Presentation is loading. Please wait.

Presentation is loading. Please wait.

Department of Neurology, Mayo Clinic Arizona

Similar presentations


Presentation on theme: "Department of Neurology, Mayo Clinic Arizona"— Presentation transcript:

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

23

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


Download ppt "Department of Neurology, Mayo Clinic Arizona"

Similar presentations


Ads by Google