1. Can Alzheimer’s dementia be prevented
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

2. 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

3. The Continuum of Alzheimer’s Disease
Normal Aging
Cognitive
function
Preclinical
MCI
(Prodromal AD)
Dementia
Years

4. 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

5. Preclinical Alzheimer’s disease?
1/3 of CN with elevated Ab accumulation CN
Ab- CN
Ab+ AD
Ab+
Harvard Aging Brain Sudy
Sperling, Mormino, Johnson Neuron 2014

6. Preclinical Alzheimer’s Disease?10 20 30 40 50 60 70 80 90
100
Prevalence (%)
Age (years)
Prevalence
of PiB+ve PET
in HC
Prevalence of plaques
in HC
(Davies, 1988, n=110)
(Braak, 1996, n=551)
(Sugihara, 1995, n=123)
Prevalence
of AD
(Tobias, 2008)
~15 yrs +
Rowe C et al Neurobiology of Aging 2010

7. 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

8. Bateman R et al NEJM 2012

9. 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

10. Amyloid and memory decline in preclinical and clinical Alzheimer’s disease
AIBL data
Lim Y et al Brain 2014

11. Amyloid-Related Cognitive Decline
Petersen R et al. JAMA Neurology 2015

12. Preclinical Alzheimer’s disease NIA-AA Preclinical Workgroup
Stage 0
No biomarker abnormalities
Staging Framework for
Preclinical Alzheimer’s disease
NIA-AA Preclinical Workgroup
Stage 1
Asymptomatic amyloidosis
-High PET amyloid retention
-Low CSF Ab1-42
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
MCI Dementia
due to AD
SNAP
Suspected non-Alzheimer pathology
- Neurodegeneration markers without evident amyloidosis
Sperling, Mormino, Johnson Neuron 2014
Adapted from Sperling 2011, Jack 2012

13. Prediction of progression to symptomatic AD by preclinical stages2 4 6 8 10 12 14
Vos et al Lancet Neurology 2013

14. Harvard Aging Brain Study
Relationship between markers of Amyloid b deposition and markers of neurodegeneration
Harvard Aging Brain Study
FDG+
N=25
FDG-
N=47
florbetapir-
N=49
Increase over time  worse
controlling for age, sex, edu, ApoE4 status
Stage 0 Ab-/ND-
Stage 1 Ab+/ND-
Stage 2 Ab+/ND+
SNAP Ab-/ND+
Mormino E et al JAMA Neurology 2014

15. Subjective cognitive concerns associated with advancing stages of preclinical AD
181 subjects
n= 85
n= 21
n= 28
n= 47
Amariglio et al. Neurology 2015

16. PET Amyloid and Tau ImagingAb
(PiB)
Tau
(T807) CN CN
AD Dementia
Sperling, Mormino, Johnson Neuron 2014

17. Higher Amyloid Burden Associated with Higher Tau Burden in CN
Harvard Aging Brain Study (n=97)
r=0.37
p=0.0002
Inferior Temporal T807 SUVR
PiB-
PiB+
Mean Cortical PiB DVR
Adjusted model for age, gender, education r= 0.34; p=0.0004

18. Regional Tau Burden (T807) by Preclinical AD Stages
All black dots
Mormino E et al JAMA Neurology 2016

19. Relationship of Tau and Memory by Amyloid Status (HABS data)
PiB- Slope= -1.07
r =
p=0.35
Memory Factor Score (adj)
PiB+ Slope= -3.42
r =
p =
Interaction term
(PiB x T807)
p=0.089
Inferior Temporal T807 SUVR (adj)
Sperling et al AAIC 2015

20. Hypothetical Interaction of Amyloid and Tau
in Preclinical AD
Age
Amyloid-b
Accumulation
MTL Tau
Cognitive Decline ?
Neocortical Tau
Accumulation
Synaptic Dysfunction
Glial Activation
Neuronal Loss ?
Age
Genetics
Sperling, Mormino, Johnson Neuron 2014

21. Why would we want to detect AD a decade before dementia?

22. Treatment of Alzheimer’s Disease
Cognitive Function
Symptomatic Therapy
Disease-Modifying Therapy
Natural History of Alzheimer’s Disease
Years

23. 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?

24. 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

25. “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

26. 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, placebo-controlled 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

27. The continuum of Alzheimer’s disease
“Normal” Aging
Preclinical
Cognition
MCI }
Dementia
Years

28. Harvard Aging Brain Study Data
Preclinical Alzheimer Cognitive Composite (PACC)
Harvard Aging Brain Study Data
beta= -0.12±0.0;2 p<
Mormino et al Alzheimer’s & Dementia 2017

29. The A4 Study Anti-Amyloid Treatment Amyloid - Amyloid + Treated A4
Cognition
Amyloid +
Treated A4 }
Amyloid +
Placebo

30. Higher levels of Tau in Ab+ Normals
Entorhinal Tau
Inferior Temporal Tau
A4 vs. HABS low PiB T=5.85; p<0.0001
A4 vs. HABS low PiB T=5.15; p<0.0001

31. Greater Amyloid Associated with Greater Tau Burden (A4 Baseline Data)
FTP PET Vertex correlations
with cortical FBP SUVR (n=239)
Left Fusiform Peak

32. Greater Tau Burden Associated with Worse Memory Performance (A4 Baseline Data)
FTP PET Vertex correlations
with FCSRT Free Recall (n=239)
Left Entorhinal Peak

33. 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 A4
Normal
Preclinical
MCI
Dementia
Clinical Disease Stage
Figure adapted from Jack et al. 2010, Sperling et al. 2011

34. 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
Dementia
Clinical Disease Stage
Figure adapted from Jack et al. 2010, Sperling et al 2011

35. Longitudinal Amyloid-b Accumulation in Clinically Normal Elders
Harvard Aging Brain Study
Aaron Schultz and Keith Johnson HAI 2015

36. 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
Dementia
Clinical Disease Stage

37. 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

38. COMBAT = COMBination Amyloid and Tau
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

39. Combination treatment for Alzheimer’s disease
Age
Amyloid-b
Accumulation
MTL Tau
Cognitive Decline
Neocortical Tau
Accumulation
Synaptic Dysfunction
Glial Activation
Neuronal Loss
Age
Genetics
Amyloid-b Production
Amyloid-b Clearance +
 Tau
accumulation +
Neuroprotection
Hendrix et al Alz & Dementia 2016

40. 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!

41. 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