Precision Medicine

Dementia
Ronald C. Petersen, Ph.D., M.D.
Alzheimers Disease Research
Center
Mayo Clinic College of Medicine
Rochester, MN
Precision Medicine
Rochester, MN
May 18, 2015

Disclosures
Pfizer, Inc. and Janssen Alzheimer
Immunotherapy : Chair DMC

Roche: Consultant
Merck, Inc.: Consultant
Genentech: Consultant
Funding

National
National Institute
Institute on Aging:
U01
U01 AG006786
AG006786
P50
P50 AG016574
AG016574
U01
U01 AG011378
AG011378

Terminology

Dementia
Biomarkers
Genetics
Prediction
Prevention

Dementia

Alzheimers disease
Frontotemporal lobar degeneration
Dementia with Lewy bodies
Mild cognitive impairment

Dementia
Alzheimers
disease (AD)

AD vascular dementia
10%
8%

Vascular
dementia

8%
53%

Frontotemporal
dementia

6%
5%

10%

Other
DLB

AD + dementia with
Lewy bodies (DLB)

FTD and PPA

Genetics

The majority of patients with FTD or PPA do

not have any known genetic cause of their illness

However, some do, and the information that

follows will hopefully help in making decisions
regarding:
Genetic testing to aid in the diagnosis
Genetic testing to aid in future planning
Genetic testing to aid in family planning

FTD and PPA

Genetics

= affected by FTD or PPA (or Parkinsons disease or

ALS)

FTD and PPA

Genetics

Sporadic, and probably not related to any genetic

mutation

FTD and PPA

Genetics

While there is some + family history of neurologic

disease, this person probably does not have any
genetic cause

FTD and PPA

Genetics

There is + family history of neurologic disease in one

side of the family affecting multiple first-degree
relatives, so this person is more likely to have a
genetic cause

FTD and PPA

Clinical Syndromes

PAOS
Progressive
apraxia
of speech
Behavioral
Variant FTD

FTD-Motor
Neuron
Disease/ALS

Decreased
comprehensio
Segmenting
n
slow speech
& recognition
Sound
of objects
distortions
& people
Cognitive loss
Disinhibition
Inflexibility
Decreased
insight

Cognitive loss
Behavior impairment
Motor symptoms

ALS

svPPA
Semantic
variant

Motor symptoms
Upper and/or lower
Motor neuron pathways

naPPA
Nonfluent/
agrammatic
variant

lvPPA
Logopenic
variant

Grammar errors
Short phrases
Haulting
Spontaneous but
speech
slow speech
Corticobasal
output
Syndrome
Word retrieval
problems
Cognitive loss
Behavioral impairment
Asymmetric rigidity
Apraxia
Eye movement
Disturbances, falls,
parkinsonism

Progressive
Supranuclear
Palsy

FTD and PPA

Genetic Overview

Behavioral
Variant FTD

FTD -Motor Neuron

Disease/ALS

C9ORF72
GRN
TARDBP
FUS
VCP

ALS

C9ORF72
GRN
FUS
OPTN
PNF1

PAOS
Progressive
apraxia
of speech

C9ORF72
GRN
MAPT
VCP
CHMP2B

SOD1
TARDBP
UBQLN2
VCP

Sporadic

svPPA
Semantic
variant

Sporadic

naPPA
Nonfluent/
agrammatic
variant

GRN
C9ORF72
MAPT-unclear

lvPPA
Logopenic
variant

(AD)
GRN
GRN
MAPT
C9ORF72

MAPT

Corticobasal
Syndrome

Progressive
Supranuclear
Palsy

Alzheimers Disease

2012 MFMER | 3238583-13

Alzheimers Disease
Genetics

Deterministic variants
Known genes
Young onset
50% risk

Genes with moderate effects

Genes that influence levels of proteins
Late onset runs in families

Alzheimers Disease

Usually gradual memory loss

Other cognitive functions impaired
Loss of ability to do daily functions
Pathologically
Plaques amyloid protein
Tangles tau protein

CP926864- 31

CP926864- 29

CP926864- 30

Introduction to the Recommendations

from the National Institute on
Aging-Alzheimers Association
Workgroups on Diagnostic Guidelines
for Alzheimers Disease
Clifford R. Jack, Jr, Marilyn S. Albert, David S. Knopman,
Guy M. McKhann, Reisa A. Sperling, Maria C. Carrillo,
Bill Thies, Creighton H. Phelps

Alz and Dementia, 2011

2012 MFMER | 3238583-19

Biomarker magnitude

Hypothetical Model of Dynamic Biomarkers

of the Alzheimers Pathological Cascade

Abnormal

A
Tau-meditated neuronal injury and dysfunction
Brain structure
Memory
Clinical function

Normal
Cognitively normal

MCI

Dementia

Clinical disease stage

Jack et al: Lancet Neurol 2010

Prevalence (%)

Prevalence of PiB PET in Normals

Prevalence
of plaques
in HC

~15 yr
Prevalence
of AD

Age (years)
Rowe et al: 2010

Biomarkers for AD

Early biomarkers
Amyloid deposition
PET imaging
CSF amyloid

Later biomarkers
Neurodegeneration
Structural MRI
FDG PET
CSF tau

Neuroimaging in AD

Neuroimaging in AD

Structural MRI
Functional imaging
FDG PET

Molecular imaging
Amyloid PET imaging

Structural Imaging in AD

Structural MRI: Atrophy and AD

Stage
Control, 70, F

MCI, 72, F

AD, 74, F

MRI Gray Matter Differences

Cognitively Normal vs. AD Dementia

2013 MFMER | 3269444-27

Functional Imaging in AD

FDG PET Differences

Cognitively Normal vs. AD Dementia

2013 MFMER | 3269444-30

Molecular Neuroimaging

PIB Idealized
CN

aMCI

AD
3
2.5
2

00-863-895

02-310-847

06-209-892

1.5
1
0.5
0

PIB Examples Full Spectrum

Low

CN

00-863-895

High

CN

02-155-940

aMCI
3
2.5
2
1.5
1
0.5
0

01-873-114

aMCI

02-310-847

AD

06-209-892

3001475-2

Amyloid (PiB) PET Differences

Cognitively Normal vs. AD Dementia

2013 MFMER | 3269444-34

Newest Imaging Modality

Tau PET scanning

[18F]-T807 PET (80-100 Min PI)

HC
(56 yr)

MCI
(MMSE = 26)

AD
(MMSE = 21)

AD
(MMSE = 7)

Chien et al: J Alzheimers Disease 34:457, 2012; Xia et al: Alzheimers & Dementia, 2012 (in
press); Zhang et al: J Alzheimers Disease 31:601, 2012
2013 MFMER | 3270183-36

Criteria Approach

Clinical criteria
Biomarkers
Molecular neuropathology (Amyloid)
CSF AB42
Amyloid imaging

Measures of neuronal injury

(Neurodegeneration)
Structural, e.g., MRI
Functional, e.g., FDG PET
CSF tau

Mild Cognitive Impairment

Alzheimers Disease Spectrum

Preclinical AD

MCI Due to AD

Dementia Due to AD

Mild Cognitive Impairment

Ronald C. Petersen, MD, PhD
N Engl J Med 2011:364-2227-34

2012 MFMER | 3219504-40

Case

3047674-4

53 y/o woman

1 yr history loss of self-confidence

Not want to move
Says cant think
Forgets rapidly in conversation
Daughters have noticed x 1 yr
Decreased reading comprehension
Family human compass
Sleep ok
Concerned but not depressed

3047674-4

53 y/o woman

Family history negative for dementia

PMH: Good health, postpartum
hemorrhage

Med: supplements, Zoloft, ASA

3047674-4

53 y/o woman
STMS: 37/38
VIQ: 107, PIQ: 97
Attention/Executive
Trails A and B: 50th %ile
Stroop: 50th %ile
Language
Fluency: 90th %ile
BNT: 59/60

3047674-4

53 y/o woman

Visuospatial
Rey O copy: 50th %ile
JLO: 50th %ile

Memory
Logical Memory: 17/10
Visual Reproductions: 64/21
AVLT: 7,6,11,10,8; DR 3

3047674-4

MCI Due to AD
Diagnostic category
MCI

Biomarker
probability of AD
etiology
Uninformative

A
(PET or CSF)

Neuronal injury
(tau, FDG, sMRI)

Conflicting/
indeterminant or unavailable

MCI due to AD
intermediate
likelihood

Intermediate
Intermediate

Positive
Untested

Untested
Positive

MCI due to AD
high likelihood

Highest

Positive

Positive

MCI unlikely due to

AD

Lowest

Negative

Negative

Albert et al: 2011

2012 MFMER | 3219504-46

2008

5/22/2008 MRI Scan

Hippvol in normal range
(-0.31; greater than -0.70
is normal)

Mayo MCI Subject

2/4/2008 FDG Scan

Parietal temporal hypometabolism
(Global FDG AD score of 1.14 is abnormal)

2/4/2008 PIB Scan

Positive ; Ratio 2.5

MCI Due to AD
Diagnostic category
MCI

Biomarker
probability of AD
etiology
Uninformative

A
(PET or CSF)

Neuronal injury
(tau, FDG, sMRI)

Conflicting/
indeterminant or unavailable

MCI due to AD
intermediate
likelihood

Intermediate
Intermediate

Positive
Untested

Untested
Positive

MCI due to AD
high likelihood

Highest

Positive

Positive

MCI unlikely due to

AD

Lowest

Negative

Negative

Albert et al: 2011

2012 MFMER | 3219504-51

Clinical Progression 2 yr later

Getting lost
Frequent forgetting
Not driving
Despondent
Needs assistance

3047674-5

55 y/o woman
STMS: 32/38
VIQ: 107, PIQ: 97
Attention/Executive
Trails A and B: 25th %ile
Stroop: 30th %ile
Language
Fluency: 60th %ile
BNT: 50/60

3047674-5

55 y/o woman

Visuospatial
Rey O copy: 30th %ile
JLO: 25th %ile

Memory
Logical Memory: 12/5
Visual Reproductions: 32/15
AVLT: 3,4,3,5,4; DR 0

3047674-5

2008 (-0.31)

2010 (-0.91)

Mayo MCI Subject

7/1/2010 FDG Scan

Progressive hypometabolism; Ratio 1.08

7/1/2010 PIB Scan

Progressive
Ratio 2.7

Dementia Due to AD
Diagnostic category
Probable AD
dementia
Probable AD with
evidence of path AD

Biomarker
probability of AD
etiology
Uninformative/
available

A
(PET or CSF)

Neuronal injury
(tau, FDG, sMRI)

Conflicting/
indeterminant or unavailable

Intermediate
Highest

?
Positive

Positive
Positive

Possible AD
dementia atypical
with path

High consider
secondary

Positive

Positive

Dementia unlikely
AD

Lowest

Negative

Negative

McKhann et al: 2011

2012 MFMER | 3219504-59

Do the Criteria Work in the

General Population?

3047674-6

Mayo Clinic
Study of Aging
Population-based study of 5000+
(2800 active) nondemented
persons age 50-89 years in
Olmsted County, MN
CP1265413-14

Mayo Clinic Study of Aging

2004

06

08

10

14

12

Oct.
Enrollment
F-U Cycle 2
F-U Cycle 3
F-U Cycle 4
F-U Cycle 5
Data analysis
F-U Cycle 6
Data analysis

Replen
cohort

Replen
cohort

Replen
cohort

Replen
cohort

F-U Cycle 7
Data analysis

F-U = follow-up
2013 MFMER | 3263944-62

Mayo Clinic Study of Aging

70 year olds
2004

06

08

10

14

12

Oct
Enrollment
F-U Cycle 2
F-U Cycle 3
F-U Cycle 4
F-U Cycle 5
F-U Cycle 6

n=2000

F-U Cycle 7

50 year olds
2011

12

13

14

Enrollment
F-U Cycle 2

n=2000

F-U Cycle 3

F-U = follow-up
2013 MFMER | 3270183-63

Mayo Clinic Study of Aging

Renewed through 2019

Continuing to recruit non-demented**
70-89 y/os
50-69 y/os
30-49 y/os soon

Evaluation
Consent
Consent form
form
Blood
Blood draw
draw
Clinical
Clinical evaluation
evaluation
Nurse/SC
Nurse/SC interview
interview

Neurological
Neurological evaluation
evaluation

Participant
Participant
Family
Family history
history
Current
medications
Current medications
Demographic
Demographic information
information
Memory
Memory &
& orientation
orientation
Medical
Medical history
history &
&
risk
assessment
risk assessment
Neuropsychiatric
Neuropsychiatric inventory
inventory
Study
Study partner
partner
Clinical
dementia
Clinical dementia rating
rating
Functional
Functional
assessment
assessment (FAQ)
(FAQ)

Neurological
Neurological history
history
Short
Short test
test of
of mental
mental status
status
Modified
Hachinski
scale
Modified Hachinski scale
Prime
Prime MD
MD (physician
(physician form)
form)
Neurological
Neurological examination
examination
and
and modified
modified UPDRS
UPDRS

Consensus
Consensus conference
conference

Cognitive
Cognitive assessment
assessment
Memory
Memory
Logical
Logical memory
memory (delayed)
(delayed)
Visual
Visual reprod
reprod (delayed)
(delayed)
AVLT
AVLT
Executive
Executive function
function
Trails
A
Trails A &
&B
B
Digit
symbol
substitution
Digit symbol substitution
Visuospatial
Visuospatial
Picture
Picture completion
completion
Block
Block design
design
Language
Language
Boston
Boston naming
naming test
test
Category
Category fluency
fluency

CP1333643-2

Resources Acquired

5000+ non-demented subjects

75% cognitively normal
24% MCI

3500 quantitative MRI scans

~ 5000 DNA samples
~ 5000 frozen plasma/serum samples
plus annual samples

Clinical and performance measures

Continuation of MCSA

Add new subjects to cohort

Continue annual clinical follow-ups
Continue serial MRI/PET scans
Collect annual plasma/serum
Collect 1000 CSFs
Perform 1500 FDG-PET scans
Perform 1500 PiB PET scans
Beginning tau PET scans

Modeling Costs of Dementia

Cost Difference Analysis

(Cost
(Cost == A)
A)
Cost
Cost == A
A (untreated)
(untreated)
Cost
Cost B
B << X
X
Cost
Cost B
B ++ C
C << X
X

DiseaseDiseasemodifying
modifying
therapy
therapy

(Cost
(Cost savings
savings == X)
X)

Diagnostic
Diagnostic

Cost

(Cost
(Cost == B)
B)
(Cost
(Cost == C)
C)

Normal

MCI

AD

3046383-6

So, where are we?

Is Precision Medicine Working in AD?

Criteria give us framework
Clinical features plus biomarkers can
be quite accurate
Better in symptomatic phases, MCI
and dementia
Genetics direct us
Ultimately, yes, but work to do

Mayo Clinic AD Research

Rochester

Jacksonville

Brad Boeve

Neill Graff-Radford

Dave Knopman

Steve Younkin

Cliff Jack

Dennis Dickson

Daniel Drubach

John Lucas

Val Lowe

Tanis Ferman

Bob Ivnik

Rosa Rademakers

Mary Machulda

Nilufer Taner-Erketin

Michelle Mielke

Len Petrucelli

Rosebud Roberts

Gojuin Bu

Walter Rocca

Otto Pedraza

Shane Pankratz

Scottsdale

Kejal Kantarci
Joe Parisi
Eric Tangalos

Rick Caselli
Bryan Woodruff
Yonas Geda

Thank You