Transcript No Slide Title

Preclinical Stage Alzheimer's Disease
Defining and Characterizing the Transition Between
Normal and Pathological Cognitive Aging
Richard J. Caselli, MD
Department of Neurology, Mayo Clinic Arizona
Funding: NIA P30AG19610, NIA R01AG031581, and the Arizona
Alzheimer’s Research Consortium
Definitions
1.
2.
Dementia is the disabling impairment of
multiple cognitive functions. It is not
memory loss alone.
Mild Cognitive Impairment
1.
Single domain
1.
2.
2.
3.
Amnestic (memory loss alone)
Non-amnestic (language, executive, spatial)
Multiple domain
Preclinical Alzheimer’s disease is…?
1.
Objective:
1.
2.
3.
4.
2.
Neuropsychological decline
Abnormal imaging (MRI, fMRI, FDG, PiB)
CSF Biomarkers
Neuropathology
Subjective: symptoms without “objective
findings”
The Genetic Basis of Alzheimer’s Disease
Causative
(Consider genetic testing and
counselling)
• Chromosome 21: (APP)
• Chromosome 14:
Presenilin 1
• Chromosome 1:
Presenilin 2
Susceptibility
• Chromosome 19:
Apolipoprotein E
• TOMM40
Milder Risk Factors
CYP46
GAB2
SORL1
Other
APOE e4 - a Susceptibility Gene Variant
Associated with Alzheimer’s Disease - 1993
Proportion of each
genotype unaffected
1.0
2/3
0.8
0.6
3/3
2/4
0.4
3/4
0.2
0
60
4/4
65
70
75
80
Age at onset
85
Global APOE Allele Distribution: Highest
e4
(Corbo and Scacchi, Am Hum Genet 1999)
Pygmies
Khoi San
Papuans
Lapps
Nigerians
Sudanese
Cayapas
Polynesian
s
Aborigines
E2
0.057
0.077
0.145
0.050
0.027
0.081
0.0
0.110
E3
0.536
0.553
0.486
0.640
0.677
0.619
0.720
0.630
e4
0.407
0.370
0.368
0.310
0.296
0.291
0.280
0.260
0.0
0.740
0.260
Global APOE Allele Distribution: Lowest
e4
(Corbo and Scacchi, Am Hum Genet 1999)
Sardinians
Greeks
Chinese
Turks
Moroccans
Mayans
Spaniards
Italians
Japanese
E2
0.050
0.054
0.105
0.061
0.065
0.0
0.052
0.060
0.048
E3
0.898
0.878
0.824
0.860
0.850
0.911
0.856
0.849
0.851
e4
0.052
0.068
0.071
0.079
0.085
0.089
0.091
0.091
0.101
Defining Preclinical MCI (NIA-AA 2011)
0 APOE 4 alleles
<
1 APOE 4 allele
2 APOE 4 alleles
64mm
56mm
48mm
40mm
32mm
24mm
16mm
8mm
0mm
-8mm
-16mm
-24mm
-32mm
-40mm
64mm
56mm
48mm
40mm
32mm
24mm
16mm
8mm
0mm
-8mm
-16mm
-24mm
-32mm
-40mm
64mm
56mm
48mm
40mm
32mm
24mm
16mm
8mm
0mm
-8mm
-16mm
-24mm
-32mm
0.05
P-values
-40mm
2.4e-06
Methods
• Subject selection
– APOE Genotyping
– Screening tests
– APOE and ADC Cohorts
• Screening tests
–
–
–
–
–
Medical history
Neurologic Exam
Psychiatric Exam
Folstein MMSE
Hamilton Depression
Scale
• Test Procedures
–
–
–
–
Neuropsychology
PET (FDG, PiB)
MRI (volumetric, DTI)
Other
• Longitudinal Study
– Every 2 years
• Statistical Model
– Isolate longitudinal
change from entry
performance
– Linear vs quadratic
Brain Imaging
DTI of 50-70 year old Healthy
APOE e4 Carriers
(courtesy of Leslie Baxter)
(13 e4 carriers vs 18 e4 noncarriers, mean age 60 yrs)
PIB PET in Presymptomatic 60 YO’s
(Reiman EM et al, PNAS 2009)
0 APOE 4 alleles
1 APOE 4 allele
2 APOE 4 alleles
64mm
56mm
48mm
40mm
32mm
24mm
16mm
8mm
0mm
-8mm
-16mm
-24mm
-32mm
-40mm
64mm
56mm
48mm
40mm
32mm
24mm
16mm
8mm
0mm
-8mm
-16mm
-24mm
-32mm
-40mm
64mm
56mm
48mm
40mm
32mm
24mm
16mm
8mm
0mm
-8mm
-16mm
-24mm
-32mm
-40mm
0.05
P-values
2.4e-06
APOE modifies the association between A load and cognition in
cognitively normal older adults
• 408 cognitively normal adults in their 70s and 80s participated in the populationbased Mayo Clinic Study of Aging (MCSA) Pittsburgh compound B (PiB) PET study
from January 2009 through March 2011
• 34% had high amyloid load on PiB PET (PiB positive)
PiB retention
by APOE
status
Kantarci et al. Neurology 2012
APOE modifies the association between A load and cognition in
cognitively normal older adults
Associations between cortical PiB
retention and standardized
cognitive domain scores according
to APOE status
Interaction between APOE status and
PiB retention (p<0.05; sequential
ANOVA):
• memory function
• visual-spatial performance
• global cognition
● APOE ε2 carrier
● APOE ε3 homozygote
● APOE ε4 carrier
Kantarci et al. Neurology 2012
Neuropathology
Neuropathology in APOE e4 Carriers: Tampere
Autopsy Series (Finland)
(Kok et al, Ann Neurol 2009)
AD Pathology in Young APOE e4 Carriers
(Kok et al, Ann Neurol 2009)
40% of 50-59 yo e4’s have AP’s
40% of 50-59 yo e4’s have NFT’s
AD Pathology in Normal Elderly: SHRI Subject Data
Neuropsychology
• APOE e4 effect
• Superimposed CV risk factor effects
• Correlates of preclinical frontal amyloid
Longitudinal Modeling of Age-Related
Memory Decline and APOE e4
(Normal Controls from APOE and ADC Cohorts)
NC
(n=498)
61.4
e3/4
(n=238)
58.4
e4/4
(n=79)
56.8
<.001
Ed (yr)
% Female
15.4
69.1
15.4
68.9
15.4
68.4
.98
.99
% FDR
% >1
Epoch
Duration
(yrs)
52.8
73.1
68.8
73.1
87.2
84.8
<.001
.08
4.7
5.1
5.7
.01
Age (yr)
p
Auditory Verbal Learning Test
Onset of diverging memory trajectories (5 year blocks) at
similar age as presymptomatic amyloid deposition, MRI,
FDG, and PIB changes completes the clinical-pathological
pairing that defines Alzheimer’s disease
(Caselli RJ et al, NEJM 2009)
APOE e4 Carrier Vulnerability
• Increased memory decline with fatigue
• Greater adverse cognitive effects of
lorazepam
• Greater decline in problem solving with
anxiety
• Worse outcomes from neurological injuries:
head trauma, cardiac arrest, subarachnoid
hemorrhage
• Brain radiation and chemotherapy effects less
clear
Aerobic Fitness and Visual Memory Performance
Low Risk Group
High Risk Group
Bivariate Scattergram w ith Regression
Bivariate Scattergram w ith Regression
40
40
35
35
30
CFT
20
15
CFT recall
CFT recall
30
25
25
20
15
10
10
5
5
0
0
5
10
15
20
25
30
35
0
40
0
15
20
25
30
35
40
VO2MAX (ml/kg/min)
CFT recall = -7.927 + 1.05 * VO2MAX (ml/kg/min); R^2 = .35
VO2MAX (ml/kg/min)
CFT recall = 6.456 + .456 * VO2MAX (ml/kg/min); R^2 = .13
Bivariate Scattergram w ith Regression
5
10
Bivariate Scattergram w ith Regression
10
10
9
8
8
VRT
4
7
6
VRT
VRT
6
5
4
3
2
2
1
0
0
5
10
15
20
25
30
35
VO2MAX (ml/kg/min)
VRT = 3.172 + .147 * VO2MAX (ml/kg/min); R^2 = .14
40
0
0
5
10
15
20
25
30
35
VO2MAX (ml/kg/min)
VRT = -.107 + .256 * VO2MAX (ml/kg/min); R^2 = .402
40
Lorazepam Challenge
(Stonnington et al, 2009)
85
80
80
70
75
Score
Score
60
50
40
70
65
60
30
55
20
50
10
0
1
2
3
4
5
Time (Hours)
Mean AVLT Long Term Percent Recall score over time
0
1
2
3
4
5
Time (Hours)
Mean Groton Maze Learning Trials Total Errors
score over time. (p=.04)
(p=.005).
Solid circles indicate ApoE ε4 carriers (n=18), open circles indicate noncarriers
(n=18), solid lines indicate the lorazepam period, and dashed lines indicate the
placebo period. Matched pairs, mean age 60 years.
Prevalence of CV Risk Factors
HTN
E4
E4
E4 NC Total
HMZ
HTZ
32.4% 31.4% 37% 34.9%
.1
DM
1.4%
CIG
28.8% 22.1%
CHOL
10.3%
8.1%
.01
32%
28.7%
.01
33.8% 33.5% 35.2% 34.6%
.6
CVany 54.8% 54.5% 60.4% 58.1%
.27
MI
.23
2.7%
5.4%
p
6.3%
7.9%
7.0%
Added Impact of CV Risk Factors (Any of HTN, DM, CHOL,
CIG) on e4 Homozygotes
P = NS
P < .001
Caselli RJ et al, Neurology 2011 (in press)
Frontal Lobe Battery
(APOE Cohort alone)
• Psychomotor Speed
– Controlled Oral Word Association Test
– WAIS-R Digit Symbol Substitution
• Working Memory
– PASAT 2 and 3 second versions
– WAIS-R Mental Arithmetic
– WAIS-R Digit Span
• Problem Solving
– Wisconsin Card Sorting Test
Entry Demographics
NC
(n=356)
57.2
15.5
e3/4
(n=194)
56.0
15.7
e4/4
(n=71)
55.6
15.5
.37
.57
% Female
69.4
70.6
85.9
<.001
% FDR
% >1
Epoch
56.1
74.7
72
77.8
87.2
87.3
<.001
.07
Duration
(yrs)
6.2
6.3
6.6
.72
Age (yr)
Ed (yr)
p
Caselli RJ et al, Neurology 2011, in press
Results: AVLT (Cohorts are Comparable)
Prior study: Combined APOE and ADC Cohort, n=815
P=.03
P=.009
Current Study: APOE Cohort, n= 621
P=.04
P=.01
Results Summary (avlt adjusted)
R (w avlt)
P
P(avlt adj)
C/NC
HMZ/NC
C/NC
HMZ/NC
COWA
.12
.78
.6
.95
.81
DSS
.21
.01
.12
.03
.23
PASAT-2
.22
.06
.004
.08
.01
PASAT-3
.22
.02
.01
.03
.03
DigSp
.001
.49
.51
.65
.75
Arith
.035
.20
.05
.33
.12
WCST-Ca
.23
.88
.99
.91
.92
WCST-Er
-.28
.91
.56
.80
.74
WCST-PE
-.25
.81
.24
.99
.42
Results: Working Memory (PASAT)
Linear, p=.06
Linear, p=.02
HMZ linear p=.004
HMZ linear, p=.01
Iowa Gambling Task (age 50 and older)
e4 HMZ
e4 HTZ
e4 NC
p
n
16
35
64
age
63.1 (7.6)
64.9 (7.8)
63.9 (7.6)
NS
educ
16.3 (2.0)
15.9 (2.5)
16.1 (2.4)
NS
T-score
49.1 (9.5)
49.7 (9.7)
49.5 (8.8)
NS
Net Raw
17.0 (27.1)
16.9 (28.3)
16.9 (26.0)
NS
$$
-$264.69
-$221.69
-$311.72
NS
Neuropsychology Battery
• Intellectual Domains
–
–
–
–
–
Memory
Executive
Language
Spatial
“General”
• Subjective
– Observer
– Self
• Behavioral
–
–
–
–
–
Depression
Anxiety
Paranoia
Somatization
Aggression
Linear
Quadratic
Gene dose
AVLT-LTM*
.001
.009
.005
SRT-total free*
<.001
<.001
<.001
CFT recall
.25
.42
.44
VRT correct*
.045
.004
<.001
WCST-Cat
.88
.16
.09
PASAT-3 sec
.02
.16
.10
COWAT
.84
.38
.27
TMT-A
.83
.72
.68
BNT
.03
.25
.88
Token
.07
.70
.60
WAIS-Similar
.96
.13
.14
WAIS-Vocab
.008
.57
.72
JLO
.10
.56
.11
Faces
.78
.19
.25
CFT-copy
.43
.19
.97
WAIS-Blocks
.04
.45
.28
Linear
Quadratic
Gene Dose
MMSE
.02
.41
.19
DRS*
.001
<.001
.001
WAIS-Info
.01
.92
.37
FAQ
.09
.04
.06
Observer
.27
.29
.08
Self
.02
.06
.33
Ham-D
.09
.31
.72
Beck
.26
.96
.89
PAI-Depress
.51
.07
.17
PAI-Anxiety
.06
.64
.75
PAI-Paranoia
.18
.04
.12
PAI-Aggress
.96
.35
.49
PAI-Neg Image
.29
.17
.46
Memory
Preclinical Battery (age 50-65)
NC
n=258
HTZ
n=110
HMZ
n=59
P
(NC v HMZ)
Age
57.2 (4.6)
57.4 (4.3)
56.2 (4.9)
.15
Education
15.6 (2.3)
16.1 (2.4)
15.8 (2.4)
.53
AVLT-LTM
9.6 (3.1)
9.2 (3.4)
9.8 (3.5)
.72
SRT-free
87.8 (11.0)
88.4 (10.7)
88.0 (10.2)
.95
VRT
7.0 (1.8)
7.0 (1.9)
6.6 (1.9)
.10
DRS
140.9 (3.0)
140.8 (2.6)
141.4 (2.3)
.34
Summary
• Presymptomatic neuropathology, neuroimaging, and
neuropsychological changes in genetically predisposed
individuals define and characterize preclinical stage
Alzheimer’s disease
• Preclinical stage AD begins in APOE e4 carriers on
average during our 50’s with a clinical lag time of 10-15
years.
• Stress such as CV risk factors, medications, fatigue, and
anxiety as well as physical fitness have a greater impact
on e4 carriers (especially homozygotes) than on e4
noncarriers
• Despite preclinical frontal amyloid deposition, the
earliest neuropsychological change reflects medial
temporal dysfunction likely due to NFT pathology
• Despite longitudinal declines on memory sensitive
measures, cross sectional comparisons using these
same tests fail to distinguish preclinical AD from controls
•
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•
Banner/Good Samaritan
Eric M. Reiman, MD*
Kewei Chen, PhD
Adam Fleisher, MD
Anita Palant
Dan Bandy
•
•
TGen
Matt Huentleman, PhD
•
•
•
Barrow Neurological Institute
Leslie Baxter, PhD
Jiong Shi, MD
•
•
ASU
Graciela Gonzalez, PhD
•
•
Mayo Clinic Jacksonville
Rosa Rademakers, PhD
•
•
•
•
Sun Health Research Institute
Marwan Sabbagh, MD
Thomas Beach, MD
Paul Coleman, PhD
•
•
•
•
•
•
•
•
•
Mayo Clinic Arizona
Dona Locke, PhD
Amylou Dueck, PhD
Sandra Yee-Benedetto, MA
Bruce Henslin
Jessie Jacobsen
Marci Zomok, RN
Charlene Snyder, DNP
Bryan Woodruff, MD
•
•
•
•
UCSF
Yadong Huang, PhD
Nga Bien-Ly, PhD
Aubrey Bernardo, PhD
•
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•
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University of Arizona
Alfred Kaszniak, PhD
Geoffrey Ahern, MD, PhD
Stephen Rapcsak, MD
•
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Duke University
Allen Roses, MD
Ann Saunders, PhD
Mike Lutz, PhD
APOE
Collaborators