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1
Alzheimer’s Disease ResearchWhere We Have Been and Where We Are Going
Heather M. Snyder, Ph.D.
Director, Medical & Scientific Relations
2
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
3
CONNECTOR, CONVENER,
FUNDER, & GLOBAL LEADER
Amyloid Imaging
Taskforce (AIT)
4
Convening & Connecting
Scientists Around the Globe
5
G8 Dementia Summit Adopted Goal:
To Prevent or Effectively Treat
Alzheimer’s by 2025
6
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
2
7
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
8
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
9
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
10
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
11
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
12
Family History and Genetic
Susceptibility
• First degree family member (parent or
sibling) – increased risk
• Genetics: Deterministic and Risk
3
13
• Cardiovascular Risk Factors:
• Diabetes
• Mid-Life Obesity
• Mid-Life Hypertension
• Cholesterol
Factors Possibly Related to Alzheimer’s
14
Factors Possibly Related to Alzheimer’s
• Lifestyle Risk Factors:
• Current Smoking
• Physical Activity
• Diet
• Cognitive training/ lifelong learning
15
Modernizing the Diagnosis of
Alzheimer’s Based on a Continuum
2011
16
Normal Alzheimer’s disease
Continuum of Alzheimer’s Disease
Adapted from Sperling et al. 2011
17
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
18
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
4
19Clark et al. (2011) JAMA 305(1).
RED = maximum uptake
VIOLET = minimum uptake
Amyloid PET Imaging
20
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
21
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
22
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
23
Pathway to Your Medicine Cabinet
PhRMA 2012 Annual Report
24
Current Alzheimer’s Therapies
Cholinesterase Inhibitors
tacrine (Cognex)
donepezil (Aricept)
rivastigmine (Exelon)
galantamine (Razadyne)
Glutamate Moderators
Memantine (Namenda)
5
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
28
Preclinical
MCI
Dementia
2º Prevention
3º Prevention
END STAGE
Degrees of Prevention
1º Prevention
[Accumulation Pathology]
29
Collaboration for Alzheimer’s
Prevention
30
Accelerating Medicines
Partnership (AMP)
6
31
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
32
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
33
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)
35
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
36
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
7
37
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
39
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
41
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