December, 2010

NEED FOR VALIDATED

BIOMARKERS FOR AD TRIALS
• Biomarkers useful in Phase 2 to make
decisions about Phase 3 (e.g. doses)
• Biomarkers useful in Phase 3
– Provide additional evidence to support
primary outcome findings
– Provide evidence for “disease
modification” and not simply symptomatic
improvement
 GOALS OF THE ADNI:
LONGITUDINAL MULTI-SITE OBSERVATIONAL
STUDY

• Major goal is collection of data and samples to establish

a brain imaging, biomarker, and clinical database in
order to identify the best markers for following disease
progression and monitoring treatment response
• Determine the optimum methods for acquiring,
processing, and distributing images and biomarkers in
conjunction with clinical and neuropsychological data in
a multi-site context
• “Validate” imaging and biomarker data by correlating
with neuropsychological and clinical data.
• Rapid public access of all data and access to samples
Normal MCI AD

ADNI 2 ADNI 1
(EMCI) (LMCI)

0 0.5 1
CDR 3004153-1
 STUDY DESIGN-ADNI1
• MCI (n= 400): 0, 6, 12, 18, 24, 36 months
• AD (n= 200): 0, 6, 12, 24 months
• Controls (n= 200): 0, 6, 12, 24, 36 months
• Clinical/neuropsychological evaluations, MRI (1.5 T)
at all time points
• FDG PET at all time points in 50%
• 3 T MRI at all time points in 25%
• PIB sub-study on 120 subjects
• Blood and urine at all time points from all subjects;
CSF from 50% of subjects 0, 1 yr, 2 yr (subset); DNA
and immortalized cell lines from all subjects
• GWAS study
 Subject Evaluation
• Baseline/screening eval • Neuropsyc(B and q 6 mo)
and q 6 mo. – Logical Memory(S)
– Labs, Apo E – AVLT
– Hamilton(S) – BNT
– Beck – Trails A &B
– MMSE – Symbol digit
– ANART – Clock drawing
– ADAS-cog – Category fluency
– NPI
– CDR
– ADL
 ADNI Public-Private Partnership Structure

David Lee
Private/Philanthropic
Alison Drone
+
Public FDA

Neil Buckholtz
NIBIB, NINDS, NIMH, NIDA, NCRR, NINR
ADNI Executive Steering Committee PI: Mike Weiner Publications Core: Biostatistics Core:

PET Core: MRI Core: Clinical Core: Administrative Core: UCSF BostonU: Green UCD: Beckett

Berkeley: Mayo: Jack UCSD: Aisen Biomarkers Core: Informatics Core: Neuropathology Core:
Jagust Mayo: Peterson UCLA: Toga WashU: Morris
UPenn: Trojanowski/Shaw

57 Clinical Sites: ADNI PIs and Cores

 Data and Sample Sharing
• Goal is rapid public access of all raw and processed
data
• Central repository for all QA’d MRI and PET
[Laboratory of Neuroimaging, UCLA (LONI)]
• Clinical data base at UCSD is linked to LONI
• Databases- in the public domain, available to all
qualified investigators
• Sample sharing-Resource Allocation Review
Committee
• No special access
• Data Sharing & Publication Committee (DPC)
-ADNI Data Use Agreement
ADNI Demographics

Normal controls MCI AD

(n=229) (n=398) (n=192) P

Age, mean (SD) 76.4 (5.0) 75.3 (7.5) 75.8 (7.4) 0.15

Female (%) 48.0 35.4 47.4 0.002

Years of education, 15.6 (3.1) 16.0 (2.9) 14.7 (3.1) <0.001

mean (SD)

Apolipoprotein E e4: 26.6 53.5 65.6 <0.001

Positive (%)

CP1307278-1
ADAS Cog 11
Feb-09; N. Schuff
 ADNI Conversion Rates
Year Normal  MCI MCI  AD

0-1 1.4% (0.0-3.2) 16.0% (11.3-20.4)

1-2 2.4% (0.0-4.7) 23.9% (19.0-29.5)

2-3 0.0% (0.0-3.4) 9.1% (5.8-13.5)

Diagnosed as AD

+2%
Diagnosed as NC

-2%

Lateral View Medial View Holland et al.

 Statistical ROI’s of 12-Month CMRglDecline
AD

MCI
 3

2.5
Mean Cortical SUVR

1.5
Cutoff > 1.46
PIB+
(Berkeley Data)
1
Normals MCI AD
9/19 (47%) 47/63 (68%)17/19 (89%)
PIB+ PIB+ PIB+
Follow-Up of PIB-Positive ADNI MCI’s

ADNI PiB MCI’s

N = 65, 12 mo. follow-up

PiB(-) 18
Converters to AD 3

PiB(+) 47
Converters to AD 21
 ADNI BASELINE CSF biomarker concentrations show the
expected average differences between AD and MCI and NC

AD (n=102) Tau Ab1-42 P-Tau181P Tau/Ab1-42 P-Tau181P/Ab1-42

Mean±SD 122±58 143±41 42±20 0.9±0.5 0.3±0.2

MCI (n=200)
Mean±SD 103±61 164±55 35±18 0.8±0.6 0.3±0.2

NC (n=114)
Mean±SD 70±30 206±55 25±15 0.4±0.3 0.1±0.1

p<0.0001, for each of the 5 biomarker tests for AD vs NC and for MCI vs NC.
For AD vs MCI:p<0.005, Tau; p<0.01, Ab1-42; p<0.01, P-Tau 181P; p<0.0005, Tau/Ab1-42; p<0.005, P-
Tau 181P/Ab1-42.
Mann-Whitney test for statistical differences used for these non-normally distributed data sets.
 MCI progressors to AD at YEAR
1(n=37)

MCI converters to normal

Ab1-42 concentrations in CSF, collected at the baseline visit, of 37 ADNI MCI subjects who at their one year visit converted to a diagnosis of probable AD. The
data points for the MCI→AD converters are presented as a horizontal dot plot with the x axis scale identical to that of the Ab1-42 frequency plot for the entire
ADNI MCI group. The vertical line indicates the Ab1-42 cutoff concentration obtained from ROC analysis of an ADNI-independent cohort of autopsy-based AD
subjects’ CSF.
 Recommendation for revised
Project Plan study design

• RBM has agreed to run 1,000 samples using the full panel
(500 at baseline, 500 at one year):
• 300 MCI samples each
• 100 AD samples each
• 100 control samples each
• Include all subjects with CSF and PIB PET data.
• Try to balance non-progressor MCI vs progressing MCI.
Hippocampal atrophy rates (L+R) – free surfer data – in ADNI
subjects with CSF Ab1-42 >192 pg/mL or <192 pg/mL

Hippocampal % atrophy rates

(BL→12 mos), for ADNI subjects
with Ab1-42< 192 or >192 pg/mL
Ab1-42 Ab1-42
<192pg/mL >192pg/mL
ALL -5.6±4.7 -2.6±4.1
AD -8.0±5.9 -4.2±3.5
MCI -4.8±3.6 -2.9±3.7
NC -3.6±3.2 -2.2±4.3
These data show that in ADNI AD, MCI and NC
subjects the rate of hippocampal atrophy
increases at a significantly higher rate in
subjects with Ab1-42 <192 pg/mL cutoff
concentration compared to those >192 pg/mL
 POWER OF CLINICAL/COGNITIVE TESTS
25% CHANGE 1YR STUDY (2 ARM) :
AD

Test Sample Size

MMSE 803
RAVLT 607
ADAS 592
CDR SOB 449
 1.5T MRI Comparisons - AD (n=69)

Lab Variable SS/arm

Alexander L. Hippo. Formation 334
Dale Whole Brain 207
Schuff - FS Hippocampus 201
Dale Ventricles 132
Dale Hippocampus 126
Studholme Temporal lobe % change 123
Schuff - FS Ventricles 119
Studhome CV - % change 106
Fox VBSI % change 105
Fox BSI % change 71
Thompson CV - % change 54

22
 ADNI Genotyping
• Initial goal: high density genome wide scan
– Identified major microarray platforms for GWAS
• Compared marker selection strategies, HapMap
coverage of genome, performance & reliability, as well
as cost/sample
– Illumina platform was selected by consensus of the
Genetics Committee & ISAB for this project
– TGen (Phoenix, AZ) was selected to perform the assays
– Illumina Human 610-Quad
 Shen et al 2010: Overview
FreeSurfer: 56 volume or QC’ed genotyping data
cortical thickness measures
530,992 SNPs
Baseline MRI Scans

142 QTs
GWAS of Imaging Phenotypes

Strong
associations
represented by
VBM: 86 GM density measures heat maps

R L L R

R L R

Refined modeling of
GWAS of candidate QT VBM of candidate SNP candidate association
 FDG-PET

CSF Aβ42
MRI hipp

Cog

Amyloid imaging CSF tau

Fxn
 EMCI: 200 new subjects
 Continued follow-up of LMCI and controls
from ADNI 1
 All subjects to have LP, AV-45 amyloid
imaging, FDG-PET, vMRI
 Some adjustments to cognitive assessment
 Additional analysis funds
 Continue to follow all EMCI, LMCI and NC
from ADNI 1 and ADNI GO for 5 more years
 Enroll:
 100 additional EMCI (supplements 200 from GO)
 150 new controls, LMCI, and AD
 MRI at 3, 6, months and annually
 F18 amyloid (AV-45)/FDG every other year
 LP on 100% of subjects at enrollment
 Genetics
 ADNI 1 ADNI GO ADNI 2 Cumulative

CN 202 – 150 352

EMCI – 200 100 300

LMCI 274 – 150 424

AD 200 – 150 350

 Standardization: imaging, biomarkers
 Neuroscience: relationships among biomarker
trajectories elucidate neurobiology
 Trials: new understanding of biomarkers has
facilitated interventional studies in very early
AD
 Data sharing: ADNI has demonstrated the
power of real-time public data sharing
 Collaboration: academia, industry, non-profits,
regulatory agencies world-wide
 J-ADNI
EU-ADNI
NA-ADNI

A-ADNI
WW-ADNI
 Parkinson’s disease
 FTD
 Atherosclerosis
 Interaction with Wellcome Trust UK Biobank
Project through NCI
 http://www.adni-info.org
http://www.loni.ucla.edu/ADNI