : 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 than combined vitamin E and placebo groups at 1.7 years, 2.2 years, and marginally lower at 2.7 yearslower at 2.7 years• Nondepressive subjectsNondepressive subjects: no difference between the three treatment groups: no difference between the three treatment groups

ConclusionsConclusions• Depressive symptoms may be predictive of progression from aMCI to ADDepressive symptoms may be predictive of progression from aMCI to AD• Treatment with donepezil delayed progression to AD in depressive Treatment with donepezil delayed progression to AD in depressive subjects with aMCIsubjects with aMCI

Lu, et al., Neurology 2009 Lu, et al., Neurology 2009

SurvivalSurvival

0

5

10

15

20

25

30

1 2 3 4 5 6 7 8 9

MM

SE

Years

Early

Mild-moderate

Severe

Cognitive symptoms

Loss of functionalindependence

Behavioural problems

Nursing home placement

Death

Feldman H and Gracon S in: Clinical Diagnosis and Management of Alzheimer’s Disease 1998.

Natural History of AD: Natural History of AD: Moderate to severe stageModerate to severe stage

Natural History of AD: Natural History of AD: Moderate to severe stageModerate to severe stage

-6

-4

-2

0

2

4

6

Donepezil

Placebo

Donepezil vs Placebo in Nursing Home Study in Donepezil vs Placebo in Nursing Home Study in Severe AD (MMSE 1-10): Cognition (SIB)Severe AD (MMSE 1-10): Cognition (SIB)

3 6ITT LOCF

Clinicalimprovement

Clinicaldecline

Baseline

MonthsMonths

Mea

n C

hang

e F

rom

Bas

elin

eM

ean

Cha

nge

Fro

m B

asel

ine

in S

IB S

core

in S

IB S

core

*OC analysis; †LOCF analysis.

p=0.003*

p=0.008*

p=0.008†

0

SIB

Winblad et al. Lancet, 2006.

Functional Abilities Also Functional Abilities Also Showed Less Decline Showed Less Decline

-4

-3

-2

-1

0

1

2

3

4 Donepezil

Placebo

3 6 ITT LOCF

Months

Me

an

Cha

nge

Fro

m B

ase

line

in A

DC

S-A

DL

ClinicalImprovement

ClinicalDecline

BaselineP = 0.031* P = 0.029†P = 0.086*

*OC analysis; †LOCF analysis.

0

Winblad et al Lancet, 2006

-8

-6

-4

-2

0

2

4

6

8

Study weekStudy week

SIB

sco

res:

LS

mea

n ch

ange

fro

m

SIB

sco

res:

LS

mea

n ch

ange

fro

m

base

line

(SE

)ba

selin

e (S

E)

DonepezilPlacebo

d

Clinicalimprovement

Clinicaldecline

0

Less Cognitive Decline in Community Less Cognitive Decline in Community Dwelling Severe AD (MMSE1-12)Dwelling Severe AD (MMSE1-12)

24 ITT LOCF8

p =0 .0001

16

10mg/d

Black et al Neur 2007Black et al Neur 2007

► Level 1 evidence for different Level 1 evidence for different compounds according to studies compounds according to studies undertaken undertaken ● Donepezil in vascular dementiaDonepezil in vascular dementia● Rivastigmine in parkinson/diffuse lewy Rivastigmine in parkinson/diffuse lewy

body dementiabody dementia● Galantamine in mixed vascular dementiaGalantamine in mixed vascular dementia● (Memantine also shows efficacy in (Memantine also shows efficacy in

moderate to severe AD) moderate to severe AD)

Cholinesterase Inhibitor Use in Cholinesterase Inhibitor Use in Other DementiasOther Dementias

Cholinesterase Inhibitor Use in Cholinesterase Inhibitor Use in Other DementiasOther Dementias

Use of Higher Doses, Use of Higher Doses, New FormulationsNew Formulations



Once Daily FormulationsOnce Daily FormulationsOnce Daily FormulationsOnce Daily Formulations

Galantamine Galantamine extended release extended release 8mg od –16mg od– 24mg od8mg od –16mg od– 24mg od

Galantamine Galantamine extended release extended release 8mg od –16mg od– 24mg od8mg od –16mg od– 24mg od

Rivastigmine patchRivastigmine patch4.6-mg od –9.5mg od4.6-mg od –9.5mg odGI tolerability better than oral GI tolerability better than oral formulationformulation(eg nausea: oral 23 vs patch 7% (eg nausea: oral 23 vs patch 7% vs placebo 5%)vs placebo 5%)Skin sensitivity (erythema, edema,Skin sensitivity (erythema, edema,pruritus, pain) pruritus, pain)

Recent caution due to additive dose effectsRecent caution due to additive dose effectsif patch not removed daily before new one appliedif patch not removed daily before new one applied

Rivastigmine patchRivastigmine patch4.6-mg od –9.5mg od4.6-mg od –9.5mg odGI tolerability better than oral GI tolerability better than oral formulationformulation(eg nausea: oral 23 vs patch 7% (eg nausea: oral 23 vs patch 7% vs placebo 5%)vs placebo 5%)Skin sensitivity (erythema, edema,Skin sensitivity (erythema, edema,pruritus, pain) pruritus, pain)

Recent caution due to additive dose effectsRecent caution due to additive dose effectsif patch not removed daily before new one appliedif patch not removed daily before new one applied

Winblad et al. Int J Geri Psych. 2007Winblad et al. Int J Geri Psych. 2007

Doody, et al., Drugs Aging 2008Doody, et al., Drugs Aging 2008

PurposePurpose

• To evaluate the safety and tolerability of donepezil at doses of 15 and 20mg/dayTo evaluate the safety and tolerability of donepezil at doses of 15 and 20mg/day


• A 24-week, randomized, double-blind, placebo controlled, pilot studyA 24-week, randomized, double-blind, placebo controlled, pilot study

• 31 patients (male and female) aged 50-86 years31 patients (male and female) aged 50-86 years

•All patients had been treated with 10mg/day donepezil for 12-30 months prior to All patients had been treated with 10mg/day donepezil for 12-30 months prior to enrollmentenrollment

• Primary outcome measures:Primary outcome measures:

• TolerabilityTolerability (discontinuations, dose modifications, and adverse events) (discontinuations, dose modifications, and adverse events)

• SafetySafety (monitored by adverse events, physical examinations, clinical lab tests, (monitored by adverse events, physical examinations, clinical lab tests, and ECGs)and ECGs)

• Secondary outcome measures:Secondary outcome measures:

• Psychometric measures: ADAS-Cog, MMSE, CIBIC+, Psychometric measures: ADAS-Cog, MMSE, CIBIC+, pharmacokinetic/pharmacodynamic parameterspharmacokinetic/pharmacodynamic parameters

Safety & Tolerability of Higher Dose Safety & Tolerability of Higher Dose Donepezil (20mg)Donepezil (20mg)

Safety & Tolerability of Higher Dose Safety & Tolerability of Higher Dose Donepezil (20mg)Donepezil (20mg)


•Higher-dose group:Higher-dose group:

•15 of 16 patients tolerated the maximum 20 mg/day dose by week 2415 of 16 patients tolerated the maximum 20 mg/day dose by week 24

• Standard-dose group:Standard-dose group:

•14 of 15 patients tolerated donepezil 10 mg/day plus placebo 10 mg/day by 14 of 15 patients tolerated donepezil 10 mg/day plus placebo 10 mg/day by the end of the studythe end of the study

• Adverse events possibly related to treatment were reported by Adverse events possibly related to treatment were reported by 3 3 patients in the patients in the standard-dose group and standard-dose group and 66 patients in the higher-dose group patients in the higher-dose group

• No difference between groups on psychometric measuresNo difference between groups on psychometric measures


• Doses of 15 and 20 mg/day of donepezil appeared to be safe and well toleratedDoses 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 May justify larger clinical trials for the safety and efficacy of donepezil at higher doses in patients with AD.doses in patients with AD.

Doody, et al., Drugs Aging 2008Doody, et al., Drugs Aging 2008

Safety & Tolerability of higher dose Safety & Tolerability of higher dose Donepezil (20mg)Donepezil (20mg)

Safety & Tolerability of higher dose Safety & Tolerability of higher dose Donepezil (20mg)Donepezil (20mg)

PurposePurpose► To determine effectiveness, safety and tolerability of To determine effectiveness, safety and tolerability of

23 mg vs 10mg donepezil in mod-severe AD already 23 mg vs 10mg donepezil in mod-severe AD already on 10 mg donepezil on 10 mg donepezil

DesignDesign► 1467 patients (465 US) in 209 sites randomized to 1467 patients (465 US) in 209 sites randomized to

23mg (n=972) vs 10mg (n= 479)23mg (n=972) vs 10mg (n= 479)► MMSE: 76%: 0-16; 34%: 17-20MMSE: 76%: 0-16; 34%: 17-20► Approx 36% also on memantine (75% in US)Approx 36% also on memantine (75% in US)

ResultsResults► Discontinuation higher forDiscontinuation higher for 23 mg vs 10mg:23 mg vs 10mg:

● 30% (18% for AE’s vs 18% (8% for AE’s)30% (18% for AE’s vs 18% (8% for AE’s)

High Dose (23mg/d) vs Standard 10mg Dose High Dose (23mg/d) vs Standard 10mg Dose Donepezil in Moderate to Severe Stage ADDonepezil in Moderate to Severe Stage AD

High Dose (23mg/d) vs Standard 10mg Dose High Dose (23mg/d) vs Standard 10mg Dose Donepezil in Moderate to Severe Stage ADDonepezil in Moderate to Severe Stage AD

Effectiveness analysis:CognitionEffectiveness analysis:Cognition

Farlow et al. Clinical Therapeutics 2010. Farlow et al. Clinical Therapeutics 2010.

Severe Impairment BatterySevere Impairment BatterySevere Impairment BatterySevere Impairment Battery MMSEMMSEMMSEMMSE

Less decline from baseline on SIB P<0.001Less decline from baseline on SIB P<0.001

Frequency Distribution of CIBICFrequency Distribution of CIBICScores at Week 24Scores at Week 24

Farlow et al. Clinical Therapeutics2010. Farlow et al. Clinical Therapeutics2010.

No difference in ADL scoresNo difference in ADL scores

Adverse Events: 23 vs 10Nausea % 11.8 vs 3.4Vomiting % 9.3 vs 2.5Diarrhea % 8.3 vs 5.3Anorexia %

SAE % 8.6 vs 9.6

No difference in ADL scoresNo difference in ADL scores

Adverse Events: 23 vs 10Nausea % 11.8 vs 3.4Vomiting % 9.3 vs 2.5Diarrhea % 8.3 vs 5.3Anorexia %

SAE % 8.6 vs 9.6

Is There Any Evidence for Is There Any Evidence for Longer Term Use of Longer Term Use of

Cholinesterase Inhibitors?Cholinesterase Inhibitors?



Proj. placebo Dose optimization with rivastigmine (6-12 mg/day)

*

*

*

*

* *

**

*

0 10 20 30 40 50

2

0

–2

–4

–6

–8

AD

AS

-Cog

mea

n ch

ange

AD

AS

-Cog

mea

n ch

ange

from

bas

elin

efr

om b

asel

ine

Study weekStudy week

6–12 mg/day rivastigmine 1–4 mg/day rivastigmine

Placebo

All patients restarted on rivastigmine

B352 patients in Study B353 (OC) at week 52 *p<0.05 vs projected placebo

26

Messina et al., 2000

Rivastigmine-Placebo Group Does not Catch Rivastigmine-Placebo Group Does not Catch Up to Treated GroupUp to Treated Group

Rivastigmine-Placebo Group Does not Catch Rivastigmine-Placebo Group Does not Catch Up to Treated GroupUp to Treated Group

Mea

n ch

ange

from

bas

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ean

chan

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asel

ine

((±S

E±S

E))

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S-C

og/1

1 in

AD

AS

-Cog

/11

Time (months)Time (months)

–4

0

4

8

12

16

BaselineBaseline 3 6 9 12 24 36

20

24 Galantamine 24–32/24 mg

2848

(103)(322) (140)(309) (310) (233) (298) (228)

12-month placebo

Expected decline in untreated patients of 6–9 points/year

Database and from Raskind et al Arch Neurol 2004.

(n)

Mean Change in ADAS-Cog Score from Baseline: Mean Change in ADAS-Cog Score from Baseline: OpenOpen Label Label Galantamine Over 4 YearsGalantamine Over 4 Years

Mean Change in ADAS-Cog Score from Baseline: Mean Change in ADAS-Cog Score from Baseline: OpenOpen Label Label Galantamine Over 4 YearsGalantamine Over 4 Years

DesignDesign► 1-year, randomized, placebo-controlled, double-blind1-year, randomized, placebo-controlled, double-blind

SubjectsSubjects► 431 patients with mild-to-moderate AD 431 patients with mild-to-moderate AD ► Aged 49-94, mean MMSE 17.1Aged 49-94, mean MMSE 17.1

Primary OutcomePrimary Outcome► Time to clinically evident functional decline’, defined by:Time to clinically evident functional decline’, defined by:

● Decline in Decline in 1 basic ADL present at baseline 1 basic ADL present at baseline● Decline of Decline of 20% of the instrumental ADL present at 20% of the instrumental ADL present at

baseline baseline ● Increase Increase 1 point from baseline in global CDR score 1 point from baseline in global CDR score

(Clinical Dementia Rating scale)(Clinical Dementia Rating scale)Mohs et al.Mohs et al. Neurology. Neurology. 20012001

1-year Preservation of Function Study 1-year Preservation of Function Study with Donepezilwith Donepezil

1-year Preservation of Function Study 1-year Preservation of Function Study with Donepezilwith Donepezil

*As judged by investigator, ITT population

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 6 12 18 24 30 36 42 48 54

Duration of treatment (weeks)

Pro

bab

ilit

y o

f su

rviv

al

Donepezil 10 mg/day

Placebo

Mohs et al. Neurology. 2001

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)

Time to Clinically Evident Time to Clinically Evident Functional Decline*Functional Decline*

Time to Clinically Evident Time to Clinically Evident Functional Decline*Functional Decline*

Two-year, double blind, RCT in AD of Two-year, double blind, RCT in AD of donepezil versus placebo in a family donepezil versus placebo in a family practice setting in the UK sponsored by practice setting in the UK sponsored by local health authority (AD2000)local health authority (AD2000)

Small improvements shown but not Small improvements shown but not considered clinically significant since no considered clinically significant since no delay in NHP, loss of milestones or delay in NHP, loss of milestones or decrease in caregiver costs decrease in caregiver costs

(AD 2000, Courtney et al., Lancet, (AD 2000, Courtney et al., Lancet, 2004)2004)

Issues: Issues: a) Large dropout (40% 1-year, 77% 2-year)a) Large dropout (40% 1-year, 77% 2-year) b) Not clear if samples used for analyses b) Not clear if samples used for analyses

were matched after run in; also used were matched after run in; also used washout washout

c) 51% of total sample had CVDc) 51% of total sample had CVD

Longer-Term Effects: Non-Pharmaceutical Longer-Term Effects: Non-Pharmaceutical Sponsored StudySponsored Study

Longer-Term Effects: Non-Pharmaceutical Longer-Term Effects: Non-Pharmaceutical Sponsored StudySponsored Study

► Potential for symptom stabilization – 50% of Potential for symptom stabilization – 50% of patients with no change or improvement on patients with no change or improvement on SIB after 1 year, and 35% after 2 years in SIB after 1 year, and 35% after 2 years in head to head trial of rivastigmine and head to head trial of rivastigmine and donepezildonepezil11

► Compared with placebo or untreated Compared with placebo or untreated populations,populations,2–72–7 ChE-I therapy may delay ChE-I therapy may delay cognitive and functional decline and the cognitive and functional decline and the progression of neuropsychiatric symptoms progression of neuropsychiatric symptoms by up to a year by up to a year 11Bullock R Bullock R et al.et al. CMROCMRO 2005 2005

22Schmitt Schmitt et alet al. . Alzheimer Dis Assoc DisordAlzheimer Dis Assoc Disord 1997 19973 3 Feldman Feldman et alet al. . NeurologyNeurology 2001 200144Winblad Winblad et al. et al. NeurologyNeurology 2001; 2001;55Klatte Klatte et al. Alzheimer Dis Assoc Disordet al. Alzheimer Dis Assoc Disord 2003 200366Small et al Small et al Int J Clin Pract Int J Clin Pract 2005 200577Aisen Aisen et alet al. . JAMAJAMA 2003 2003

Other Studies Suggesting Symptomatic Other Studies Suggesting Symptomatic Stabilization over Longer Periods Stabilization over Longer Periods

Other Studies Suggesting Symptomatic Other Studies Suggesting Symptomatic Stabilization over Longer Periods Stabilization over Longer Periods

N= 65 in each of N= 65 in each of treated vs untreated treated vs untreated group, well-matched on group, well-matched on age, edcuation, severity, age, edcuation, severity, comorbidities, vasc risk comorbidities, vasc risk factors and medicationsfactors and medications

Less decline in:Less decline in:• Overall cognition Overall cognition • Naming Naming • Visuospatial and Visuospatial and

visuoconstructive skillsvisuoconstructive skills• Executive functionsExecutive functions

90

95

100

105

110

115

120

125

baseline follow-up

Mea

n D

RS

sco

res

untreatedtreated

p<0.0001

Effect size d = 0.7

Dementia Rating Scale

Behl et al Dem Ger Cog Dis 2006Behl et al Dem Ger Cog Dis 2006

Patients on ChEI’s Had Less Decline inPatients on ChEI’s Had Less Decline in Multiple Cognitive Domains over 1 YearMultiple Cognitive Domains over 1 Year

Patients on ChEI’s Had Less Decline inPatients on ChEI’s Had Less Decline in Multiple Cognitive Domains over 1 YearMultiple Cognitive Domains over 1 Year

Treated patients Treated patients showed less showed less decline on:decline on:• Overall cognition Overall cognition • MemoryMemory• Naming Naming • Executive Executive

functions functions

0

5

10

15

20

25

30

baseline follow-up1 follow-up2

Mea

n CV

LT a

cqui

sitio

n

untreated

treated

p=0.007

ES: d1 =0.8; d2 = 0.4

Verbal Memory

Behl et al Dem Ger Cog Dis 2006Behl et al Dem Ger Cog Dis 2006

Patients on ChEI’s Continued to Show Less Decline Patients on ChEI’s Continued to Show Less Decline on Select Cognitive Domains at Two Yearson Select Cognitive Domains at Two Years

Patients on ChEI’s Continued to Show Less Decline Patients on ChEI’s Continued to Show Less Decline on Select Cognitive Domains at Two Yearson Select Cognitive Domains at Two Years

0

10

20

30

40

50

60

70

80

90


Mean

overa

ll DAD

initia

tion

untreated

treated

Pyear1=0.036; Pyear2=0.001

ES 1= 0.5; ES 2= 0.8

Overall DAD

0

10

20

30

40

50

60

70

80


Mean

Instru

menta

l initia

tion sc

ores

untreated

treated

Instrumental

Pyear1=0.04; Pyear2=0.001

ES 1 =0.6; ES 2= 0.9

0

20

40

60

80

100

120

baseline follow -up1 follow -up2

mean

basic A

DLs in

itiatio

n untreated

treated

Basic

Pyear1=0.08 ; Pyear2=0.001

ES 1= 0.4; ES 2 = 0.7

Behl et al, Int Psychoger 2008

Patients on ChEI’s also showed less decline in functional Patients on ChEI’s also showed less decline in functional abilities over 2 years, especially in initiation (DAD)abilities over 2 years, especially in initiation (DAD)

Patients on ChEI’s also showed less decline in functional Patients on ChEI’s also showed less decline in functional abilities over 2 years, especially in initiation (DAD)abilities over 2 years, especially in initiation (DAD)

0

10

20

30

40

50

60

70

80

90


Mean

overa

ll DAD

plan

ning

untreated

treated

Pyear1= 0.038; Pyear2=0.006

ES 1=0.8; ES 2 =1.0

Overall DAD

0

20

40

60

80

100

120


mea

n bas

ic AD

Ls pl

annin

g

untreated

treated

Basic

Pyear1=0.039; Pyear2=0.001

ES 1 = 0.7; ES = 1.0

Behl et al, Int Psychoger 2008

Also Planning and OrganizationAlso Planning and OrganizationAlso Planning and OrganizationAlso Planning and Organization

Rountree, et al., Alzheimer’s Res. & Ther. 2009 Rountree, et al., Alzheimer’s Res. & Ther. 2009

Does Persistent Use of Antidementia Drugs Slow Does Persistent Use of Antidementia Drugs Slow Clinical Progression of AD over 20 Years?Clinical Progression of AD over 20 Years?


• 641 probable AD patients were followed for 20 years in a single centre 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 Cumulative drug exposure was expressed as a persistency index (PI) reflecting total years of drug use divided by total years of disease symptomsyears of drug use divided by total years of disease symptoms

• Measures: annual change in slope of neuropsychological and functional tests as Measures: annual change in slope of neuropsychological and functional tests as predicted by follow up time, PI, and the interaction between these variablespredicted by follow up time, PI, and the interaction between these variables


• PI was associated with significantly slower rates of decline on MMSE, Physical Self-PI was associated with significantly slower rates of decline on MMSE, Physical Self-Maintenance Scale (PSMS), IADL, CDR-SBMaintenance Scale (PSMS), IADL, CDR-SB

• Results suggest that PI (cumulative drug exposure) slowed ADAS-Cog decline for Results suggest that PI (cumulative drug exposure) slowed ADAS-Cog decline for 3.3 years, with effect then lost3.3 years, with effect then lost


• Persistent drug treatment had a positive impact on AD progression in terms of Persistent drug treatment had a positive impact on AD progression in terms of cognitive, functional, and global outcome measurescognitive, functional, and global outcome measures

• Positive treatment effects extended to those at more advanced stages of diseasePositive treatment effects extended to those at more advanced stages of disease


► Cholinesterase inhibitors have modest symptomatic Cholinesterase inhibitors have modest symptomatic benefits in cognition, function, and behavior in mild-benefits in cognition, function, and behavior in mild-moderate AD and remain the only proven therapy moderate AD and remain the only proven therapy for these disease stages after 20 years. They may for these disease stages after 20 years. They may be associated with increase risk of syncope and fallsbe associated with increase risk of syncope and falls

► Their benefits are also seen in more advanced Their benefits are also seen in more advanced stages, but are not evident in MCI though some MCI stages, but are not evident in MCI though some MCI subgroups may be more responsivesubgroups may be more responsive

► Duration of benefits may go beyond the 6 months Duration of benefits may go beyond the 6 months used in the pivotal trials but Level 1 evidence for used in the pivotal trials but Level 1 evidence for this is scarce and ethically difficult to obtain this is scarce and ethically difficult to obtain

► Cognitive benefits are likely selective to the Cognitive benefits are likely selective to the processes most affected by acetylcholineprocesses most affected by acetylcholine (attention/executive, initiation and social (attention/executive, initiation and social engagement)engagement)

Translating Advances in Translating Advances in Biomarker-based Detection Biomarker-based Detection

into Clinical Practiceinto Clinical Practice

Implications for Current Therapies and Implications for Current Therapies and BeyondBeyond

SERGE GAUTHIER, MDSERGE GAUTHIER, MDDirector of the Alzheimer’s Disease Research Unit Director of the Alzheimer’s Disease Research Unit

McGill Centre for Studies in Aging McGill Centre for Studies in Aging Professor of Neurology and Neurosurgery, Psychiatry and Professor of Neurology and Neurosurgery, Psychiatry and

Medicine Medicine McGill University McGill University

Montreal, Quebec CanadaMontreal, Quebec Canada



OutlineOutline

► Case histories of persons at riskCase histories of persons at risk

► Case history of person with MCICase history of person with MCI

► Case histories of persons with ADCase histories of persons with AD

► ConclusionsConclusions

► Age: 40Age: 40► Cognitive symptoms: noneCognitive symptoms: none► Family history of AD: mother d55, Family history of AD: mother d55,

sister d53sister d53► Biomarkers: genetic (PS, APP); Biomarkers: genetic (PS, APP);

neuro-imaging (FDG-PET)neuro-imaging (FDG-PET)► Current Rx: enroll in DIANCurrent Rx: enroll in DIAN► Future Rx: anti-amyloid Future Rx: anti-amyloid

Young Person with Young Person with Strong Family History of ADStrong Family History of AD

FDG-PET IN ADFDG-PET IN AD

► Age: 50Age: 50► Cognitive symptoms: noneCognitive symptoms: none► Family history of AD: mother d85Family history of AD: mother d85► Biomarkers: genetic (apoE); Biomarkers: genetic (apoE);

neuro-imaging (MRI)neuro-imaging (MRI)► Current Rx: assess risk using mid-Current Rx: assess risk using mid-

life risk score life risk score ► Future Rx: enhance protective Future Rx: enhance protective

factors factors

Middle-age Person with Concern About Middle-age Person with Concern About Family History of ADFamily History of AD

CAIDE Dementia Risk ScoreCAIDE Dementia Risk Score

Age < 47 years

47-53 years>53 years

034

Formal education ≥10 years7-9 years0-6 years

023

Sex WomenMen

01

Systolic BP 140 mm Hg> 140 mm Hg

02

BMI 30 kg/m2> 30 kg/m2

02

Total cholesterol 6.5 mmol/l> 6.5 mmol/l

02

Physical activity ActiveInactive

01

Kivipelto et al., Kivipelto et al., Lancet Neurol Lancet Neurol 20062006

CAIDE Dementia Risk ScoreCAIDE Dementia Risk Score

SCORESCORE All /Demented, nAll /Demented, n % Risk (95% CI)% Risk (95% CI)

0-5 401 / 4401 / 4 1.0 (0.0-2.0)1.0 (0.0-2.0)

6-7 270 / 5270 / 5 1.9 (0.2-3.5)1.9 (0.2-3.5)

8-9 312 / 13312 / 13 4.2 (1.9-6.4)4.2 (1.9-6.4)

10-11 245 / 18245 / 18 7.4 (4.1-10.6)7.4 (4.1-10.6)

12-15 122 / 20122 / 20 16.4 (9.7-23.1)16.4 (9.7-23.1)

The overall occurrence of dementia 4.4%The overall occurrence of dementia 4.4%

Kivipelto et al., Lancet Neurology 2006Kivipelto et al., Lancet Neurology 2006

Probability of Dementia in Late-life According to Probability of Dementia in Late-life According to the Risk Score Category in Middle Agethe Risk Score Category in Middle Age

► Age: 76Age: 76► Cognitive symptoms: noneCognitive symptoms: none► Family history of AD: mother d93Family history of AD: mother d93► Biomarkers: genetic (apoE); Biomarkers: genetic (apoE);

neuro-imaging (MRI)neuro-imaging (MRI)► Current Rx: assess risk using late-Current Rx: assess risk using late-

life dementia risk index life dementia risk index ► Future Rx: enhance protective Future Rx: enhance protective

factors, reduce risk factors factors, reduce risk factors

Older Person with Concern About Older Person with Concern About Family History of ADFamily History of AD

The Late-Life Dementia Risk IndexThe Late-Life Dementia Risk Index

Barnes DE, et al. Barnes DE, et al. Neurology 2009;73;173-179;

OutlineOutline





► Age: 70Age: 70► Cognitive symptoms: mildCognitive symptoms: mild► Family history of AD: mother d87Family history of AD: mother d87► Biomarkers: genetic (apoE); Biomarkers: genetic (apoE);

CSF (ß42, total tau, phospho tau); CSF (ß42, total tau, phospho tau); neuro-imaging (MRI, FDG-PET)neuro-imaging (MRI, FDG-PET)

► Current Rx: follow over timeCurrent Rx: follow over time► Future Rx: anti-amyloid Future Rx: anti-amyloid

Older Person with MCIOlder Person with MCI

Dubois et al., Lancet Neurology 2007Dubois et al., Lancet Neurology 2007

Slope Analyses According to Slope Analyses According to AD CSF Profile at BaselineAD CSF Profile at Baseline

Visser PJ, et al. Visser PJ, et al. Lancet Neurol 2009; 8: 619–27Lancet Neurol 2009; 8: 619–27

OutlineOutline





► 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 Mild ADOlder Person with Mild AD

► Age: 75Age: 75► Cognitive symptoms: early Cognitive symptoms: early

dementiadementia► Family history of AD: noneFamily history of AD: none► Biomarkers: Neuro-imagimg Biomarkers: Neuro-imagimg

(MRI); CSF low ß42, very high (MRI); CSF low ß42, very high phospho tauphospho tau

► Current Rx: ChEICurrent Rx: ChEI► Future Rx: anti-amyloid and anti-Future Rx: anti-amyloid and anti-

tautau

Older Person with AD and Older Person with AD and High Tau Levels in CSFHigh Tau Levels in CSF

Distribution of CSF total tau, phosphorylated tau Distribution of CSF total tau, phosphorylated tau (P-tau), and ß-amyloid 1-42 ((P-tau), and ß-amyloid 1-42 (AAßß4242) levels) levels

Wallin AK, et al. Wallin AK, et al. Neurology 2010;74;1531-1537

Five-Year Survival in the Three ClustersFive-Year Survival in the Three Clusters

Wallin AK, et al. Wallin AK, et al. Neurology 2010;74;1531-1537

Pathology by Clinical Status Pathology by Clinical Status Proximate to DeathProximate to Death

Schneider JA, et al. Schneider JA, et al. Ann Neurol 2009;66:200–208

OutlineOutline





Biomarkers for the Diagnosis and Biomarkers for the Diagnosis and Management of ADManagement of AD

► Assessment of risk is possible using mid-Assessment of risk is possible using mid-life and late-life risk profiles, including life and late-life risk profiles, including apoE genotypingapoE genotyping

► Earlier diagnosis of AD is now possible Earlier diagnosis of AD is now possible using neuro-imaging and CSF analysisusing neuro-imaging and CSF analysis

► Better selection of disease-modifying Better selection of disease-modifying treatments may be possible using CSF treatments may be possible using CSF analysis and neuro-imaging, knowing the analysis and neuro-imaging, knowing the relative weight of each pathological relative weight of each pathological componentcomponent

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