The Meaning of Alzheimer’s Disease Across Time and Place:From the Bedside to the Desktop
Jason Karlawish
University of Pennsylvania
Disclosures: Site PI for Pfizer/NIA sponsored clinical trial in persons with ADProfessional advisory board for Senior Bridge Inc.
Support
• Robert Wood Johnson Foundation Investigator Award in Health Policy Research
• National Institute on Aging P30-AG10124• The Marian S. Ware Alzheimer Program
• Very special thanks to Kristin Harkins and Sarah Maceda-Maciel for their assistance with research and slide preparation.
The meaning of Alzheimer’s disease
• Alzheimer’s disease is a disease
• The disease is caused by pathology in the brain that leads to…– Disability– Lost productivity– Mortality
• Physicians diagnose Alzheimer’s disease using a careful history and physical
“Soon she developed a rapid loss of memory...”
“…only a tangle of fibrils indicates the place where a neuron was previously located.”
“Both Alzheimer disease and senile dementia are progressive dementias …
that are indistinguishable by careful clinical analyses.”
“The pathological findings are identical.”
Archives of Neurology. 33; 1976: 217-18.
Petersen RC et al. Current concepts in Mild Cognitive Impairment. Arch Neurol 2001;58:1985-1992.
Survival curve of persons characterized as having a mild cognitive impairment for 6 years
The Fourth Age of Alzheimer's Disease
• The meaning of Alzheimer's disease has changed.
• In this century it is changing again: from pathology in a person that is the cause of disability to the risk of disability that a person faces.
• What are the clinical and policy implications of this new meaning of Alzheimer's disease?
MEDLINE citations for "biomarker," per 100,000 articles
0 0.73 3.90 18.6193.79
247.00
536.92
1785.23
0
200
400
600
800
1000
1200
1400
1600
1800
2000
1970-1974 1975-1979 1980-1984 1985-1989 1990-1994 1995-1999 2000-2004 2005-2009
Year (5 year span)
Sear
ch re
sults
Articles with "biomarker" found in title, abstract, text word
MEDLINE citations for [biomarker AND Alzheimer’s], per 100,000 articles
0 0.251.31
9.96
39.71
0.26
0
5
10
15
20
25
30
35
40
45
1980-1984 1985-1989 1990-1994 1995-1999 2000-2004 2005-2009
Year (5 year span)
Sea
rch
res
ults
Articles with Alzheimer's AND biomarker found in title, abstract, text word
Probable AD: A plus one or more supportive features B, C, D, or E
Core diagnostic criteriaA. Presence of an early and significant episodic memory impairment:1. Gradual and progressive change in memory function reported by
patients or informants over more than 6 months2. Objective evidence of significantly impaired episodic memory on
testing3. The episodic memory impairment can be isolated or associated
with other cognitive changes at the onset of AD or as AD advancesSupportive featuresB. Presence of medial temporal lobe atrophyC. Abnormal cerebrospinal fluid biomarkerD. Specific pattern on functional neuroimaging with PETE. Proven AD autosomal dominant mutation within the immediate
family
Lancet Neurology. 6;2007: 734-46.
Desktop diseases
Disease Diagnostic tool (DT)
Discrete clinical event (DCE)
Intervention to validate link between DT and DCE
Dyslipemia or high cholesterol
NCEPIII 10-year risk calculator
stroke, MI statin drug
National Cholesterol Education Program (NCEP) Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Risk Assessment Tool for Estimating Your 10-year Risk of Having a Heart Attack. The National Heart, Lung, and Blood Institute (NHLBI). (Accessed June 8, 2010, at http://hp2010.nhlbihin.net/atpiii/calculator.asp?usertype=pub.)
Desktop diseasesDisease Diagnostic
tool (DT)Discrete clinical event (DCE)
Intervention to validate link between DT and DCE
dyslipemia NCEPIII 10-year risk calculator
stroke, MI Statin drug
hypertension Blood pressure reading
stroke, MI, CHF Thiazide, beta-blocker
osteoporosis FRAX bone fracture Bisphosphonate
World Health Organization. FRAX: WHO fracture risk assessment tool. World Health Organization Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, UK, 2008. (Accessed January 19, 2010, at http://www.shef.ac.uk/FRAX/index.htm.)
Feeling risk: getting the gist
“‘I know what you told me, but this is what I think:’ Perceived risk of Alzheimer disease among individuals who accurately recall their genetics-based risk estimate.”
• Among 158 participants who accurately recalled their AD risk assessment 6 weeks after risk disclosure…– 75 (47.5%) said AD risk was more than 5%
points different from their calculated AD risk estimate.
Linnenbringer et al. Genetics in Medicine. in press.
National Cholesterol Education Program (NCEP) Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Risk Assessment Tool for Estimating Your 10-year Risk of Having a Heart Attack. The National Heart, Lung, and Blood Institute (NHLBI). (Accessed June 8, 2010, at http://hp2010.nhlbihin.net/atpiii/calculator.asp?usertype=pub.)
CountryOld Age Dependency Ratio
(2020) (medium variant)
Japan 47.7
Finland 36.5
Italy 36.1
Germany 35.5
Sweden 34.0
France 33.9
Belgium 32.3
Denmark 31.8
Greece 31.6
Bulgaria 31.6
The old-age dependency ratio is the ratio of the population aged 65 years or over to the working age population (ages 15-64), presented as number of elderly per 100 persons of working age.
Red = national dementia plan
Nations with highest old age dependency ratios - 2020
Blue = some nation-wide
efforts or initiatives
Desktop diseasesDisease Diagnostic
tool (DT)Discrete clinical event (DCE)
Intervention to validate link between DT and DCE
Dyslipemia NCEPIII stroke, MI statin drug
HTN BP stroke, MI thiazide, beta-blocker
Osteoporosis FRAX bone facture
bisphosphonate
Diabetes HgA1C Dx of DM insulin, thiaglitazone
Alzheimer's Disease
??? ??? ???
The Fourth Age of Alzheimer's Disease
• Drugs & multivariate models will define the disease– What will be the discrete clinical event?– How can we break the logjam that proprietary
control and asymmetric information create?– Who will control the drugs and models?
The Fourth Age of Alzheimer's Disease
• Drugs & multivariate models will define the disease
• Risk information will be on-line and with wide access– How will we foster better risk perception and
communication?– How will we foster appropriate and sustained
risk reduction behaviors (e.g. retention in a RCT and adherence to an Rx)?
The Fourth Age of Alzheimer's Disease
• Drugs & multivariate models will define the disease
• Risk information will be on-line and with wide access
• Risk is a continuum -- treatment recommended beyond upfront clinical trial results– How will we develop guidelines that are fair
and unbiased and use all the data?
The Meaning of Alzheimer's Disease Across Time and Place:From the Bedside to the Desktop
Jason Karlawish
University of Pennsylvania
The Fourth Age of Alzheimer's Disease
• Drugs & multivariate models will define the disease
• Alzheimer's disease may not work as our organizing term
• Risk information will be on-line and with wide access– How will we foster better risk perception and
communication?– How will we foster sustained risk reduction (AKA
retention in a RCT and to an Rx)?
The Fourth Age of Alzheimer's Disease
• Drugs & multivariate models will define the disease
• Alzheimer's disease may not work as our organizing term
• Risk information will be on-line and with wide access
• Risk is a continuum -- treatment recommended beyond upfront clinical trial results– How will we develop guidelines that are fair and
unbiased using all the data?