Can Alzheimer’s dementia be
prevented?
Prevention trials in preclinical AD
Reisa Sperling, M.D.
Center for Alzheimer Research and Treatment
Brigham and Women’s Hospital
Massachusetts General Hospital
Harvard Medical School
Disclosures and Funding
Consultant to:
Abbvie, Biogen, Bracket, Genentech, Lundbeck, Merck,
Otsuka,
Pfizer, Roche, Sanofi
Clinical Trial Site Investigator:
Eli Lilly, Avid, Janssen
Research funding from:
National Institute on Aging:
P01AG036694; R01AG027435; K24AG035007
U19AG010483; P50AG005134
Alzheimer’s Association
Fidelity Biosciences, GHR Foundation
Eli Lilly, Janssen
Accelerating Medicines Partnership FNIH
The Continuum of Alzheimer’s Disease
Cognitive
function Preclinical
Normal Aging
MCI
(Prodromal AD)
Dementia
Years
Background
• Converging evidence that the pathophysiological
process of AD begins years, perhaps more than a
decade, prior to the diagnosis of dementia
• This long preclinical phase of AD provides a
critical opportunity for potential intervention
with disease-modifying therapy
• Need to elucidate the link between the
pathophysiological process of AD and the
emergence of the clinical syndrome, and
determine the best predictors of clinical decline
Preclinical Alzheimer’s disease?
1/3 of CN with elevated Ab accumulation
CN
Ab-
CN
Ab+
AD
Ab+
Harvard Aging Brain Sudy
5
Sperling, Mormino, Johnson Neuron 2014
Preclinical Alzheimer’s Disease?
Prevalence
of PiB+ve PET
in HC
60
Prevalence (%)
50
Prevalence of plaques
in HC
40
(Davies, 1988, n=110)
(Braak, 1996, n=551)
(Sugihara, 1995, n=123)
30
~15 yrs
Prevalence
of AD
20
(Tobias, 2008)
10
0
30
+
40
50
60
70
80
90
100
Age (years)
Rowe C et al Neurobiology of Aging 2010
Evidence of Amyloid-Related Alterations in
Brain Function and Structure in “Normals”
PiB-PET
fMRI
FDG-PET
vMRI
Sperling RA Neuron 2009; Hedden J Neurosci 2009; Shelline Bio Psych 2010; Becker
JA Ann Neurol. 2011; Mormino Cerebral Cortex 2011; Drzezga Brain 2011; Vannini
Neurobiology of Aging 2011; Vannini Cerebral Cortex 2012; Kennedy NeuroImage 2012;
Chételat G Neurology. 2012; Dickerson BC Cereb Cortex. 2009; Dickerson BC, Neurology.
2011; Schott JM, Ann Neurol. 2010; Fjell A Cereb Cortex 2010; Sabuncu MR, Arch Neurol.
2011; Knopman D JAMA Neurology 2013; Andrews KA PLoS One 2013; Villeneuve S
Neurology 2014; Mosconi L Neurology 2014; Huijbers W J Neuroscience 2014;
Mormino JAMA Neurology 2014, Song J Neurosci 2015; Wang Neurology 2015
Bateman R et al NEJM 2012
Cognition in Amyloid Pos vs. Neg
in HC > 70 years old
WMS Immediate
WMS Delayed
Digit-Symbol
*
*
Sperling R et al Neurobiology of Aging 2013
Amyloid and memory decline in preclinical
and clinical Alzheimer’s disease
AIBL data
Lim Y et al Brain 2014
Amyloid-Related Cognitive Decline
Petersen R et al. JAMA Neurology 2015
Stage 0
No biomarker
abnormalities
Stage 1
Asymptomatic amyloidosis
-High PET amyloid retention
-Low CSF Ab1-42
Staging Framework for
Preclinical Alzheimer’s disease
NIA-AA Preclinical Workgroup
Stage 2
Amyloidosis + Neurodegeneration
-Neuronal dysfunction on FDG-PET/fMRI
-High CSF tau/p-tau
-Cortical thinning/Hippocampal atrophy on sMRI
Stage 3
Amyloidosis + Neurodegeneration + Subtle Cognitive Decline
-Evidence of subtle change from baseline level of cognition
-Poor performance on more challenging cognitive tests
-Does not yet meet criteria for MCI
SNAP
Suspected non-Alzheimer
pathology
- Neurodegeneration
markers without evident
amyloidosis
MCI Dementia
due to AD
Sperling, Mormino, Johnson Neuron 2014
Adapted from Sperling 2011, Jack 2012
Prediction of progression to symptomatic
AD by preclinical stages
2
4
6
8
10
12
14
Vos et al Lancet Neurology 2013
Relationship between markers of Amyloid b
deposition and markers of neurodegeneration
Harvard Aging Brain Study
FDG+
N=25
florbetapirN=49
FDGN=47
Stage 0
Stage 1
Stage 2
SNAP
Ab-/NDAb+/NDAb+/ND+
Ab-/ND+
Mormino E et al JAMA Neurology 2014
Subjective cognitive concerns associated with
advancing stages of preclinical AD
p = 0.0001
p = 0.025
p = 0.053
n= 85
n= 21
n= 28
n= 47
Amariglio et al. Neurology 2015
PET Amyloid and Tau Imaging
Ab
(PiB)
Tau
(T807)
CN
CN
AD Dementia
Sperling, Mormino, Johnson Neuron 2014
1
Higher Amyloid Burden Associated
with Higher Tau Burden in CN
0
-1
-2
T807
Inferior Temporal
InfTemp T807
(raw) SUVR
Harvard Aging Brain Study (n=97)
1.5
r=0.37
p=0.0002
1.4
1.3
PiBPiB+
1.2
1.1
1.0
1.0
1.2
1.4
1.6
Mean Cortical PiB DVR
Mean Cortical PIB (raw)
1.0
1.2age, gender,
1.3 education
1.4
1.50.34; p=0.0004
Adjusted1.1
model for
r=
Regional Tau Burden (T807)
by Preclinical AD Stages
1.30
A)
1.25
PHG T807 (SUVR)
EC T807 (SUVR)
1.25
1.20
1.15
1.10
1.05
1.00
1.30
B)
1.20
1.15
1.10
1.05
SNAP
N=19
Stage 0 Stage 1 Stage 2
N=31
N=13
N=17
1.00
C)
1.25
IT T807 (SUVR)
1.30
1.20
1.15
1.10
1.05
SNAP
N=19
Stage 0 Stage 1 Stage 2
N=31
N=13
N=17
1.00
SNAP
N=19
Stage 0 Stage 1 Stage 2
N=31
N=13
N=17
Mormino E et al JAMA Neurology 2016
.0
Memory Factor Score (adj)
Relationship of Tau and Memory
by Amyloid Status (HABS data)
1.1
PiB- Slope= -1.07
r = -0.09
p=0.35
PiB+ Slope= -3.42
r = -0.52
p = 0.0014
1.2
1.3
1.4
1.5
Interaction term
(PiB x T807)
p=0.089
Inferior Temporal T807 SUVR (adj)
InfTemp T807 (raw)
Sperling et al AAIC 2015
Hypothetical Interaction of Amyloid and Tau
in Preclinical AD
MTL Tau
Accumulation
Age
?
Amyloid-b
Accumulation
Synaptic Dysfunction
Glial Activation
Neuronal Loss
Neocortical Tau
Accumulation
Cognitive Decline
?
Age
Genetics
Sperling, Mormino, Johnson Neuron 2014
Why would we want to detect AD
a decade before dementia?
Treatment of Alzheimer’s Disease
Cognitive
Function
Symptomatic
Therapy
DiseaseModifying
Therapy
Natural
History of
Alzheimer’s
Disease
Years
Need for Earlier Intervention
• Ten Phase III trial failures at stage of AD
dementia over the past decade!
• Intervention prior to dementia (widespread
irreversible brain cell loss) may have better
chance of changing clinical course of the disease
• Delaying dementia by 5 years would reduce
projected Medicare costs by nearly 50%
• Think about what happens in cancer, stroke,
HIV, diabetes, osteoporosis …. if we wait to
treat until after symptoms appear?
Testing the Right Target and the Right Drug
at the Right Stage of Alzheimer’s Disease
Sperling RA, Jack CR, Aisen P Sci Transl Med 2011
“Secondary Prevention” AD Trials
• Dominantly Inherited Alzheimer Network (DIAN)
– PS-1, PS-2, APP – Solanezumab, Gantanerumab, BACEi
• Alzheimer Prevention Initiative (API)
– PS-1 Colombian kindred – Crenezumab
– APOE 4/4 – Active Vaccine, BACEi
– TOMMorrow Trial – TOMM40- Pioglitazone
• Anti-Amyloid Treatment in Asymptomatic AD (A4)
– A4 – Amyloid + normal 65-85yo– Solanezumab
– EARLY (“A5 )– Amyloid + normal 60-90yo– Janssen
BACE inhibitor
– A3 – Ante-Amyloid Prevention of Alzheimer’s disease
Anti-Amyloid Treatment in
Asymptomatic AD (A4) Study
• Secondary prevention trial in clinically normal older
individuals (age 65-85) who have evidence of
amyloid-b accumulation on screening PET imaging
• Phase 3 randomized, double-blind, placebocontrolled trial of solanezumab vs. placebo for 168w
• Trial N=1150 (N=575+ per treatment arm)
• Observational cohort of Ab negative “screen fails” –
LEARN study (funded by Alzheimer’s Association)
• Ethics component – Disclosure of amyloid status
The continuum of Alzheimer’s disease
A4
Cognition
“Normal” Aging
Preclinical
MCI
}
Dementia
Years
Preclinical Alzheimer Cognitive Composite (PACC)
Harvard Aging Brain Study Data
beta= -0.12±0.0;2 p<0.00001
Mormino et al Alzheimer’s & Dementia 2017
The A4 Study
Anti-Amyloid
Treatment
Amyloid Cognition
A4
Amyloid +
Treated
}
Amyloid +
Placebo
Higher levels of Tau in Ab+ Normals
Entorhinal Tau
A4 vs. HABS low PiB T=5.85; p<0.0001
Inferior Temporal Tau
A4 vs. HABS low PiB T=5.15; p<0.0001
Greater Amyloid Associated with Greater
Tau Burden (A4 Baseline Data)
FTP PET Vertex correlations
with cortical FBP SUVR (n=239)
Left Fusiform Peak
Greater Tau Burden Associated with Worse
Memory Performance (A4 Baseline Data)
FTP PET Vertex correlations
with FCSRT Free Recall
(n=239)
Left Entorhinal Peak
A4 Study - Anti-Amyloid Treatment in Asymptomatic AD
Abnormal
Amyloid-b accumulation (CSF/PET)
Synaptic dysfunction (FDG-PET/fMRI)
Neocortical Tau-mediated neuronal injury
Brain structure (volumetric MRI)
Cognition
Clinical function
Normal
Preclinical
MCI
Dementia
Clinical Disease Stage
Figure adapted from Jack et al. 2010, Sperling et al. 2011
EARLY (“A5”) = Janssen BACE inhibitor trial
Abnormal
Amyloid-b accumulation (CSF/PET)
Synaptic dysfunction (FDG-PET/fMRI)
Neocortical Tau-mediated neuronal injury
Brain structure (volumetric MRI)
Cognition
Clinical function
A5
Normal
Preclinical
MCI
Clinical Disease Stage
Dementia
Longitudinal Amyloid-b
Accumulation in Clinically Normal Elders
Harvard Aging Brain Study
Aaron Schultz and Keith Johnson HAI 2015
A3 = Ante-Amyloid prevention of Alzheimer’s disease
(Getting closer to primary prevention…)
Abnormal
Amyloid-b accumulation (CSF/PET)
Synaptic dysfunction (FDG-PET/fMRI)
Neocortical Tau-mediated neuronal injury
Brain structure (volumetric MRI)
Cognition
Clinical function
A3
Normal
Preclinical
MCI
Clinical Disease Stage
Dementia
Encouraging history from other fields
• Cholesterol Wars in Cardiology
• Good vs. bad cholesterol
• Secondary prevention trials in familial
hypercholesterolemia and in post-MI
• Reduction of cholesterol estimated to have reduced
cardiac morbidity and mortality by 28%
• Amyloid does not have to be “the” cause of AD,
merely “a” critical factor to impact the disease
• Ultimately will likely need combination therapy
(COMBAT trial) to fully prevent AD dementia
COMBAT = COMBination Amyloid and Tau
Abnormal
COMBAT
Amyloid-b accumulation (CSF/PET)
Synaptic dysfunction (FDG-PET/fMRI)
Neocortical Tau-mediated neuronal injury
Brain structure (volumetric MRI)
Cognition
Clinical function
Normal
Preclinical
MCI
Clinical Disease Stage
Dementia
Combination treatment for Alzheimer’s disease
MTL Tau
Accumulation
Age
Amyloid-b
Accumulation
Neocortical Tau
Accumulation
Synaptic Dysfunction
Glial Activation
Neuronal Loss
Cognitive Decline
Age
Genetics
Amyloid-b Production
Amyloid-b Clearance
+
 Tau
accumulation
+
Neuroprotection
Hendrix et al Alz & Dementia 2016
Summary
• The pathophysiological process of AD begins
well more than a decade before dementia
• Evidence of both amyloid accumulation and
neurodegeneration required for imminent
cognitive decline
• Sensitive imaging and cognitive measures can
track progression in preclinical stages of AD
• Must consider treating AD much earlier (at least
with anti-Ab monotherapy) and combination
therapies to increase our chances for success!
Acknowledgments
• Keith Johnson, Dorene Rentz, and colleagues from
the Harvard Aging Brain Study
• Paul Aisen and the A4 team at ATRI and ADCS
• A4 Team at Eli Lilly, Avid , CogState
• Colleagues from DIAN and API and the
Collaboration for Alzheimer’s Prevention (CAP)
• Alzheimer’s Association, Fidelity, GHR,
Accelerating Medicine Partnership (AMP)
• National Institute on Aging