1. WISCONSIN ALZHEIMER’S DISEASE RESEARCH CENTER
Pre-Clinical Dementia and Early Detection: Epidemiology and Recent Advances
May 2, 2013
Cynthia M. Carlsson, MD, MS
Associate Professor of Medicine, Division of Geriatrics
Vilas Distinguished Achievement Professor
University of Wisconsin School of Medicine and Public Health
Madison VA Geriatric Research, Education and Clinical Center (GRECC)
Wisconsin Alzheimer’s Disease Research Center (ADRC)
Madison, Wisconsin

2. Disclosures No financial disclosures Studies funded by:
National Institute on Aging
American Federation for Aging Research
State of Wisconsin
University of Wisconsin Dept. of Medicine
Merck and Co., Inc. supplied study drugs
for our investigator-initiated NIH-funded trial

3. Outline Epidemiology of dementia
Early detection of Alzheimer’s disease and non-Alzheimer’s dementias
Preclinical dementia biomarkers
Conclusions and future directions

4. Alzheimer’s Disease Prevalence in the United States
No. of Persons with AD, Millions
Year
Hebert et al., Arch Neurol 2003;60(8):

5. Alzheimer’s Disease Prevalence: Changes with Aging
Years
Alzheimer’s Association 2013 Alzheimer’s Disease Facts and Figures, Alzheimer’s & Dementia 2013:9(2).

6. Types of Dementia FTD VaD AD LBD AD + other
Schneider JA et al. Brain Oct;135(Pt 10): Schneider JA et al. Ann Neurol Aug;66(2):200-8.

7. NIH Initiatives to Improve Recognition & Treatment of Dementias Through Identifying Research Priorities
National Institute of Neurological Diseases and Stroke
National Institute on Aging

8. Identifying Dementia in Primary Care
Alzheimer’s disease
Lewy body dementia
Fluctuating attention, visual hallucinations, parkinsonism
Vascular dementia
Acute onset, neuroimaging findings of stroke
Frontotemporal dementia
Socially inappropriate, lack of inertia and empathy, perseverative, hyperoral
Language/spelling problems
Parkinson’s disease dementia
Has had PD for 5+ years
DLB: fluctuating attention, recurrent visual hallucinations, and parkinsonism. Suggestive features include REM sleep behavior disorder, severe neuroleptic sensitivity, and low dopamine transporter uptake in the basal ganglia on functional neuroimaging. Additional supportive features that commonly occur in DLB, but with lower specificity, include repeated falls and syncope, transient, unexplained loss of consciousness, severe autonomic dysfunction, hallucinations in other modalities, systematized delusions, depression, relative preservation of medial temporal lobe structures on structural neuroimaging, reduced occipital activity on functional neuroimaging, prominent slow wave activity on electroencephalogram, and low uptake myocardial scintigraphy.

9. Can we improve our detection of AD in clinic?
Preclinical Stages of Alzheimer’s Disease
Can we improve our detection of AD in clinic?
Normal aging
Mild Cognitive Impairment
Alzheimer’s Disease
Cognitive
Function
Accumulating AD Pathology
Age
Death

10. Mild Cognitive Impairment
Preclinical Stages of Alzheimer’s Disease
Preventive Therapy???
No symptoms,
BUT
early pathology
Normal aging
Mild Cognitive Impairment
Alzheimer’s Disease
Cognitive
Function
Accumulating AD Pathology
Age
Death
40s-60s

11. Identifying Asymptomatic At-Risk Adults
Neuroimaging
Magnetic resonance imaging (MRI)
Structure – atrophy, white matter hyperintensities
Function – cerebral blood flow
Positron emission tomography (PET)
FDG-PET – glucose uptake patterns
Amyloid imaging – amyloid burden
Cerebrospinal fluid biomarkers
β-amyloid, tau
Cognitive tests
Genetic tests (APOE4 allele)

12. Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Currently in its third phase (ADNI, ADNI-GO, ADNI-2)
Older controls (n=150), MCI (n=450), AD (n=150), subjective memory complaint (n=100)
Developed standardized MRI, PET, CSF methods
Identified earliest biomarker changes in AD pathology
Elucidated patterns & rates of change of imaging & CSF biomarkers in controls, MCI, & AD pts
Identified at-risk participants for clinical trials
Now in its third phase (ADNI, ADNI GO and ADNI 2), ADNI 2 is studying the rate of change of cognition, function, brain structure, and biomarkers in 150 elderly controls, 450 subjects with mild cognitive impairment, 150 with mild to moderate AD and a new group of 100 people with significant, yet subtle, memory complaints, referred to as the significant memory concern cohort.
Weiner MW et al.. Alz Dementia 8 (2012):S1-S68.

13. Hippocampal Atrophy in AD
Scheltens et al. Lancet Neurol 2002;1:13-20.

14. Neuroimaging for Alzheimer’s Disease
Control AD
PIB-PET: Greater amyloid deposition
MRI: Greater atrophy
FDG-PET: Reduced glucose uptake
Blennow K et al. Lancet 2006; 368: 387–403

15. Regional Cerebral Blood Flow Is Reduced in AD Patients
Statistical parametric maps of regional reduced blood flow in R inf parietal cortex, bil posterior cingulate (P <.001), bil superior and middle frontal gyri (P <.001), and L inf parietal lobe (P=.007) in AD patients compared to controls
Blood flow is reduced in areas of the brain related to memory & learning in persons with AD compared to people without AD
Johnson NA et al. Radiology 2005;234:

16. N Engl J Med 355;13 www.nejm.org September 28, 2006
Cerebrospinal Fluid (CSF) Biomarkers
N Engl J Med 355;13 September 28, 2006

17. Mild Cognitive Impairment
CSF Biomarker Changes in AD
CSF -amyloid levels
Spinal Fluid Levels
Tau
CSF tau levels
Time
Mild Cognitive Impairment
Amyloid
Healthy Memory
Alzheimer’s disease

18. Hypothetical Model of Dynamic Biomarkers in AD
Cerebrovascular dysregulation?
Jack et al. Lancet Neurol 2010;9:

19. Model of Preclinical Stages of AD
Stage 1: Asymptomatic amyloidosis
- High PET amyloid tracer retention
- Low CSF Aβ42
Stage 2: Amyloidosis + Neurodegeneration
- Neuronal dysfunction on FDG-PET/fMRI
- High CSF tau/p-tau
- Cortical thinning/Hippocampal atrophy
Stage 3: Amyloidosis + Neurodegeneration + Subtle Cognitive Decline
- Subtle change from baseline level of cognition
- Poor performance on challenging cognitive tests
- Does not yet meet criteria for MCI
Mild cognitive impairment (MCI) →AD
Sperling RA, Aisen PS, Beckett LA, et al. Alzheimers Dement 2011;7:

20. How Do We Identify Asymptomatic At-Risk Adults?
Middle-aged adults w/ parental history of AD
Wisconsin Registry for Alzheimer’s Prevention (WRAP) (PI: Mark Sager, MD)
N=1,527
mean age 54 yrs
72% with parental history of AD
46% APOE 4 carriers.
Parental history effect independent from APOE4 allele carrier status
Cognitively normal yet have CSF, MRI, and subtle cognitive changes suggested of preclinical disease

21. Neuropathologic Changes in AD:
CSF Biomarkers in Middle-aged At-risk Adults
N=50 middle-aged adults
with parental history of AD
Carlsson CM et al. J Alzheimer’s Dis 2008 Mar;13:

22. Hippocampal Atrophy Precedes Cognitive Decline in Middle-aged, At-risk Adults
Parental history positive (n=60)
Parental history negative (n=48)
Mean age 54 yrs
4-year longitudinal follow-up L R
Among all participants: persons with parental history of AD had more atrophy in the L hippocampus (red area above)
In APOE4- participants: persons with parental history of AD had more atrophy in the R hippocampus (light blue area above).
Okonkwo OC et al. Neurology 2012;78:1769–1776

23. Do AD Biomarkers Have a Role in Clinical Practice?
U.S. Food and Drug Administration approves Amyvid (Florbetapir F 18 Injection) a drug for Positron Emission Tomography (PET)

24. AD CSF Signature in Asymptomatic Middle-aged At-risk Adults
Cognitively normal older adults from ADNI (mean age 76 yrs)
Cognitively normal middle-aged adults with parental history of AD from ESPRIT trial (mean age 53 yrs)
Normal (n=114)
Normal (n=96)
CSF P-Tau 181P Level, pg/mL (Log Transformed)
CSF A1-42 Level, pg/mL
■ = APOE4 pos, AD sig
O = APOE4 neg, AD sig
■ = APOE4 pos, healthy sig
O= APOE4 neg, healthy sig
Signature 1 (red) = Alzheimer’s disease signature
Signature 2 (green) = healthy signature
De Meyer G et al. Arch Neurol 2010;67: Carlsson CM et al. AGS Plenary Session 2012.

25. In Vivo Amyloid Imaging Predicts Progression from MCI to AD
Doraiswamy PM et al. Neurology Oct 16;79(16):

26. Appropriate Use Criteria for Amyloid PET
Patients with persistent or progressive unexplained MCI
Patients with possible AD (i.e., atypical clinical course or mixed features)
Patients with atypical young-onset dementia
K.A. Johnson et al. Alzheimer’s & Dementia 9 (2013) e1–e16.

27. How Might We Use Biomarkers in the Future?
High risk
Moderate risk
Low risk
Very low risk
Alzheimer’s Risk
Profile
Does this patient need newly-approved AD preventive therapy?

28. Conclusions
Early recognition of AD and non-AD dementias in primary care:
helps families better understand the disease and how to plan for the future
will prepare us to efficiently prevent & treat dementia as therapies are identified
will allow us to refer our patients earlier into clinical studies
Biomarkers are effective research tools to identify persons at risk for cognitive decline, but have limited clinical utility currently.

29. Dementia Treatment & Prevention: Opportunities for Primary Care Providers
Improve our identification of AD and non-AD dementias
Familiarize ourselves with new biomarkers and their clinical indications
Aggressively control vascular risk factors
Emphasize healthy lifestyles (exercise, weight management)
Encourage participation in clinical research

30. Alzheimer’s Association Trial Match
NIA Alzheimer’s Disease Centers
NIA Alzheimer’s Disease Centers

31. A special thanks to all of our dedicated research participants.
Acknowledgments
Wisconsin Alzheimer’s Disease Research Center:
Sanjay Asthana, MD
Craig Atwood, PhD
Ben Austin, PhD
Hanna Blazel, MS
N. Maritza Dowling, PhD
Carey Gleason, PhD
Bruce Hermann, PhD
Laura Jacobson, BS
Sterling Johnson, PhD
Ozioma Okonkwo, PhD
Luigi Puglielli, MD, PhD
Howard Rowley, MD
Mark Sager, MD
Funding:
NIA
NCRR
UW Department of Medicine
Madison VA GRECC
WI Comprehensive Memory Program Pilot Award
AFAR
Merck and Co., Inc. supplied study drugs for NIH-funded study
Sahlgrenska Academy, Sweden:
Henrik Zetterberg, MD, PhD
Kaj Blennow, MD, PhD
A special thanks to all of our dedicated research participants.