The Meaning of Alzheimer’s Disease Across Time and Place:From the Bedside to the Desktop

Jason Karlawish

University of Pennsylvania

Jason.karlawish@uphs.upenn.edu

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.

Neurofibrillary tangles, neuritic plaques, and dystrophic neurites in CA1 subfield

PHF1

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

From: http://www.rxlist.com/osteoporosis_slideshow/article.htm

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

Jason.karlawish@uphs.upenn.edu

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?