1. Department of Neurology, Mayo Clinic Arizona
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

2. Definitions
Dementia is the disabling impairment of multiple cognitive functions. It is not memory loss alone.
Mild Cognitive Impairment
Single domain
Amnestic (memory loss alone)
Non-amnestic (language, executive, spatial)
Multiple domain
Preclinical Alzheimer’s disease is…?
Objective:
Neuropsychological decline
Abnormal imaging (MRI, fMRI, FDG, PiB)
CSF Biomarkers
Neuropathology
Subjective: symptoms without “objective findings”

3. 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

4. APOE e4 - a Susceptibility Gene Variant Associated with Alzheimer’s Disease - 1993
1.0
0.8
0.6
0.4
0.2
Proportion of each
genotype unaffected
Age at onset
2/3
2/4
3/3
3/4
4/4
Since 1993, the strongest confirmed genetic factor associated with late-onset Alzheimer’s disease has been the APOE gene and specifically the E4 allele. Multiple genome-wide association studies have confirmed the significance of a locus on chromosome 19 that includes several genes – APOE, TOMM40 and APOC1 – with extremely significant associations on order of and high linkage disequilibrium within the region.
The characteristic age of onset curves for Alzheimer’s disease stratified by APOE genotype have been confirmed in numerous studies. Note that the age of onset at the 50 percent affected point is approximately 75 years for APOE e3/4.
60 to 80 percent of the risk for late-onset Alzheimers disease is considered to be due to genetic factors. We asked the question, are there other genetic factors, especially factors linked to the APOE e3 allele, in this locus associated with the risk of late-onset Alzheimers disease? 4

5. Global APOE Allele Distribution: Highest e4 (Corbo and Scacchi, Am Hum Genet 1999)
Pygmies
0.057
0.536
0.407
Khoi San
0.077
0.553
0.370
Papuans
0.145
0.486
0.368
Lapps
0.050
0.640
0.310
Nigerians
0.027
0.677
0.296
Sudanese
0.081
0.619
0.291
Cayapas
0.0
0.720
0.280
Polynesians
0.110
0.630
0.260
Aborigines
0.740

6. Global APOE Allele Distribution: Lowest e4 (Corbo and Scacchi, Am Hum Genet 1999)
Sardinians
0.050
0.898
0.052
Greeks
0.054
0.878
0.068
Chinese
0.105
0.824
0.071
Turks
0.061
0.860
0.079
Moroccans
0.065
0.850
0.085
Mayans
0.0
0.911
0.089
Spaniards
0.856
0.091
Italians
0.060
0.849
Japanese
0.048
0.851
0.101

7. Defining Preclinical MCI (NIA-AA 2011)
<

8. Methods Subject selection Test Procedures Longitudinal Study
APOE Genotyping
Screening tests
APOE and ADC Cohorts
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

9. Brain Imaging

10. DTI of year old Healthy APOE e4 Carriers (courtesy of Leslie Baxter) (13 e4 carriers vs 18 e4 noncarriers, mean age 60 yrs)

11. PIB PET in Presymptomatic 60 YO’s
(Reiman EM et al, PNAS 2009)

12. PiB retention by APOE status
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 population-based 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

13. 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
There was a modest association between PiB retention and cognitive function in cognitively normal older adults and this relationship between A load and cognitive function is modified by APOE status. Whereas A load is associated with greater cognitive impairment in APOE 4 carriers, the cognitive function in APOE 4 noncarriers is influenced less by the A load, suggesting that APOE isoforms modulate the harmful effects of A on cognitive function.
● APOE ε2 carrier
● APOE ε3 homozygote
● APOE ε4 carrier
Kantarci et al. Neurology 2012

14. Neuropathology

15. Neuropathology in APOE e4 Carriers: Tampere Autopsy Series (Finland) (Kok et al, Ann Neurol 2009)

16. AD Pathology in Young APOE e4 Carriers (Kok et al, Ann Neurol 2009)
40% of yo e4’s have AP’s
40% of yo e4’s have NFT’s

17. AD Pathology in Normal Elderly: SHRI Subject Data

18. Neuropsychology APOE e4 effect Superimposed CV risk factor effects
Correlates of preclinical frontal amyloid

19. Longitudinal Modeling of Age-Related Memory Decline and APOE e4
(Normal Controls from APOE and ADC Cohorts)
NC (n=498)
e3/4 (n=238)
e4/4 (n=79) p
Age (yr)
61.4
58.4
56.8
<.001
Ed (yr)
15.4
.98
% Female
69.1
68.9
68.4
.99
% FDR
52.8
68.8
87.2
% >1 Epoch
73.1
84.8
.08
Duration
(yrs)
4.7
5.1
5.7
.01

20. Auditory Verbal Learning Test

21. 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)

22. 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

24. Aerobic Fitness and Visual Memory Performance
Low Risk Group
High Risk Group
CFT
VRT

25. Lorazepam Challenge (Stonnington et al, 2009)
Mean Groton Maze Learning Trials Total Errors score over time. (p=.04)
Mean AVLT Long Term Percent Recall score over time
(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.

26. Prevalence of CV Risk Factors
E4 HMZ
E4 HTZ
E4 NC
Total p
HTN
32.4%
31.4%
37%
34.9% .1 DM
1.4%
5.4%
10.3%
8.1%
.01
CIG
28.8%
22.1%
32%
28.7%
CHOL
33.8%
33.5%
35.2%
34.6% .6
CVany
54.8%
54.5%
60.4%
58.1%
.27 MI
2.7%
6.3%
7.9%
7.0%
.23

27. Added Impact of CV Risk Factors (Any of HTN, DM, CHOL, CIG) on e4 Homozygotes
P = NS
Caselli RJ et al, Neurology 2011 (in press)

28. 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

29. Entry Demographics NC (n=356) e3/4 (n=194) e4/4 (n=71) p Age (yr) 57.2
56.0
55.6
.37
Ed (yr)
15.5
15.7
.57
% Female
69.4
70.6
85.9
<.001
% FDR
56.1 72
87.2
% >1 Epoch
74.7
77.8
87.3
.07
Duration
(yrs)
6.2
6.3
6.6
.72
Caselli RJ et al, Neurology 2011, in press

30. 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

31. Results Summary (avlt adjusted)
R (w avlt) P
P(avlt adj)
C/NC
HMZ/NC
COWA
.12
.78 .6
.95
.81
DSS
.21
.01
.03
.23
PASAT-2
.22
.06
.004
.08
PASAT-3
.02
DigSp
.001
.49
.51
.65
.75
Arith
.035
.20
.05
.33
WCST-Ca
.88
.99
.91
.92
WCST-Er
-.28
.56
.80
.74
WCST-PE
-.25
.24
.42

32. Results: Working Memory (PASAT)
Linear, p=.06
HMZ linear p=.004
Linear, p=.02
HMZ linear, p=.01

33. 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)
T-score
49.1 (9.5)
49.7 (9.7)
49.5 (8.8)
Net Raw
17.0 (27.1)
16.9 (28.3)
16.9 (26.0) $$
-$264.69
-$221.69
-$311.72

34. Neuropsychology Battery
Intellectual Domains
Memory
Executive
Language
Spatial
“General”
Subjective
Observer
Self
Behavioral
Depression
Anxiety
Paranoia
Somatization
Aggression

35. Linear
Quadratic
Gene dose
AVLT-LTM*
.001
.009
.005
SRT-total free*
<.001
CFT recall
.25
.42
.44
VRT correct*
.045
.004
WCST-Cat
.88
.16
.09
PASAT-3 sec
.02
.10
COWAT
.84
.38
.27
TMT-A
.83
.72
.68
BNT
.03
Token
.07
.70
.60
WAIS-Similar
.96
.13
.14
WAIS-Vocab
.008
.57
JLO
.56
.11
Faces
.78
.19
CFT-copy
.43
.97
WAIS-Blocks
.04
.45
.28

36. Linear
Quadratic
Gene Dose
MMSE
.02
.41
.19
DRS*
.001
<.001
WAIS-Info
.01
.92
.37
FAQ
.09
.04
.06
Observer
.27
.29
.08
Self
.33
Ham-D
.31
.72
Beck
.26
.96
.89
PAI-Depress
.51
.07
.17
PAI-Anxiety
.64
.75
PAI-Paranoia
.18
.12
PAI-Aggress
.35
.49
PAI-Neg Image
.46

37. Memory

38. 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

39. 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 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

40. APOE Collaborators Banner/Good Samaritan Eric M. Reiman, MD*
Kewei Chen, PhD
Adam Fleisher, MD
Anita Palant
Dan Bandy
ASU
Graciela Gonzalez, PhD
Mayo Clinic Jacksonville
Rosa Rademakers, PhD
University of Arizona
Alfred Kaszniak, PhD
Geoffrey Ahern, MD, PhD
Stephen Rapcsak, MD
Duke University
Allen Roses, MD
Ann Saunders, PhD
Mike Lutz, PhD
TGen
Matt Huentleman, PhD
Barrow Neurological Institute
Leslie Baxter, PhD
Jiong Shi, MD
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
APOE Collaborators