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, PICALM, 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 of 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

Individuals 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)

Stan

dard

ized

Dif

fere

nce

Estimated Yr From Expected Symptom Onset

-2

-1

0

1

2

-35 -30 -25 -20 -15 -10 -5 0 5 10 15

Aβ deposition

CSF tau

CDR - SOB

CSF Aβ42

HippocampalVolumeGlucose 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 Injury 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/behavioral 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 Impairment

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 objective 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 Impairment only?

Single nonmemory Cognitive domain

Impaired?

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/Undetermined/Untested

Conflicting/Undetermined/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 Interventions for aMCI Donepezil Rivastigmine Galantamine

Long-term ‘conversion’ trials

ADCS

(3 years) InDDEx

(3-4 years) Gal 11 and Gal 18

(2 years)

‘Symptomatic’ trials

401 (24 weeks)

412 (52 weeks) - -

Co-Primary outcomes 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 Insidious 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, other dementias

•25

New Research Criteria for AD Diagnosis Biomarker

Probability of AD Aβ (PET or CSF) Neuronal Injury

(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 Inhibitors (donepezil/Aricept; rivastigmine/Exelon; galantamine/Reminyl) NMDA Receptor Antagonist

(memantine/Namenda) Anti-oxidant Vitamins? (Vitamin E 1000

IU; Vitamin C 1000 mg) Medications for Behavioral and

Psychological Symptoms of Dementia

AD Treatments Treatment Indication 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 one 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

It is global

It is is based upon diverse mechanisms

It is shifting to earlier disease stages

It 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 Intranasal 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 or Treatment

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

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

Increasing 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;

Immunotherapy 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 IV Ig

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

Active monoclonal antibody vaccines (ACC-001, CAD-106, V950)

Anti-fibril, anti-aggregation, altered cleavage (Curcumin, Scyllo-Inositol, 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

It 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 Inhibitors Immunotherapies

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