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Alzheimer’s Disease ResearchWhere We Have Been and Where We Are Going

Heather M. Snyder, Ph.D.

Director, Medical & Scientific Relations

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Overview

• Role of the Alzheimer’s Association in

advancing science

• History of Alzheimer’s disease

• Modernization of Alzheimer’s disease

diagnosis and advances in early detection

• Current therapies and advances in clinical

studies

• Next generation of clinical trials – possible

prevention of Alzheimer’s

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CONNECTOR, CONVENER,

FUNDER, & GLOBAL LEADER

Amyloid Imaging

Taskforce (AIT)

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Convening & Connecting

Scientists Around the Globe

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G8 Dementia Summit Adopted Goal:

To Prevent or Effectively Treat

Alzheimer’s by 2025

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Types of Dementia

Alzheimer’s disease

Vascular Dementia

Frontotemporal

dementia

Lewy Body

Dementia

Dementia is the loss of

memory due to

changes in the brain

Alzheimer’s is the most

common form

Definite diagnosis used

to require autopsy

Many mixed cases

Many memory

disorders are

reversible and not truly

dementia

Parkinson’s

disease

dementia

Mixed

dementiaOther

dementia

DEMENTIA

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History of Alzheimer’s Disease

• November 1906: Alois Alzheimer presented first case in Germany

• 51-year-old Auguste D. had profound memory loss, confusion, language difficulty, unfounded suspicions about husband and hospital staff

• Her young age made Alzheimer think Auguste had a rare disease associated with middle age

tangles

plaques

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oMore than 5 million people living with Alzheimer’s

o Including 200,000 <65 with younger-onset.

o 1 in 9 over age 65 and 1 in 3 over age 85

oOver 15 million people providing care / support for

someone with Alzheimer’s or related dementia

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Breast Cancer

-2% Prostate

Cancer-8%

Heart Disease-16%

Stroke-23%

HIV

-42%

Alzheimer's

Disease 68%

Based on preliminary 2010

Landscape of Alzheimer’s

Hope In Research

• 6th leading cause of

death across all ages

• 5th leading cause of

death for those aged

65 and older

• Only cause of death

among the top 10 in

America without a way

to prevent, cure or

even slow its

progression.

• Change in the

Number of

Deaths: 68%

• Between 2000

and 2010

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National Plan to Address

Alzheimer’s disease• Goal: “Prevent and

Effectively Treat Alzheimer’s

by 2025”

• Key strategies:

– Increase clinical studies

enrollment

– Expand scale and scope of

research

– Accelerate drug development

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Largest Non Profit Funder of

Alzheimer's Research in the World

• Over $335 million to nearly 2,250

scientific investigations since 1982

• Funded nearly $14 million to 88

scientific investigations in 2014

• Currently, nearly 350 on-going

research projects in 20 countries

• Community of >6,000 active peer-

review volunteer scientists from over

60 countries

• Fund broad spectrum of research

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Family History and Genetic

Susceptibility

• First degree family member (parent or

sibling) – increased risk

• Genetics: Deterministic and Risk

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• Cardiovascular Risk Factors:

• Diabetes

• Mid-Life Obesity

• Mid-Life Hypertension

• Cholesterol

Factors Possibly Related to Alzheimer’s

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Factors Possibly Related to Alzheimer’s

• Lifestyle Risk Factors:

• Current Smoking

• Physical Activity

• Diet

• Cognitive training/ lifelong learning

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Modernizing the Diagnosis of

Alzheimer’s Based on a Continuum

2011

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Normal Alzheimer’s disease

Continuum of Alzheimer’s Disease

Adapted from Sperling et al. 2011

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What is a Biomarker?

• Biological marker to measure change

• Reliable predictor and indicator of disease

and disease progression

• Examples include:

– Glucose for insulin resistance and diabetes

• Hemoglobin A1C

– T cell count for HIV/AIDS

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Normal Pre-clinical MCI Alz dementia

Clear deficits in 2 or

more core cognitive

domains;

ADLs affected

Subjective problem

in memory or another

domain, informant

corroborated and

measurable on tests;

normal overall

cognition and ADLs

APOE

Protein or gene

“barcodes”

Family history

Tau/Abeta (CSF,

blood, eye)

MRI, CT

PET, fMRI

Modernizing the Diagnosis of

Alzheimer’s Based on a Continuum

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19Clark et al. (2011) JAMA 305(1).

RED = maximum uptake

VIOLET = minimum uptake

Amyloid PET Imaging

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Healthy

IndividualMild Cognitive

Impairment

Mild

Alzheimer’s

Severe

Alzheimer’s

JT Chien et al. Journal of Alzheimer’s Disease 2013

Alzheimer’s disease: Tau Imaging

80

min

ute

s1

00

min

ute

s

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CSF as a Potential Biomarker• On-going research to improve

diagnostic accuracy

• Potentially detects early biological changes

• Lumbar puncture (spinal tap)

• Identify & monitor the biochemical effect of a drug candidate in clinical trials

• Global Biomarkers Standardization Consortium (GBSC)

Spinal

columnImage from http://reidhosp.adam.com/content.as

px?productId=39&pid=1&gid=003768

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Alzheimer’s disease: Blood Test

• Active area of research

• State of Science meeting –

April 2013

• ISTAART PIA working on

standardization and developing

resources to accelerate

discovery

• No blood test available for use

Mapstone et al. 2014 Nature Medicine

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Pathway to Your Medicine Cabinet

PhRMA 2012 Annual Report

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Current Alzheimer’s Therapies

Cholinesterase Inhibitors

tacrine (Cognex)

donepezil (Aricept)

rivastigmine (Exelon)

galantamine (Razadyne)

Glutamate Moderators

Memantine (Namenda)

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Phase I-II Clinical Trials for Alzheimer’s

Target Diverse Biological Mechanisms

(October 21, 2014)

Tau

NGF

Insulin

Monoamine

oxidase

AADvac1

ABT-957

Allopregnenalone

Anatabloc

Atomoxetine

AZD3293

BAN2401

Bexarotene

BIIB037

Blood plasma

Bryostatin 1

CERE-110

CPC-201

Crenezumab(MABT5102A)

DAIO-B

DBS-f (Deep brain stimulation of the fornix)

D-ribose

Encenicline

Exendin-4

Genistein

Insulin

IVIg

JNJ-54861911

KHK6640

Ladostigil

Levetiracetam

Lipoic Acid, Omega-3

Liraglutide

LY3002813

Magnesium L-threonate

MEDI1814

Mesenchymal stem cells

Metformin

MK-7622

NIC5-15

Nicotinamide

n-PUFA

RO4602522

RPh201

R-Pramipexole

SAR228810

Sargramostim

Simvastatin, L-arginine, tetrahydrobiopterin

Sodium oligo-mannurarate

T-817MA

TPI-287

tDCS (Transcranial direct current stimulation)

TMS (Transcranial magnetic stimulation)

Therapeutic Agents in Phase III Clinical Trials• MK-8931

– Merck

– BACE inhibitor

• Nivaldipine– St. James Hospital

– Calcium Channel Blocker

• Pioglitazone– Takeda

– PPAR-gamma activator

• Solanezumab– Eli Lilly

– Humanized antibody - beta-amyloid

• TRx0237 – TauRX

– Tau aggregation inhibitor

(Jan 1, 2014)

• Encenicline– Forum Pharmaceuticals

– Nicotinic receptor agonist

• Gantenerumab– Hoffman-La Roche

– Monoclonal antibody - beta amyloid

– Part of DIAN-TU

• Gantenerumab + Solanezumab– Eli Lilly, Hoffman-La Roche

• Insulin– Alzheimer’s Disease Cooperative Study

• IVIg and Albumin– Grifols

– Intravenous immunoglobulin

• LU AE58054– H. Lundbeck

– 5HT6 receptor antagonist• Masitinib

– AB Science

– Inhibitor of c-KIT cell signaling

(October 21, 2014)

INTENSIVE INTERVENTION

6 9 12 15 18 21 24

COGNITIVE TRAINING:9 group sessions

Independent training

MONITORING AND MANAGEMENT OF

METABOLIC AND VASCULAR RISK FACTORSNurse: Visit every 3 months, Physician: 3 additional visits

FINGER Study: Receipe of Lifestyle

Interventions

COGNITIVE TRAINING:2 group sessios

Independent training

Kivipelto et al., Alzheimer & Dementia 2013

• Gold standard of testing any type of therapy or

intervention – Randomized Control Trial (RCT)

• Large, rigorous study

• First solid evidence that recipe of lifestyle

interventions reduces cognitive decline

• Needs to be replicated in more diverse

populations

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Preclinical

MCI

Dementia

2º Prevention

3º Prevention

END STAGE

Degrees of Prevention

1º Prevention

[Accumulation Pathology]

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Collaboration for Alzheimer’s

Prevention

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Accelerating Medicines

Partnership (AMP)

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DIAN-TUADAD Trial

– Familial Alzheimer’s

– Three simultaneous trials to test

potential therapies

– Started enrollment in Dec 2012

and study April 2013

– Alzheimer’s Association provided

$4.2 million to support study

infrastructure

– Received up to $6 million from

NIH in fall 2013

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Anti-Amyloid in Asymptomatic

Alzheimer’s (A4) Study

• Clinically normal, Age 65+

• Positive Amyloid PET

• Testing Solanezumab (Lilly)

• Lead Investigators: Dr. Reisa

Sperling and Dr. Paul Aisen

• LEARN leverages work of A4

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LEARN

• Longitudinal Evaluation of Amyloid

Risk and Neurodegeneration

(LEARN)

• Natural history study of 400 people

with low/intermediate levels of

amyloid

• Leveraging the A4 trial

• Focus on diverse populations

• Largest award ever given by

Alzheimer’s Association

• First funded tau imaging study

JT Chien et al. Journal of Alz Dis 2013

TOMMORROW Trial

- Takeda-Zinfandel Alliance

- 5,800 volunteers enrolled

End-point is conversion to Mild

Cognitive Impairment

- Algorithm for enrollment:

APOE status

TOMM40

- Low dose Pioglitazone (Actos)

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Alzheimer’s Prevention Initiative

ADAD Trial– Largest single kindred with familial

Alzheimer’s

– In Colombia

– Crenezumab (Genentech)

– Received $16 million from NIH

ApoE Trial– Risk gene for Alzheimer’s

– 1,300 adults, age 60-75 with two copies APOE4

– Two drugs:

• CAD106 – active immunotherapy (Novartis)

• Beta secretase inhibitor – just entering phase 1 now (Novartis)

– Received $33.2 million from NIH

– Expected to launch 2015

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FDA Fellowship in the Division of

Neurology Products• New liaison position approved by FDA, sponsored

through the Reagan-Udall Foundation

• Fellow will receive input from various stakeholders in

Alzheimer’s drug development and share that input

with the FDA.

• Liaison for stakeholders who are developing or

conducting clinical trials by giving them greater insight

into FDA strategic thinking and current guidelines

• Launch Spring/ Summer 2015

• First of its kind disease-specific

fellowship

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Alzheimer’s in the News:

Vitamin D & Alzheimer’s• Lower levels of Vitamin D

associated with increased

dementia

• Shows correlation between

Vitamin D and dementia,

not causation

• Next step is clinical trial to

see if changing Vitamin D

levels is possible treatment

Littlejohns TJ et al. Neurology 201438

Alzheimer’s in the News:

“Recipe” Intervention & Alzheimer’s?

• “Recipe” of different factors linked to

improvements in cognition for 10

individuals (Bredesen et al, 2014)

• Small trial (n=10), no biomarker data

• Difficult to conclude anything from this

study– needs replication in larger studies

Bredesen et al. 2014

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Alzheimer’s in the News:

Alzheimer’s in a Dish?• Boston research team engineered

human brain cells that develop

plaques and tangles in a test tube

• Potentially exciting step, but test

tube is not a brain and there are

fundamental differences

• May allow researchers to test

potential drugs in early pre-clinical

models more accurately than before

• Unclear whether this tool will be

more predictive than current models

Kim et al. Nature. 201440

www.alz.org/research

Alzheimer’s Association Research Website

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In Summary …

• Alzheimer’s disease a continuum, opens

door for possible prevention

• Significant advances have been made in

research – understanding the disease,

therapy development and early detection

• Advocacy and awareness key factors to

advancing research

• Alzheimer’s Association is a global leader

in research – because of each of you!

• Research offers us hope in the future

alz.org