Alzheimers Disease Rachelle S. Doody, MD, PhD Effie Marie Cain - - PowerPoint PPT Presentation

Alzheimer’s Disease

Rachelle S. Doody, MD, PhD

Effie Marie Cain Chair in Alzheimer’s Disease Research Director Alzheimer’s Disease and Memory Disorders Center Baylor College of Medicine

Key Questions

What causes AD? How do you know when someone has AD? When do you have to intervene in order to

prevent or effectively treat AD?

What are current treatments? What is the status of treatments under

development?

Classic Elements of Alzheimer Neuropathology

Neuritic (Senile) Plaques Central element: β-amyloid Neurofibrillary Central element: hyperphosphorylated tau

From: http:/ / www.neuropat.dote.hu/ alzheim.htm

What causes AD?

 Plaques and tangles?  Loss of reserve?  Biochemistry of aging?  “Weak” genetic

background?

 Bad habits?  Chronic inflammation?  All of the above?

Doody Alzheimer’s Dementia Ed Doody RS Carma Publishing, 2008

Risk factors for AD

Age, menopause Genetics: Apo E 4, TOMM 40, CR1, CLU, PI CALM,

SORL1 , TREM 2 Genetic risk is probably cumulative

Elevated glucose or diabetes Elevated cholesterol Elevated homocysteine Major head injury with LOC Chronic inflammation?

What do we know about preventing AD?

Large (N> 2K) AD Prevention Trials

Study Population Treatment Study Design Results GuidAge SML Ginkgo Biloba Randomized, PC, 5 years incidence Primary NS Those on >4 years 50% decrease GEMS ≥ Age 75 Normal or MCI Ginkgo Biloba Randomized, PC, 5 years incidence NS WHIMS PM Women ≥ 65 Estrogen ± Progesterone Randomized, PC, 3 arm, 5 year Incidence MCI or dementia and cognitive change Worse in treated

• groups. Early

termination ADAPT ≥Age 70 +FHx in first degree relative NSAIDs, Naproxen and Celecoxib Randomized, PC, 3 arm cognitive change Worse in Naproxen

• group. Early

termination (1.5/7 years)

Possible Preventive Measures

Weight control/ Dietary factors Exercise (mental & physical) Normalizing

• Blood pressure
• Blood sugar
• Cholesterol
• Vitamin B12 and Homocysteine levels
• Preventing immune over-activation?

Planned AD Prevention Trials

Study Population Treatment Study Design Alz Prevention Initiative FAD esp Colombian Crenezumab Delay AAO, reduce incidence of AD DIAN FAD Solanezumab, Gantanerubab, Lilly BACE inhibitor Delay AAO, reduce cognitive loss ADCS A4 Trial NC with Aβ, stratified by APO E Solanezumab Prevent worsening

• f cognition on

composite Sargramostim Prevention of AD MCI Sargramostim (GM CSF) Prevent progression to AD TOMM 40 /Pioglitazone NC with high and low risk Pioglitazone (low dose) Qualify biomarker

• algorithm. Prevent

MCI due to AD. ADCS Exercise Study MCI Structured exercise program Prevent progression to AD

Speculation Regarding Prevention of AD

Public health measures may reduce the

number of cases but will not prevent disease

I ndividuals with pre-symptomatic

disease will already be biologically conditioned to respond differently to different treatments (endophenotype theory)

How do we know when someone has AD?

Markers of Asymptomatic AD?

Strong

• AD genetic mutations
• Multiple biological markers of AD neuropathology
• Multiple neuroimaging markers C/W AD

Variable

• Biomarkers of AD neurodegeneration
• Neuroimaging (metabolic, functional, structural)

Weak

• One or more AD risk factors (genetic and non-

genetic)

Standardized Difference Estimated Yr From Expected Symptom Onset

• 2
• 1

1 2

• 35
• 30
• 25
• 20
• 15
• 10
• 5

5 10 15

Aβ deposition CSF tau CDR - SOB CSF Aβ42 Hippocampal Volume Glucose Metabolism

Clinical, Cognitive Structural, Metabolic, and Biochemical Changes as a Function of Estimated Years from Expected Symptom Onset

Modified from Bateman et al NEJM 2012;367(9):795-804

Role of Biomarkers in Diagnosis

• For deposition of beta amyloid (Aβ)
• Low CSF Aβ1-42
• Positive PET amyloid imaging
• For downstream neuronal degeneration and

injury

• Elevated CSF tau (total and phosphorylated)
• Decreased FDG uptake on PET in

temporoparietal cortex and post. cingulate

• Disproportionate atrophy on structural MR

images in medial, basal, lateral temporal lobe, and medial parietal cortex

• 14

Amyloid imaging slides

Negative Scan Positive Scan

New Research Criteria for Preclinical AD

Stage Description Aβ PET or CSF Neuronal I njury Tau, FDG PET sMRI Subtle Cognitive Change

1 Asx cerebral amyloid Positive Negative Negative 2 1 + downstream neurodegeneration Positive Positive Negative 3 2 + subtle cognitive/behavior al decline Positive Positive Positive

Sperling etal Alz & Dem 2011;7:280-292

Developing Treatments for Early Preclinical AD

Amyloid accumulation in the brain is

not the same thing as AD

Have to use biomarkers to select

patients and as the outcome since there are no clinical symptoms

Very high screen failure rates ie >

80%

Risk factors are uncontrolled

Early Symptomatic AD: Mild Cognitive I mpairment

A set of mild cognitive disorders Amnestic MCI likely a transitional state

between normal and clinical AD

Non-amnestic MCI may also evolve to

AD

“Diagnosing” MCI takes skill and

• bjective test measures

MCI Subtypes

Cognitive Complaint Not normal for age Not demented Cognitive decline Essentially normal functional activities MCI Memory impaired? Amnestic MCI Non-Amnestic MCI Memory I mpairment only? Single nonmemory Cognitive domain I mpaired? Amnestic MCI Single Domain Amnestic MCI Multiple Domain Non-Amnestic MCI Multiple Domain Non-Amnestic MCI Single Domain Yes Yes Yes No No No

Peterson RC. Continuum. 2004;10:9-28.

How is aMCI determined?

Patient and/ or informant notices a

change

Demonstrable problem with delayed

verbal recall on testing (-1.5 SD)

Originally, no second domain Normal activities of daily living

Petersen etal Arch Neurol 1999; Petersen and Doody et al Arch Neurol 2001, Rountree et al Dementia 2007

New Research Criteria for MCI due to AD

Diagnosis/ Liklihood Biomarker Probability of AD Aβ (PET or CSF) Neuronal injury (tau, FDG, sMRI )

MCI core Uninformative Conflicting/Undete rmined/Untested Conflicting/Undete rmined/Untested MCI due to AD Intermediate Intermediate Positive Untested Untested Positive MCI due to AD High Highest Positive Positive MCI due to AD Unlikely Lowest Negative Negative

Albert etal Alz & Dem 2011;7:270-279

Neuropathology is not as widespread Compensatory mechanisms, including

cholinergic sprouting, may play a role

Data show that response to AD

therapies and probably safety profiles differ and did not support FDA approval for routine treatment of MCI with AD drugs

MCI is Different From Early AD

Pharmacologic I nterventions for aMCI

Donepezil Rivastigmine Galantamine

Long-term ‘conversion’ trials ADCS (3 years) I nDDEx (3-4 years) Gal 11 and Gal 18 (2 years) ‘Symptomatic’ trials 401 (24 weeks) 412 (52 weeks)

• Co-Primary
• utcomes

Negative Negative Negative Other Significant short-term delay in conversion in ADCS + ve outcomes on modified ADAS-cog in 401 & 412

• Salloway S, et al. Neurology. 2004;63:651–657 Petersen RC, et al. N Engl J Med. 2005;352:2379-88

Feldman HH, et al. Lancet Neurol. 2007;6:501-12; Winblad etal Neurology 2008;70:202402035 Doody R, et al.Neurology 2009;72:1555-61

Developing Therapies for MCI

No clear regulatory pathway and no

FDA approved drugs

High screen failure rates ,ie > 70% No strong biomarkers of progression or

surrogate markers of treatment effect

Cognitive measures more challenging

than for AD (so effect sizes small)

Large, long studies required

Former AD Research Criteria

• Core clinical criteria for Dementia and AD
• I nsidious onset and clear progression

– Amnestic: most common; should include impairments

in learning and recall

– Nonamnestic » Language—eg, word-finding difficulties » Visuospatial—eg, object agnosia, impaired face

recognition

» Executive function—eg, impaired reasoning,

judgment

• Exclusions—eg, significant vascular disease,
• ther dementias
• 25

New Research Criteria for AD

Diagnosis Biomarker Probability of AD Aβ (PET or CSF) Neuronal I njury (tau, FDG-PET, sMRI

Probale AD Dementia Clinical Uninformative Unavail, Confl, Indet Unavail, Confl, Indet Pathophysiol Evid Intermediate Unavail, Indet. Positive Intermediate Positive Unavail, Indet. High Positive Positive Possible AD (Atypical Clinical) Clinical Uninformative Unavail, Confl, Indet Unavail, Confl, Indet Pathophysiol Evid High, could be secondary Positive Positive Dementia—Unlikely AD Lowest Negative Negative

McKhann etal Alz & Dem 2011;7:263-269

Current Approved AD Therapies

Cholinesterase I nhibitors

(donepezil/ Aricept; rivastigmine/ Exelon; galantamine/ Reminyl)

NMDA Receptor Antagonist

(memantine/ Namenda)

Anti-oxidant Vitamins? (Vitamin E 1000

I U; Vitamin C 1000 mg)

Medications for Behavioral and

Psychological Symptoms of Dementia

AD Treatments

Treatment I ndication Evidence Side Effects Other

Donepezil Mild-Moderate, Severe Multiple R DB PC trials 3-12 months. Low incidence GI esp diarrhea and nausea ODT and Generic available Rivastigmine Mild-Moderate Multiple R DB PC trials 6 months. Low to moderate GI incl anorexia, diarrhea and vomiting Start doses not

• effective. Patch

available. Galantamine Mild-Moderate Multiple R DB PC trials 6 months. Low incidence GI esp diarrhea and nausea ER available for QD. Start dose not

• effective. Generic

Memantine Moderate-Severe Multiple R DB PC trials 6 months. Few AE’s Four step titration to this dose Vitamin E One moderate to severe trial Few AE’s Controversy re: Survival data

Molecular Targets for Current AD Therapies

How Were Current Treatments Developed?

Three to six month randomized,

Double-Blind,Placebo-C ontrolled trials

Mild-moderate or Moderate-severe AD

populations

At least two clinical outcome

measures, usually cognition and global functioning

How Effective are Current Treatments?

Results of pivotal trials confirmed in

meta-analyses and effectiveness studies

Little information regarding

longitudinal benefit, especially beyond

• ne year

Our studies suggest that persistent

treatment changes the natural history

Doody etal AD Res and Therapy, 2010 Rountree etal AD Res and Therapy 2010, Atri et al Neurobiol Aging in press

Medical Foods

Must meet a distinctive nutritional

need of a specific population

Prescribed by an MD

• AxonaTM (Ketasyn), approved
• Souvenaid, under development

Not a nutraceutical (dietary

supplement)

Update on Drug Development

I t is global I t is is based upon diverse mechanisms I t is shifting to earlier disease stages I t is hampered by patent life and cost

issues

Strategies for Antidementia Drugs

Drugs/ nutraceuticals based upon risk Neurotransmitter-based therapies Metabolic/ Neuroprotective drugs Amyloid modulating drugs Tau modulating drugs APO E modifying drugs  Glial modulating drugs

AD Trials Based on Risk Factors

Nonsteroidal anti-inflammatory drugs do

not slow progression

Estrogen may increase the risk after age

65 and does not slow progression

Vitamins to lower blood homocysteine

did not slow progression

Statins did not slow progression DHA did not slow progression

Lesson Learned From Risk Factor Modification Studies

There may be endophenotypes of AD;

may respond to different treatments

Controlling risk factors after clinical

disease is already symptomatic may not slow the progression

Neurotransmitter-based therapies under development for AD

Acetylcholine/ Cholinergic: ST 101, AF

267B, MK 7622, AZD 3480, MEM 3454, EVP-6124, Posiphen, Huperzine

Serotonin: 5 HT4 partial agonists, 5 HT1A

agonists/ antagonists, 5HT6 antagonists

Norepinephrine/Dopamine: MAO A and MAO B

inhibitors

GABA: GABAB antagonists Glutamate: AMPA potentiators Glycine: partial agonists

Antioxidants (Vit E, Vit C, alpha lipoic

acid, CoQ10,)

Phosphodiesterase inhibitors PPARγ Agonists and I ntranasal insulin Sir1 activators or sirtuins eg Resveratrol Growth factors (BDNF, NGF) Dimebon

Metabolic/ Mitochondrial/ Neurotrophic Targets for Alzheimer’s Disease

Senile Plaque Formation

Secretion Aggregation Fibrillogenesis Microglial cell Reactive astrocyte Neural cell

Courtesy of Steven Arnold, MD.

Anti-inflammatories Anti-amyloid drugs

Anti-amyloid Strategies as Prevention

• r Treatment

β-secretase inhibitors (or antibodies) γ-secretase inhibitors Anti-aggregants or chelators I mmunization

α-secretase N β-amyloid C β-secretase γ-secretase

Toxicity of Amyloid

Scientists debate the “species” of

amyloid responsible for damage and for symptoms

I ncreasing evidence that abnormally

folded proteins (including A beta) act as “corruptive protein templates”

Jucker etal Ann Neurol 2011; 70:532-540 Stohr etal Proc Natl Acad Sci 2012;

I mmunotherapy with AN1792 Reduces Amyloid Plaques in 18-mo Old Transgenic Mice

Schenk D, et al. Nature 1999;400:173

a b 200 µm

Human study halted because of subacute meningoencephalitis Gilman etal Neurology 2005;64:1553-1562; Orgogozo et al Neurology 2003;61:46-54

Anti-amyloid strategies

Passive Antibodies and I V I g

(Bapineuzumab,Solanezumab, Crenezumab, Gantanerumab, PF 04360365, SAR228810)

Active monoclonal antibody vaccines

(ACC-001, CAD-106, V950)

Anti-fibril, anti-aggregation, altered

cleavage (Curcumin, Scyllo-I nositol, PBT2,

ST-101)

Gamma/ Beta secretase inhibitors

(Semagacestat, Avagacestat, MK 8931, LY 288671)

Recent Antibody Studies

Bapineuzumab

 Two large negative Phase

3 studies with > 1000 each

 No clinical benefits in any

group or subgroup examined

 Lowered P-tau

Solaneuzumab

 Two large negative Phase

3 studies with > 1000 each

 Benefits on cognition

(esp. mild) and ADL (combined)

 Lowered free Aβ40 in

CSF, large increases Aβ40 and 42 in plasma

H&E PHFtau PHFtau

Neurofibrillary Tangle Formation

Microtubule Abnormal phosphorylation Overactive kinase(s) Hypoactive phosphatase(s) Senile plaque Dendrites Neurofibrillary tangle Neuron death Axon Neuropil threads Tau PHFs PHFs Courtesy of Steven Arnold, MD. W/modifications

Gsk inhibitors? /Taxols?

Spread of Tangles

Hyperphosphorylated tau is relased by

neurons and taken up trans- synaptically by adjacent cells

I t triggers tangle formation in nearby

neurons

Liu etal PLoS One 2012;7(2):e3130 De Calignon etal Neuron 2012:73(4):685-697

Anti-tangle approaches

Micro-tubule stabilizers, eg NAP (AL-

108) or Methylene blue (Rember)

Kinase inhibitors (GSK3α, GSK3β, CDK

5) eg AZD-1080, Li, Minocycline

Phosphodiesterase-4 I nhibitors I mmunotherapies

APO E enhancing strategies

Bexarotene, approved for cutaneous T-cell

lymphoma, rapidly reduces soluble amyloid in WT and TG mice

• Increases transcription of ApoE by binding of

Retinoid X Receptors (RXR) to nuclear receptors

• Rate of drug metabolism increases over time
• Pancreatitis, hypothyroidism, LFT’s, lipids, insulin

Cramer etal Science 2012;335:1503-1506

Glial Modulating Drugs

Affect glial cells directly (G CSF and GM

CSF, Nitro-flurbiprofen, ONO-2506, Tacrolimus)

RAGE receptor antagonists (TTP 488) TNF alpha antagonists (Enbrel) None proven effective

Conclusions

AD is treatable There are lots of strong theories that

have treatment implications for AD

Prevention and treatment trials should

proceed in parallel

Therapy will likely be tailored to stage

as well as personal genetic and risk profile

Challenges going forward

Defining populations Recruiting enough subjects Endpoints for preclinical studies Funding so many diverse approaches