Richard J. Caselli, MD Department of Neurology, Mayo Clinic Arizona

1. Preclinical Stage Alzheimer's DiseaseDefining 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. 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 The Genetic Basis of Alzheimer’s Disease

4. APOE e4 - a Susceptibility Gene Variant Associated with Alzheimer’s Disease - 1993 1.0 2/3 0.8 2/4 0.6 3/3 Proportion of each genotype unaffected 0.4 3/4 0.2 4/4 0 60 65 70 75 80 85 Age at onset

5. Global APOE Allele Distribution: Highest e4(Corbo and Scacchi, Am Hum Genet 1999)

6. Global APOE Allele Distribution: Lowest e4(Corbo and Scacchi, Am Hum Genet 1999)

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

8. 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 Methods

9. Brain Imaging

10. 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)

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

12. 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 ● APOEε2 carrier ● APOEε3 homozygote ● APOEε4 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 50-59 yo e4’s have AP’s 40% of 50-59 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)

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

27. Added Impact of CV Risk Factors (Any of HTN, DM, CHOL, CIG) on e4 Homozygotes P < .001 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 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)

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)

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

37. Memory

38. Preclinical Battery (age 50-65)

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 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

40. 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 APOECollaborators