Karlawish, Jason

Langa, Kenneth M

English

Kosmopolis

University of Pennsylvania 
ScholarlyCommons 
Neuroethics Publications Center for Neuroscience & Society 
12-2016 
Unfinished Business in Preventing Alzheimer Disease 
Jason Karlawish 
University of Pennsylvania, jason.karlawish@uphs.upenn.edu 
Kenneth M. Langa 
Follow this and additional works at: https://repository.upenn.edu/neuroethics_pubs 
 Part of the Bioethics and Medical Ethics Commons, Neuroscience and Neurobiology Commons, and 
the Neurosciences Commons 
Recommended Citation (OVERRIDE) 
Karlawish, Jason; Langa, Kenneth M. "Unfinished Business in Preventing Alzheimer Disease." JAMA 
Internal Medicine 176(12): 1739-1740. December 1, 2016 
This paper is posted at ScholarlyCommons. https://repository.upenn.edu/neuroethics_pubs/152 
For more information, please contact repository@pobox.upenn.edu. 
Unfinished Business in Preventing Alzheimer Disease 
Keywords 
Alzheimer Disease 
Disciplines 
Bioethics and Medical Ethics | Neuroscience and Neurobiology | Neurosciences 
This journal article is available at ScholarlyCommons: https://repository.upenn.edu/neuroethics_pubs/152 
Copyright 2016 American Medical Association. All rights reserved.
Unfinished Business in Preventing
Alzheimer Disease
By law, the United States has a plan to address Alzhei-
mer disease.1 The first of the National Alzheimer Proj-
ect Act’s 5 goals is the discovery by 2025 of interven-
tions that prevent and effectively treat the disease. The
eTable in the Supplement summarizes 5 current preven-
tion trials, most supported jointly by the National Insti-
tutes of Health and pharmaceutical companies.2 This
alignment of public and private interests, shared re-
sources, and the willingness of thousands of cogni-
tively normal adults with heightened genetic or bio-
marker risk of Alzheimer disease to enroll in trials are
signs of progress. The plan is missing an important
strategy, however.
The aim of the medications being tested is to pre-
vent, or significantly delay, the onset of symptomatic
Alzheimer disease. Only 1 of the 5 trials, however
(Generation; NCT02565511), uses measures of sympto-
matic disease or function as a coprimary end point. In-
stead, most use only a measure of cognition, called an
"intermediate clinical end point" because it does not
establish meaningful clinical benefit.3 The US Food and
Drug Administration’s (FDA) accelerated approval guid-
ance, developed initially in response to public demand
to speed HIV treatments, permits this evaluation strat-
egy for serious and life-threatening diseases, such as
Alzheimer disease.4 After approval, the expectation is
that evidence will be gathered to establish meaningful
clinical benefit.3 The national Alzheimer disease plan
lacks a strategy to decide what this evidence is and how
it should be gathered and interpreted.
A strategy for gathering and interpretating infor-
mation is needed before the FDA approves a new drug
to prevent Alzheimer disease. After approval, the drug
will be marketed under a brand name, and public and
private interests and resources will begin to diverge.
Recent controversies over the cost of oncology medi-
cations show how private interests shape the evidence
that establishes that a medication has meaningful clini-
cal benefit, and therefore its price.5
The Anti-Amyloid Treatment in Asymptomatic
Alzheimer Study (A4 Study; NCT02008357) offers a case
study. The A4 Study is testing whether 3 years of treat-
ment with solanezumab, a drug designed to decrease
brain amyloid deposition and which is also being studied
in persons with mild–stage Alzheimer disease dementia,
slows the rate of cognitive decline in cognitively normal
adults ages 65 to 85 years who have evidence of el-
evated brain amyloid by positron emission tomography
scanning. The primary end point of the A4 Study is the
Alzheimer Disease Cooperative Study–Preclinical
Alzheimer Cognitive Composite (ADCS–PACC), a com-
posite of 4 cognitive tests (2 measures of memory, a
measure of executive function, and the Mini-Mental State
Exam [MMSE]). What if the trial shows that, compared
with placebo, persons on the study drug have slower cog-
nitive decline? How is it established that this is a mean-
ingful clinical benefit? At present, it is not known whether
a statistically significant difference in ADCS-PACC scores
between patients in different study groups would trans-
late to a clinically meaningful improvement in current or
future ability to perform important cognitive tasks, such
as managing finances or taking medications.
Among chronic diseases of aging, Alzheimer dis-
ease is unique. About three-quarters of the economic
effect is related to the need for long-term daily care.6
Therefore, the benefit of a prevention therapy is shown
if it allows people to remain independent (ie, not de-
mented) longer than if they did not take the treatment.
Studies should track functional outcomes such as the need
for care (either as supervision or assistance) from family
or professionals at home or in a long-term care facility.
Answers to 3 questions will help to quantify these
outcomes: (1) Is there a slowing of the trajectory of cog-
nitive decline after the onset of dementia? (2) Does treat-
ment lead to a lengthening of the mild or severe stages
of dementia? (3) Does treatment delay death and, if so,
is treatment associated with compression or expan-
sion of the time living with dementia?
A trial that measures 36 months of treatment can-
not answer these questions because the outcomes that
establish the efficacy of a drug for preventing Alzheimer
disease—maintenance of independent function and de-
creased caregiving requirements—may not become ap-
parent for considerably more than 3 years. Decision ana-
lytic models for the ADCS-PACC outcome can be used to
extrapolate effects on other outcomes in the treated
group vs the untreated group.7 Such models can provide
estimates of long-term treatment benefits under differ-
ent assumptions about how the intermediate clinical end
point relates to clinical outcomes. Decision analytic mod-
els are not a substitute for clinical outcomes, however.
The participants in Alzheimer disease prevention
trials should continue to be followed in observational
cohort studies. Tracking functional outcomes (for
example, managing finances, medications, and driv-
ing), as well as scores on cognitive tests, should make it
easier to determine whether presymptomatic treat-
ments actually prevent disability and dementia. It is also
important to study the relationships between cognitive
and clinical outcomes in patients who are more repre-
sentative than those in clinical trials. This might be pos-
sible by adding the cognitive measures used in preven-
tion trials to existing longitudinal cohorts, such as the
Medicare Current Beneficiary Survey, the Framingham
Heart Study, the Health and Retirement Study, and the
National Health and Aging Trends Study.
VIEWPOINT
Jason Karlawish, MD
Perelman School of
Medicine, Departments
of Medicine, Medical
Ethics and Health
Policy, and Neurology,
Penn Program for
Precision Medicine for
the Brain, University of
Pennsylvania,
Philadelphia.
Kenneth M. Langa,
MD, PhD
Institute for Social
Research, Institute for
Healthcare Policy and
Innovation,
Department of Internal
Medicine, University of
Michigan, Ann Arbor;
and Veterans Affairs
Ann Arbor Center for
Clinical Management
Research, Ann Arbor,
Michigan.
Supplemental
content
Corresponding
Author: Jason
Karlawish, MD,
University of
Pennsylvania,
3615 Chestnut St,
Philadelphia, PA 19104
(jason.karlawish
@uphs.upenn.edu).
Opinion
jamainternalmedicine.com (Reprinted) JAMA Internal Medicine December 2016 Volume 176, Number 12 1739
Downloaded From:  by a University of Pennsylvania User  on 01/04/2018
Copyright 2016 American Medical Association. All rights reserved.
The national strategy to establish the benefits of a treatment
to prevent Alzheimer disease should address 4 considerations.
First, the claim that such a treatment provides clinically meaningful
benefit will engage competing interests: the interest of the public—
patients, families, and public programs such as Medicare—who
want efficacious and affordable treatments and private, for-profit
interests of companies who own treatments and understandably
also want to maximize the return on their investments. The
National Alzheimer Project Act provides a public forum to assemble
these interests, prespecify approaches to interpret and weigh
evidence, and to make data and data analyses publicly available.
Second, older adults who receive therapies to prevent Alzhei-
mer disease will typically have chronic diseases (eg, cardiovascular
disease) that increase their risk of both cognitive decline and death.
A treatment-related delay in the onset of dementia should occur be-
fore an individual is likely to die from another cause. Balancing the
benefits and risks of preventing dementia should include consider-
ation of the competing risk of death from other causes.
Third, persons with Alzheimer disease are said to die twice, first
in mind and then in body years later. The judgment that a treatment
is valuable because patients lived longer should align with other val-
ues such as whether autonomy and quality of life are preserved. For
Alzheimer disease, patient-reported measures of autonomy and qual-
ity of life are problematic. Even at the mild cognitive impairment stage,
patients often underreport the severity of functional losses.8 Infor-
mation from spouses or adult children may be unavailable or of un-
certain accuracy. Automated monitoring of financial tasks or driving
might detect the earliest symptoms, but software that monitors, ag-
gregates, and analyzes financial transactions or driving behaviors raises
concerns about intrusions into privacy and independence and also
setting validated thresholds that justify intervention.
Fourth, patients may discontinue the medication. If discontinu-
ation rates of Alzheimer prevention drugs are the same as for car-
diovascular drugs (5% to 10% per year), the treatment benefit, if
there is one, is likely to decrease over time.9 The discontinuation rates
for investigational agents are not yet known; however, if they are
to prevent the onset of symptoms, they may need to be taken on a
regular basis for years.
Symptomatic Alzheimer disease is common, debilitating, and
costly. Although a national plan to prevent symptomatic disease can
address these problems, the plan needs an additional strategy to
show that expedited approval of new medications will truly
improve the lives of the millions of patients with asymptomatic
Alzheimer disease who may take them.
ARTICLE INFORMATION
Funding and Support: Dr Karlawish is supported
by the National Institute on Aging (grant No. NIA
P30 AG01024), and the Centers for Disease Control
and Prevention (CDC) Healthy Brain Research
Network is supported in part by cooperative
agreements from the CDC's Prevention Research
Centers Program (U48 DP 005006, 005002,
005053, 005000, and 005013). Dr Langa is
supported by the National Institute on Aging
(grants NIA U01 AG009740, NIA P30 AG024824,
and NIA P30 AG053760).
Role of the Funder/Sponsor: The funders/
sponsors had no role in the preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Published Online: October 17, 2016.
doi:10.1001/jamainternmed.2016.6310
Conflict of Interest Disclosures: None reported.
REFERENCES
1. National Alzheimer’s Project Act. 2016; https:
//aspe.hhs.gov/national-alzheimers-project-act.
Accessed March 8, 2016.
2. Friedrich MJ. Researchers test strategies to
prevent Alzheimer disease. JAMA. 2014;311(16):
1596-1598.
3. Kozauer N, Katz R. Regulatory innovation and
drug development for early-stage Alzheimer’s
disease. N Engl J Med. 2013;368(13):1169-1171.
4. Approval based on a surrogate endpoint or on
an effect on a clinical endpoint other than survival
or irreversible morbidity. 21 CFR §314.510.
5. Neumann PJ, Cohen JT. Measuring the value of
prescription drugs. N Engl J Med. 2015;373(27):
2595-2597.
6. Hurd MD, Martorell P, Delavande A, Mullen KJ,
Langa KM. Monetary costs of dementia in the
United States. N Engl J Med. 2013;368(14):1326-1334.
7. Cohen JT, Neumann PJ. Decision analytic models
for Alzheimer’s disease: state of the art and future
directions. Alzheimers Dement. 2008;4(3):212-222.
8. Tabert MH, Albert SM, Borukhova-Milov L, et al.
Functional deficits in patients with mild cognitive
impairment. Neurology. 2002;58(5):758-764.
9. Burke JF, Langa KM, Hayward RA, Albin RL.
Modeling test and treatment strategies for
presymptomatic Alzheimer disease. PLoS One.
2014;9(12):e114339.
Opinion Viewpoint
1740 JAMA Internal Medicine December 2016 Volume 176, Number 12 (Reprinted) jamainternalmedicine.com
Downloaded From:  by a University of Pennsylvania User  on 01/04/2018


Unfinished Business in Preventing Alzheimer Disease

ScholarlyCommons@Penn

University of Pennsylvania ScholarlyCommons Neuroethics Publications Center for Neuroscience & Society 12-2016 Unfinished Business in Preventing Alzheimer Disease Jason Karlawish University of Pennsylvania, jason.karlawish@uphs.upenn.edu Kenneth M. Langa Follow this and additional works at: https://repository.upenn.edu/neuroethics_pubs  Part of the Bioethics and Medical Ethics Commons, Neuroscience and Neurobiology Commons, and the Neurosciences Commons Recommended Citation (OVERRIDE) Karlawish, Jason; Langa, Kenneth M. "Unfinished Business in Preventing Alzheimer Disease." JAMA Internal Medicine 176(12): 1739-1740. December 1, 2016 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/neuroethics_pubs/152 For more information, please contact repository@pobox.upenn.edu. Unfinished Business in Preventing Alzheimer Disease Keywords Alzheimer Disease Disciplines Bioethics and Medical Ethics | Neuroscience and Neurobiology | Neurosciences This journal article is available at ScholarlyCommons: https://repository.upenn.edu/neuroethics_pubs/152 Copyright 2016 American Medical Association. All rights reserved.Unfinished Business in PreventingAlzheimer DiseaseBy law, theUnited Stateshas a plan to address Alzhei-mer disease.1 The first of the National Alzheimer Proj-ect Act’s 5 goals is the discovery by 2025 of interven-tions that prevent andeffectively treat thedisease. TheeTable in theSupplement summarizes5currentpreven-tion trials, most supported jointly by the National Insti-tutes of Health and pharmaceutical companies.2 Thisalignment of public and private interests, shared re-sources, and the willingness of thousands of cogni-tively normal adults with heightened genetic or bio-marker risk of Alzheimer disease to enroll in trials aresigns of progress. The plan is missing an importantstrategy, however.The aim of the medications being tested is to pre-vent, or significantly delay, the onset of symptomaticAlzheimer disease. Only 1 of the 5 trials, however(Generation;NCT02565511), usesmeasuresof sympto-matic disease or function as a coprimary end point. In-stead, most use only a measure of cognition, called an"intermediate clinical end point" because it does notestablishmeaningful clinical benefit.3 TheUS Food andDrugAdministration’s (FDA) acceleratedapproval guid-ance, developed initially in response to public demandto speed HIV treatments, permits this evaluation strat-egy for serious and life-threatening diseases, such asAlzheimer disease.4 After approval, the expectation isthat evidence will be gathered to establish meaningfulclinical benefit.3 The national Alzheimer disease planlacks a strategy todecidewhat this evidence is andhowit should be gathered and interpreted.A strategy for gathering and interpretating infor-mation is needed before the FDA approves a new drugto prevent Alzheimer disease. After approval, the drugwill be marketed under a brand name, and public andprivate interests and resources will begin to diverge.Recent controversies over the cost of oncology medi-cations show how private interests shape the evidencethat establishes that a medication hasmeaningful clini-cal benefit, and therefore its price.5The Anti-Amyloid Treatment in AsymptomaticAlzheimerStudy(A4Study;NCT02008357)offersacasestudy. The A4 Study is testing whether 3 years of treat-ment with solanezumab, a drug designed to decreasebrain amyloiddeposition andwhich is alsobeing studiedinpersonswithmild–stageAlzheimer diseasedementia,slows the rate of cognitive decline in cognitively normaladults ages 65 to 85 years who have evidence of el-evated brain amyloid by positron emission tomographyscanning. The primary end point of the A4 Study is theAlzheimer Disease Cooperative Study–PreclinicalAlzheimer Cognitive Composite (ADCS–PACC), a com-posite of 4 cognitive tests (2 measures of memory, ameasureofexecutivefunction,andtheMini-MentalStateExam [MMSE]). What if the trial shows that, comparedwithplacebo,personsonthestudydrughaveslowercog-nitive decline? How is it established that this is a mean-ingfulclinicalbenefit?Atpresent, it isnotknownwhethera statistically significant difference inADCS-PACCscoresbetweenpatients in different study groupswould trans-late to a clinicallymeaningful improvement in current orfuture ability to perform important cognitive tasks, suchasmanaging finances or takingmedications.Among chronic diseases of aging, Alzheimer dis-ease is unique. About three-quarters of the economiceffect is related to the need for long-term daily care.6Therefore, the benefit of a prevention therapy is shownif it allows people to remain independent (ie, not de-mented) longer than if they did not take the treatment.Studiesshouldtrackfunctionaloutcomessuchastheneedfor care (either as supervision or assistance) from familyor professionals at home or in a long-term care facility.Answers to 3 questions will help to quantify theseoutcomes: (1) Is there a slowingof the trajectoryof cog-nitivedeclineafter theonsetofdementia? (2)Doestreat-ment lead to a lengthening of themild or severe stagesof dementia? (3) Does treatment delay death and, if so,is treatment associated with compression or expan-sion of the time living with dementia?A trial that measures 36 months of treatment can-not answer these questions because the outcomes thatestablish the efficacy of a drug for preventingAlzheimerdisease—maintenance of independent function and de-creased caregiving requirements—may not become ap-parent for considerablymore than3years.Decisionana-lyticmodels for theADCS-PACCoutcomecanbeused toextrapolate effects on other outcomes in the treatedgroupvs theuntreatedgroup.7Suchmodels canprovideestimates of long-term treatment benefits under differ-entassumptionsabouthowthe intermediateclinicalendpoint relates toclinicaloutcomes.Decisionanalyticmod-els are not a substitute for clinical outcomes, however.The participants in Alzheimer disease preventiontrials should continue to be followed in observationalcohort studies. Tracking functional outcomes (forexample, managing finances, medications, and driv-ing), as well as scores on cognitive tests, shouldmake iteasier to determine whether presymptomatic treat-ments actuallypreventdisability anddementia. It is alsoimportant to study the relationships between cognitiveand clinical outcomes in patients who are more repre-sentative than those in clinical trials. This might be pos-sible by adding the cognitive measures used in preven-tion trials to existing longitudinal cohorts, such as theMedicare Current Beneficiary Survey, the FraminghamHeart Study, the Health and Retirement Study, and theNational Health and Aging Trends Study.VIEWPOINTJasonKarlawish,MDPerelman School ofMedicine, Departmentsof Medicine, MedicalEthics and HealthPolicy, and Neurology,Penn Program forPrecisionMedicine forthe Brain, University ofPennsylvania,Philadelphia.KennethM. Langa,MD, PhDInstitute for SocialResearch, Institute forHealthcare Policy andInnovation,Department of InternalMedicine, University ofMichigan, Ann Arbor;and Veterans AffairsAnn Arbor Center forClinical ManagementResearch, Ann Arbor,Michigan.SupplementalcontentCorrespondingAuthor: JasonKarlawish, MD,University ofPennsylvania,3615 Chestnut St,Philadelphia, PA 19104(jason.karlawish@uphs.upenn.edu).Opinionjamainternalmedicine.com (Reprinted) JAMA Internal Medicine December 2016 Volume 176, Number 12 1739Downloaded From:  by a University of Pennsylvania User  on 01/04/2018Copyright 2016 American Medical Association. All rights reserved.The national strategy to establish the benefits of a treatmentto prevent Alzheimer disease should address 4 considerations.First, the claim that such a treatment provides clinically meaningfulbenefit will engage competing interests: the interest of the public—patients, families, and public programs such as Medicare—whowant efficacious and affordable treatments and private, for-profitinterests of companies who own treatments and understandablyalso want to maximize the return on their investments. TheNational Alzheimer Project Act provides a public forum to assemblethese interests, prespecify approaches to interpret and weighevidence, and tomake data and data analyses publicly available.Second, older adults who receive therapies to prevent Alzhei-mer diseasewill typically have chronic diseases (eg, cardiovasculardisease) that increase their riskofboth cognitivedecline anddeath.A treatment-relateddelay in theonsetofdementia shouldoccurbe-fore an individual is likely to die from another cause. Balancing thebenefits and risks of preventing dementia should include consider-ation of the competing risk of death from other causes.Third, personswith Alzheimer disease are said to die twice, firstinmind and then in body years later. The judgment that a treatmentis valuable because patients lived longer should alignwith other val-ues such aswhether autonomy and quality of life are preserved. ForAlzheimerdisease,patient-reportedmeasuresofautonomyandqual-ityof lifeareproblematic.Evenatthemildcognitive impairmentstage,patients often underreport the severity of functional losses.8 Infor-mation from spouses or adult children may be unavailable or of un-certain accuracy. Automatedmonitoring of financial tasks or drivingmight detect the earliest symptoms, but software thatmonitors, ag-gregates,andanalyzesfinancialtransactionsordrivingbehaviorsraisesconcerns about intrusions into privacy and independence and alsosetting validated thresholds that justify intervention.Fourth, patientsmaydiscontinue themedication. If discontinu-ation rates of Alzheimer prevention drugs are the same as for car-diovascular drugs (5% to 10% per year), the treatment benefit, ifthere isone, is likely todecreaseovertime.9Thediscontinuationratesfor investigational agents are not yet known; however, if they areto prevent the onset of symptoms, theymay need to be taken on aregular basis for years.Symptomatic Alzheimer disease is common, debilitating, andcostly.Althoughanationalplan toprevent symptomaticdiseasecanaddress these problems, the plan needs an additional strategy toshow that expedited approval of new medications will trulyimprove the lives of the millions of patients with asymptomaticAlzheimer disease whomay take them.ARTICLE INFORMATIONFunding and Support:Dr Karlawish is supportedby the National Institute on Aging (grant No. NIAP30 AG01024), and the Centers for Disease Controland Prevention (CDC) Healthy Brain ResearchNetwork is supported in part by cooperativeagreements from the CDC's Prevention ResearchCenters Program (U48 DP 005006, 005002,005053, 005000, and 005013). Dr Langa issupported by the National Institute on Aging(grants NIA U01 AG009740, NIA P30 AG024824,and NIA P30 AG053760).Role of the Funder/Sponsor: The funders/sponsors had no role in the preparation, review, orapproval of themanuscript; and decision to submitthemanuscript for publication.Published Online:October 17, 2016.doi:10.1001/jamainternmed.2016.6310Conflict of Interest Disclosures:None reported.REFERENCES1. National Alzheimer’s Project Act. 2016; https://aspe.hhs.gov/national-alzheimers-project-act.AccessedMarch 8, 2016.2. Friedrich MJ. Researchers test strategies toprevent Alzheimer disease. JAMA. 2014;311(16):1596-1598.3. Kozauer N, Katz R. Regulatory innovation anddrug development for early-stage Alzheimer’sdisease. N Engl J Med. 2013;368(13):1169-1171.4. Approval based on a surrogate endpoint or onan effect on a clinical endpoint other than survivalor irreversible morbidity. 21 CFR §314.510.5. Neumann PJ, Cohen JT. Measuring the value ofprescription drugs. N Engl J Med. 2015;373(27):2595-2597.6. HurdMD, Martorell P, Delavande A, Mullen KJ,Langa KM. Monetary costs of dementia in theUnited States.NEngl JMed. 2013;368(14):1326-1334.7. Cohen JT, Neumann PJ. Decision analytic modelsfor Alzheimer’s disease: state of the art and futuredirections. Alzheimers Dement. 2008;4(3):212-222.8. Tabert MH, Albert SM, Borukhova-Milov L, et al.Functional deficits in patients with mild cognitiveimpairment. Neurology. 2002;58(5):758-764.9. Burke JF, Langa KM, Hayward RA, Albin RL.Modeling test and treatment strategies forpresymptomatic Alzheimer disease. PLoS One.2014;9(12):e114339.Opinion Viewpoint1740 JAMA Internal Medicine December 2016 Volume 176, Number 12 (Reprinted) jamainternalmedicine.comDownloaded From:  by a University of Pennsylvania User  on 01/04/2018

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Unfinished Business in Preventing Alzheimer Disease

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