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NIH Consensus Development Conference Statement onPreventing Alzheimers Disease and Cognitive Decline
NIH Consensus and State-of-the-Science Statements
Volume 27, Number 4April 2628, 2010
NATIONAL INSTITUTES OF HEALTHOice o the Director
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About the NIH Consensus Development Program
National Institutes o Health (NIH) Consensus and State-o-the-Science Statements are prepared by independent panels o health
proessionals and public representatives on the basis o (1) the resultso a systematic literature review prepared under contract with theAgency or Healthcare Research and Quality (AHRQ), (2) presentationsby investigators working in areas relevant to the conerence questionsduring a 2-day public session, (3) questions and statements romconerence attendees during open discussion periods that are part othe public session, and (4) closed deliberations by the panel duringthe remainder o the second day and the morning o the third. Thisstatement is an independent report o the panel and is not a policystatement o the NIH or the Federal Government.
The statement reects the panels assessment o medical knowledgeavailable at the time the statement was written. Thus, it provides asnapshot in time o the state o knowledge on the conerence topic.When reading the statement, keep in mind that new knowledge isinevitably accumulating through medical research, and that the inormationprovided is not a substitute or proessional medical care or advice.
Reference Information
Individuals who wish to cite this statement should use theollowing ormat:
Daviglus ML, Bell CC, Berrettini W, Bowen PE, Connolly ES, Cox NJ,Dunbar-Jacob JM, Granieri EC, Hunt G, McGarry K, Patel D, PotoskyAL, Sanders-Bush E, Silberberg D, Trevisan M. National Instituteso Health State-o-the-Science Conerence Statement: PreventingAlzheimers Disease and Cognitive Decline. NIH Consens State SciStatements. 2010 Apr 2628;27(4):130.
Publications Ordering Information
NIH Consensus Statements, State-o-the-Science Statements, andrelated materials are available by visiting http://consensus.nih.gov; bycalling toll ree 8886442667; or by emailing [email protected] requests can be mailed to the NIH Consensus DevelopmentProgram Inormation Center, P.O. Box 2577, Kensington, MD 20891.When ordering copies o this statement, please reerence item number
2010-00034-STMT.
The evidence report prepared or this conerence through AHRQ isavailable on the web via http://www.ahrq.gov/clinic/tp/alzcogtp.htm.Printed copies may be ordered rom the AHRQ PublicationsClearinghouse by calling 8003589295. Requesters should ask orAHRQ Publication No. 10-E005.
http:///reader/full/http://consensus.nih.govmailto:[email protected]://www.ahrq.gov/clinic/tp/alzcogtp.htmhttp:///reader/full/http://consensus.nih.govmailto:[email protected]://www.ahrq.gov/clinic/tp/alzcogtp.htm7/31/2019 Prevencin de la Enfermedad de Alzheimer y el deterioro cognitivo
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NIH Consensus Development Conference Statement on
Preventing Alzheimers Disease and Cognitive Decline
NIH Consensus and State-of-the-Science Statements
Volume 27, Number 4April 2628, 2010
NATIONAL INSTITUTES OF HEALTHOice o the Director
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Disclosure Statement
All o the panelists who participated in this conerenceand contributed to the writing o this statement wereidentifed as having no fnancial or scientifc conict ointerest, and all signed orms attesting to this act. Unlikethe expert speakers who present scientifc data at theconerence, the individuals invited to participate on NIHConsensus and State-o-the-Science Panels are reviewedprior to selection to ensure that they are not proponentso an advocacy position with regard to the topic and arenot identifed with research that could be used to answerthe conerence questions.
For more inormation about conerence procedures,please see http://consensus.nih.gov/aboutcdp.htm.
Archived Conference Webcast
The NIH State-o-the-Science Conerence: Preventing
Alzheimers Disease and Cognitive Decline waswebcast live April 2628, 2010. The webcast isarchived and available or viewing ree o chargeat http://consensus.nih.gov/2010/alz.htm.
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Abstract
Objective
To provide healthcare providers, patients, and thegeneral public with a responsible assessment o currentlyavailable data on the prevention o Alzheimers diseaseand cognitive decline.
Participants
A non-Department o Health and Human Services,nonadvocate 15-member panel representing the feldso preventive medicine, geriatrics, internal medicine,neurology, neurological surgery, psychiatry, mentalhealth, human nutrition, pharmacology, genetic medicine,nursing, health economics, health services research,amily caregiving, and a public representative. In addition,20 experts rom pertinent felds presented data to the
panel and conerence audience.
Evidence
Presentations by experts and a systematic review othe literature prepared by the Duke University Evidence-based Practice Center, through the Agency or HealthcareResearch and Quality (AHRQ). Scientifc evidence wasgiven precedence over anecdotal experience.
Conference Process
The panel drated its statement based on scientifcevidence presented in open orum and on publishedscientifc literature. The drat statement was presentedon the fnal day o the conerence and circulated to theaudience or comment. The panel released a revised
statement later that day at http://consensus.nih.gov. Thisstatement is an independent report o the panel and is nota policy statement o the NIH or the Federal Government.
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Conclusions
Cognitive decline and Alzheimers disease are majorcauses o morbidity and mortality worldwide and aresubstantially burdensome to the aected persons, theircaregivers, and society in general. Extensive researchover the past 20 years has provided important insights onthe nature o Alzheimers disease and cognitive declineand the magnitude o the problem. Nevertheless, thereremain important and ormidable challenges in conductingresearch on these diseases, particularly in the area oprevention. Currently, frm conclusions cannot be drawnabout the association o any modifable risk actor withcognitive decline or Alzheimers disease. Highly reliableconsensus-based diagnostic criteria or cognitive decline,mild cognitive impairment, and Alzheimers disease arelacking, and available criteria have not been uniormlyapplied. Evidence is insufcient to support the use opharmaceutical agents or dietary supplements to prevent
cognitive decline or Alzheimers disease. We recognizethat a large amount o promising research is under way;these eorts need to be increased and added to bynew understandings and innovations (as noted in ourrecommendations or uture research).
For example, ongoing studies including (but not limitedto) studies on antihypertensive medications, omega-3atty acids, physical activity, and cognitive engagement
may provide new insights into the prevention or delay ocognitive decline or Alzheimers disease. This importantresearch needs to be supplemented by urther studies.Large-scale population-based studies and randomizedcontrolled trials (RCTs) are critically needed to investigatestrategies to maintain cognitive unction in individualsat risk or decline, to identiy actors that may delay theonset o Alzheimers disease among persons at risk,
and to identiy actors that may slow the progressiono Alzheimers disease among persons in whom thecondition is already diagnosed.
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Introduction
Alzheimers disease is the most common cause odementia. It was frst described in 1906 by Germanpsychiatrist and neuropathologist Alois Alzheimer, whoobserved the pathological hallmarks o the diseaseabnormal clumps o protein (beta-amyloid plaques) andtangled bundles o protein fbers (neurofbrillary tangles)in the brain o a emale patient who had experiencedmemory loss, language problems, and unpredictablebehavior. An important breakthrough was the invention
o the photomicrograph in the early 1900s by SolomonCarter Fuller, an Arican American psychiatrist; this keyinnovation provided a method or taking photographsthrough the lens o a microscope, allowing visualizationo amyloid plaques and neurofbrillary tangles.
Since its frst description, Alzheimers disease hasgone rom a rarely reported disorder to one o themost common disabling diseases among older adults.
The increasing proportion o older adults in the U.S.population reinorces the urgent need or prevention andtreatment o all chronic diseases including Alzheimersdisease. In most individuals, cognitive health andperormance remain stable over the lietime, with only agradual decline in short-term memory and processingspeed. For others, however, the decline in cognitiveunction progresses to a more serious state o cognitiveimpairment or into various orms o dementia. Mildcognitive impairment is characterized by problems withmemory, language, or other essential cognitive unctionsthat are severe enough to be noticed by others and arereected on cognitive tests, but are not severe enoughto interere with daily lie. Dementia is characterized byprogressive global deterioration o cognitive abilitiesin multiple domains including memory and at leastone additional arealearning, orientation, language,comprehension, and judgmentsevere enough tointerere with daily lie.
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The diagnosis o Alzheimers disease is difcult andoten imprecise, but its importance is without question.Depending on the diagnostic and pathologic criteria
employed, Alzheimers disease accounts or 60 to80 percent o all dementia cases. As many as 5.1million Americans may currently have the disease, andthe prevalence o mild cognitive impairment is evenhigher. Furthermore, the number o persons aectedby Alzheimers disease or mild cognitive impairment isexpected to increase considerably with the aging o thebaby boomer generation. Alzheimers disease is the sixth
leading cause o death in the United States and the fthleading cause o death in Americans age 65 and older.Alzheimers disease and other dementias cost more than$148 billion in the United States annually, and theseconditions also exact a substantial toll on patients andcaregivers in terms o fnancial costs, stress, and anguish.
To date, numerous studies have attempted to describethe etiology and actors associated with the riskor development and progression o mild cognitiveimpairment and Alzheimers disease, generating anabundance o theories on potential risk actors andtherapies. Age is the strongest known risk actor orAlzheimers disease; most people with the late-onsetorm o the disease receive the diagnosis ater age 60.An early-onset amilial orm also occurs, but it is rare.
Genetic, cardiovascular, and liestyle actors also havebeen implicated.
To examine this important topic more closely, the NationalInstitute on Aging and the Ofce o Medical Applicationso Research o the National Institutes o Health conveneda State-o-the-Science Conerence on April 2628, 2010,to assess the available scientifc evidence related to theollowing questions:
1. What actors are associated with the reduction o risko Alzheimers disease?
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2. What actors are associated with the reduction o risko cognitive decline in older adults?
3. What are the therapeutic and adverse eects o
interventions to delay the onset o Alzheimersdisease? Are there dierences in outcomes amongidentifable subgroups?
4. What are the therapeutic and adverse eects ointerventions to improve or maintain cognitive abilityor unction? Are there dierences in outcomes amongidentifable subgroups?
5. What are the relationships between the actors thataect Alzheimers disease and the actors that aectcognitive decline?
6. I recommendations or interventions cannot be madecurrently, what studies need to be done to provide thequality and strength o evidence necessary to makesuch recommendations to individuals?
At the conerence, invited experts presented inormationrelevant to these questions. A systematic evidence review,prepared under contract with the Agency or HealthcareResearch and Quality (AHRQ) rom the Evidence-basedPractice Center (EPC) at Duke Universitys ClinicalResearch Institute, was summarized (available athttp://ahrq.gov/clinic/tp/alzcogtp.htm). It emphasized
randomized controlled trials (RCTs) with health outcomesas their endpoints. Conerence participants also providedoral and written comments in response to the conerencequestions, and the panel considered all o this evidencewhen preparing the consensus statement.
The panel review included relevant studies on therelationship o multiple actors, including nutritional,medical, social, economic, behavioral, environmental, andgenetic, with mild cognitive impairment or Alzheimersdisease. The scope o the review was restricted tohuman studies conducted in developed countries with
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sample sizes o at least 50 participants or RCTs and 300participants or observational studies, and a minimumduration between exposure to preventive interventions
and outcomesto assess success o interventionso 1year or studies o mild cognitive impairment and 2 yearsor studies o Alzheimers disease. The panel consideredstudies published in English that included participants50 years or older, o both sexes, and o diverse racialand ethnic populations. Studies were rated by the EPCbased on their quality by using the GRADE (Gradingo Recommendations Assessment, Development, and
Evaluation) criteria. The panels charge was confned toanswer questions related to prevention and not treatmento established Alzheimers disease and cognitive decline.
1. What Factors Are Associated With theReduction o Risk o Alzheimers Disease?
Currently, no evidence o even moderate scientifc qualityexists to support the association o any modifable actor(such as nutritional supplements, herbal preparations,dietary actors, prescription or nonprescription drugs,social or economic actors, medical conditions, toxins,or environmental exposures) with reduced risk oAlzheimers disease.
What We Know
Genetic actors, particularly the apolipoprotein E (ApoE)gene variation, are associated with risk o Alzheimersdisease. Although better understanding o genetic riskactors or Alzheimers disease may ultimately lead toeective therapies, the observed genetic associationsare currently relevant largely as stratifcation actors in
studies designed to identiy additional risk actors and inclinical trials designed to test eectiveness o therapies.
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Numerous modifable actors have been reported to showassociation with risk or Alzheimers disease across multiplestudies, but the overall scientifc quality o the evidence is
low. Thus additional studies on these actors may change,perhaps substantially, the magnitude or direction o theobserved associations. Chronic diseases and conditionssuch as diabetes, elevated blood cholesterol level in midlie,and depression have been associated with increased risko Alzheimers disease. Several dietary and liestyle actorsand medications also have been linked to a decreasedrisk o Alzheimers disease; these include adequate olic
acid intake, low saturated at consumption, high ruit andvegetable consumption, use o statins, light to moderatealcohol consumption, educational attainment, cognitiveengagement, and participation in physical activities. Currentsmoking, never having been married, and having low socialsupport are all reported to be associated with increasedrisk o Alzheimers disease. However, the quality o evidenceor the association o these actors with Alzheimers
disease is low. No consistent associations were ound orother vitamins; atty acids; the metabolic syndrome; bloodpressure; plasma homocysteine level; obesity and bodymass index; antihypertensive medications; nonsteroidalanti-inammatory drugs; gonadal steroids; or exposuresto solvents, electromagnetic felds, lead, or aluminum.
Limitations
One o the challenges o interpreting fndings o existingstudies on risk actors or Alzheimers disease is the lack oa consistent and uniormly applied defnition o Alzheimersdisease. Another key challenge is distinguishing actorsassociated with Alzheimers disease rom actors associatedwith other late-onset disorders that are prevalent in olderadults. For example, vascular disease can lead to
dementias, and because vascular disease is commonin elderly persons, it oten may be present in individualswith Alzheimers disease. Thus, it can be difcult todierentiate between actors associated with Alzheimers
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disease because o their contribution to vascular diseaseand related dementias and actors that are truly associatedwith Alzheimers disease. Similarly, it is unclear whether
some o the observed associations, such as depression,might reect early eatures o Alzheimers disease.
The primary limitation o most o these studies is thedistinction between association and causality. Diseasesare complex; they are determined and shaped by manyvariables. Factors that are reproducibly associated withdisease, even when they are not contributing causally,can still be useul as potential predictors o risk. But theprimary reason that association studies are conductedis to identiy actors that might actually contribute torisk o disease. A key problem with associations is thatthey oten involve actors that are themselves correlated.For example, individuals with higher levels o educationalso are more likely to have higher levels o cognitiveengagement. When a set o correlated actors showsan association with disease, it is difcult to determinewhether any (or all) o the actors contributes causally todisease. Alternatively, one or more unobserved actors(correlated with the others) may actually account or theobserved associations.
2. What Factors Are Associated With theReduction o Risk o Cognitive Declinein Older Adults?
Cognition is a combination o skills that include attention,learning, memory, language, visuospatial skills, andexecutive unction, such as decisionmaking, goal setting,planning, and judgment. Decline in cognition ranges romsevere dementia, such as Alzheimers disease, to mild
cognitive impairment and age-related cognitive decline.Cognitive decline is multicausal, and mild cognitiveimpairment does not always progress to dementia.Neuropsychological testing or the above-mentioned
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skills over varying time periods has been the predominantmethod or the evaluation o cognitive change, butunctional cognitive decline is only moderately associated
with pathologic changes typical o Alzheimers disease.The idea o cognitive reserve (the minds resilience toneuropathologic damage o the brain) explains variancesin ability to cope physiologically and mentally with existingpathology. Despite the hopeul insights provided by thisconcept, these issues complicate attempts to designrobust studies to determine actors that might preventcognitive decline.
What We Know
For most actors, existing studies either show noassociation with cognitive decline or provide inconclusiveevidence. Where an association was seen, the overallquality o the evidence is low.
Nutritional and Dietary Factors. The available evidence
does not support a clear role or most o the nutritionaland dietary actors that have been examined. The mostconsistent evidence is available or longer chain omega-3atty acids (oten measured as fsh consumption), withseveral longitudinal studies showing an association withreduced risk or cognitive decline. For the other actors,the evidence varies rom no consistent association(vitamin B, vitamin E, vitamin C, olate, and beta-carotene)
to very limited evidence suggesting a possible protectiveeect (low saturated at and high vegetable intake).
Medical Factors. Several cardiovascular risk actorshave been consistently associated with increased riskor cognitive decline. High blood pressure has beenmost consistently associated with cognitive decline,and particularly with severe cognitive decline. Diabetes
also has been associated with an increased risk orcognitive decline, but this association is modest andless consistent. The metabolic syndrome, a cluster ometabolic abnormalities, has been consistently associated
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with a modest risk or cognitive decline. For other medicalactors, good-quality studies are lacking (or example,sleep apnea and traumatic brain injury) or fndings have
been inconclusive (or example, obesity).Psychological and Emotional Health. Depression anddepressive symptoms have been consistently oundto be associated with mild cognitive impairment andcognitive decline.
Medications. No consistent epidemiologic evidenceexists or an association with statins, antihypertensive
medications, or anti-inammatory drugs. Data areinsufcient to comment on cholinesterase inhibitorsor memantine. Existing reports are difcult to interpretbecause o variation in ormulations, dosage, duration,route o administration (as or postmenopausalestrogens), and drug treatment eect (or example,antihypertensive medications).
Socioeconomic Factors. Childhood socioeconomic statusor cognitive milieu does not appear to strongly inuencecognitive decline later in lie. Evidence on the putativeassociation between years o education and cognitivedecline is inconsistent.
Social and Cognitive Engagement. Whereas fndingson the association o cognitive decline with living aloneor being without a partner are inconsistent, a robust
association exists between the loss o a spouse andcognitive decline. Limited but inconsistent evidencesuggests that increased involvement in cognitive activitiesin later lie may be associated with slower cognitivedecline and lower risk or mild cognitive impairment.
Physical Activity and Other Leisure Activities. Preliminaryevidence suggests benefcial associations o physical
activity and other leisure activities (such as clubmembership, religious services, painting, or gardening)with preservation o cognitive unction.
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Tobacco and Alcohol Use. Evidence indicates that currentsmoking is associated with increased risk or cognitivedecline; evidence or past smoking is less consistent.
Findings on the association between cognitive declineand alcohol use are inconsistent.
Genetic Factors. Most studies suggest that the ApoEgene variation is associated with an increased rate ocognitive decline in elderly persons, especially on somememory tasks and tasks o perceptual speed. The ApoEgene variation does not seem to aect all cognitivedomains, and there is variability among studies.
Limitations
Much o the available evidence derives rom studies thatwere originally designed and conducted to investigate otherconditions, such as cardiovascular disease and cancer.Thus, evidence rom studies conducted to date is limitedby methodological issues in the assessment o the outcome
(cognitive decline) or exposures (risk actors). Limitationsin the evaluation o outcome include the lack o a cleardefnition o and standardization o criteria or cognitivedecline (cognitive decline is not a single entity and may havedierent etiologies). Instruments used by dierent studiesvaried in their scope, making it difcult or impossible tocompare results across studies and to identiy the reasonsor inconsistency in fndings. The ascertainment o
cognitive decline was oten limited to a single measurementat ollow-up. This approach severely limits the ability todetermine validly whether cognitive decline really exists,especially because cognitive decline is not linear, manyactors aect cognitive perormance, and these actors maychange in the same individual. Many studies were limitedby the relatively short duration o ollow-up. The studiesalso dier widely in the quality o the measurements oimportant exposures (or example, dietary actors, liestylehabits, medications, health history, social actors, andengagement). Many o the available studies characterizedtheir participants only at a single time point.
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3. What Are the Therapeutic and AdverseEects o Interventions to Delay theOnset o Alzheimers Disease? AreThere Dierences in Outcomes AmongIdentifable Subgroups?
Although numerous interventions have been suggestedto delay Alzheimers disease, the evidence is inadequateto conclude that any are eective. Our conclusions arebased on a review o published literature o adequatelypowered randomized controlled trials (RCTs), the mostrigorous, highest quality evidence. RCTs are studiesin which participants are allocated by chance alone toreceive one or more treatment interventions. Becauseo the protracted course o Alzheimers disease, ourconclusions are based on RCTs that were at least 2 yearsin duration and adequately powered. Our conclusionsdo not reect the existence o observational studies inwhich the investigator does not assign the exposure ortreatment o interest to participants. However, inormationrom these observational studies has ormed, and willorm, the basis or RCTs.
Assessment of Detailed Interventions
Vitamins, Nutrients, and Dietary Supplements.Arecent RCT o vitamin E ound no evidence that this
actor changed the onset o Alzheimers disease.Other nutritional actors (such as other vitamins or theMediterranean diet) may be benefcial, but evidenceto support this conclusion is insufcient. It has beensuggested that patients with vitamin defciency maydemonstrate a greater response, but no trials haveexamined this issue. Gingko biloba was reported tohave some beneft in small, short-term clinical trials.
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However, a recent, large long-term RCT comparinggingko biloba with placebo showed no reduction inthe incidence o Alzheimers disease, leading to the
conclusion that evidence is insufcient to support theefcacy o gingko biloba.
Medications. Cholinesterase inhibitors are the mostcommon treatment or mild to moderate Alzheimersdisease and have been the ocus o several RCTsevaluating prevention o Alzheimers disease. Althoughthere is some inconsistency in the literature, the bodyo evidence led us to conclude that this class o drugsdoes not eectively prevent Alzheimers disease.Evidence rom RCTs o antihypertensive medicationsand hormone replacement (conjugated equine estrogen)is also insufcient to indicate that these agents protectagainst Alzheimers disease. Some available evidenceshows that certain medications may increase theincidence o Alzheimers disease. Two RCTs o specifcnonsteroidal anti-inammatory drugsroecoxib,naproxen, and celecoxibsuggested an increasedincidence o Alzheimers disease with treatment.However, these studies were limited by high dropoutrates and early termination because o concerns abouttoxicity. Two RCTs o conjugated equine estrogen,one combined with methylprogesterone, suggested anincreased incidence o dementia (including Alzheimers
disease) with treatment. These trials suggest that noknown medication can be said to reliably delay theonset o Alzheimers disease.
Other Factors. No RCTs were identifed that evaluatedthe eects o cognitive engagement, physical activities,or other leisure activities or delaying the onset oAlzheimers disease.
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4. What Are the Therapeutic and AdverseEects o Interventions to Improve orMaintain Cognitive Ability or Function?Are There Dierent Outcomes inIdentifable Subgroups?
Several interventions have been evaluated with respectto improving cognitive unction or preventing cognitivedecline. Despite some encouraging associations ound inobservational studies, RCTs o specifc interventions havenot defnitivelyestablished positive therapeutic eects onmaintaining or improving cognitive unction, or preventingcognitive decline. However, there also is little evidence tosuggest that interventions designed to improve cognitiveunction either worsen it or produce unwanted sideeects. In addition, no data are available rom which todraw frm conclusions about dierences in outcomesamong identifable subgroups. Some o the main reasonsor the inability to identiy successul interventionsmayinclude (1) lack o a validated and consistent defnitiono cognitive decline; (2) the small number o RCTs withcognitive decline as a primary outcome; (3) limitationso study design and analysis including short ollow-upduration, biases and inconsistencies in study subjectrecruitment, small eect sizes, and conounding eectso multiple interrelated behaviors.
Assessment of Detailed Interventions
Vitamins, Nutrients, and Dietary Supplements. SeveralRCTs did not fnd a role o vitamin supplementationin preventing cognitive decline. However, these trialsused varying doses o the nutrients, did not uniormlymeasure and monitor patients cognitive unction andbaseline nutritional status, had short and variableollow-up, and mostly measured cognitive decline asa secondary or tertiary outcome. Thus these trialsmay have been underpowered.
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In a randomized trial complicated by poor adherence totherapy, gingko biloba co-administered with vitamin Edid not improve or maintain cognitive unction in elderly
persons. A randomized trial o omega-3 atty acids withonly 26 weeks o ollow-up ound no eect on cognitiveunctioning. Other trials in progress may revise thisevidence, but currently no interventional trials convincinglydemonstrate that dietary supplements improve ormaintain cognitive unctioning.
Medications. With the exception o a single trial oantihypertensive medication in patients with hypertension,known vascular disease, and history o stroke, all existingevidence suggests that antihypertensive treatment resultsin no cognitive beneft. Similarly, treatment with statins,low-dose aspirin, or celecoxib did not result in cognitivebeneft, and naproxen was ound to possibly increasecognitive decline. Randomized trials o estrogen have notshown any preventive eects on cognitive decline, andconjugated equine estrogen plus methylprogesteronemay worsen cognitive outcome. However, trials examiningthe eect o gonadal steroids to date have had severalshortcomings, including inconsistencies in types o steroidused, duration and timing o use, type o menopause(surgical or natural), and mode o delivery. Finally,multiple trials o cholinesterase inhibitors have shownno consistently positive eects on cognitive decline.
Together, these data suggest that no currently availablemedications can prevent the onset o cognitive decline.
Cognitive Engagement. A large randomized trial ocognitive training (consisting o memory, reasoning, andspeed) over 5 to 6 weeks with a subsequent boosterperiod showed modest benefts on cognitive unctioningand a small, statistically signifcant eect on reducingthe extent o age-related cognitive decline at 5-year
ollow-up. This trial also showed a very small statisticallysignifcant beneft on instrumental activities o daily livingor example, managing fnances, managing medications,
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and keeping houseand, in a subgroup analysis, benefton driving perormance in elderly persons. However,these fndings need to be replicated to confrm the
benefts o cognitive engagement on preventing cognitivedecline over a longer period and in persons with varyinglevels o baseline cognitive abilities beore frmrecommendations can be made. The sustainabilityo these behaviors must also be assessed in large,community-based samples, in which other, lessrigorous interventions showed no beneft.
Physical Activity. Some evidence rom small interventionalstudies and selected observational studies suggests thatincreased physical activity, including walking, may helpmaintain or improve cognitive unction in normal adults. Ameta-analysis o several RCTs, many with methodologicallimitations, concluded that data were insufcient to statethat aerobic activity improves or maintains cognitiveunction. A small, higher quality randomized trial o physicalactivity in persons with confrmed memory problems showedmodest beneft in reducing cognitive decline; however,these data should be viewed as preliminary. Work is ongoingto urther investigate the benefts o physical activity.
5. What Are the Relationships Betweenthe Factors That Aect AlzheimersDisease and the Factors That AectCognitive Decline?
Inconsistent and varied assessments o age-associatedcognitive decline, mild cognitive impairment, andAlzheimers disease in the literature prevent clear andconcise answers to this question.
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What We Know
Diabetes mellitus, ApoE gene variation, current smoking,and depression are associated with increased risk oAlzheimers disease and cognitive decline. Limitedevidence indicates that estrogens and nonsteroidalanti-inammatory drugs increase the risk o Alzheimersdisease; no evidence exists that these medicationsincrease risk or age-associated cognitive decline.
There are no consistent fndings o increased risk orAlzheimers disease and cognitive decline associated
with obesity, hypertension, and blood homocysteinelevels. Likewise, no decreased risk with cholinesteraseinhibitors has been ound.
Cognitive engagement (indicated by literacy and socialenrichment), physical activities in later lie, and a dietlow in saturated at and high in vegetable intake wereassociated with decreased risk o Alzheimers disease
and cognitive decline. Light to moderate alcohol intakeis associated with reduced risk o Alzheimers disease,but fndings or cognitive decline are inconsistent.
No consistent association has been ound betweenAlzheimers disease or cognitive decline and intake ogingko biloba; beta-carotene; avonoids; multivitamins;and vitamins B12, C, and E.
Limitations
Most studies conducted to date had limited data and thequality o evidence was generally low. In addition, the riskmodifcation eect o reported associations was generallysmall to moderate or Alzheimers disease and small orcognitive decline.
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6. I Recommendations or InterventionsCannot Be Made Currently, What StudiesNeed to Be Done to Provide the Qualityand Strength o Evidence Necessaryto Make Such Recommendationsto Individuals?
This state-o-the-science review highlights thepresence o critical gaps in current knowledge aboutthe epidemiology o Alzheimers disease and cognitive
impairment. To date, numerous studies have attemptedto describe the etiology and actors associated with risko development and progression o cognitive decline ando Alzheimers disease and have generated an abundanceo theories on modifable risk actors and therapies.However, these studies have ailed to provide convincingevidence on the strength o these associations, and theseresults cannot be used as the basis to generate specifc
recommendations or preventive measures or interventions.This report underscores the need and rationale orconducting rigorous, state-o-the-art, methodologicallysound research to address these defciencies. We, thepanel, strongly recommend the ollowing:
Rigorous consensus-based diagnostic criteria orAlzheimers disease should be improved and uniormlyused across research studies. Research is criticallyrequired or identifcation o biomarkers associatedwith Alzheimers disease and or urther development obrain imaging techniques such as magnetic resonanceimaging and positron emission tomography scanningto pinpoint pathological changes specifc to Alzheimersdisease that could be assessedin vivo and serve asobjective diagnostic criteria. Alzheimers disease isknown to have a long latent period with hallmarkpathological changes seen in the brain tissue o youngeradults. Further research is required to understand and
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delineate the natural progression o Alzheimers disease,to relate progression to pathological signs and clinicalsymptoms, and to determine (or example) whether
depression and cognitive impairment are risk actorsor the development o Alzheimers disease or reectearly stages o the disease.
An objective and consensus-based defnition o mildcognitive impairment needs to be developed, includingidentifcation o the cognitive areas or domains oimpairment, the recommended cognitive measures orassessment, and the degree o deviation rom normalto meet diagnostic criteria. This consistency in defnitionand measurement is important to generate studies thatcan be pooled or compared to better assess risk actorsand preventive strategies or cognitive decline andAlzheimers disease.
We encourage the use o a standardized, well-validated,and culturally sensitive battery o outcome measures
(or example, the NIH Toolbox) that can be used acrossresearch studies to assess relevant domains o cognitiveunctioning in a manner that is appropriate or the unctionallevel o the population sample being studied (or example,cognitively normal, mild cognitive impairment) and isresponsive to detecting changes in cognitive unctionover time; age- and gender-specifc norms need to beestablished or comparison and objective assessment
o disease severity. We recommend a comprehensiveapproach to outcomes assessment that accounts or theimpact o cognitive decline on other domains o unctionand quality o lie o both the aected person and his orher primary caregiver.
The caregiver is a valuable source o inormationabout the daily unction o the elderly person with mild
cognitive impairment or early Alzheimers disease, andobservational studies and RCTs should collect data romcaregivers in a systematic manner.
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Following the model o other chronic disease epidemiology,large-scale, long-term population-based studies usingprecise, well-validated exposure and outcome measures
are required to generate strong evidence on biological,behavioral/liestyle, dietary, socioeconomic, and clinicalactors that may have protective or adverse eects on risko cognitive decline or Alzheimers disease. Individuals inthese studies should be ollowed rom middle age into oldage, with repeated measurements to take into accountthe duration and timing o exposures, as eects o variousrisk actors may be more acute and interventions more
eective during critical windows o time throughout lie.Furthermore, data rom early lie, either retrospective orprospective, are necessary to assess the importance othese inuences on later cognitive outcomes.
Existing cohorts rom ongoing, large-scale, population-based studiesincluding longitudinal cohort studies ocardiovascular and noncardiovascular risk actors andoutcomes, with rigorous, standardized measures o awide range o exposures and longitudinal socioeconomicsurveys that contain detailed health measuresshouldbe explored or opportunities or timely, cost-eectiveanalyses o the development o cognitive decline orAlzheimers disease, provided that these outcomes arevalidly measured. Any associations ound could be urthertested by RCTs or new observational studies as appropriate.
RCTs or prospective cohort studies are urgently requiredto evaluate comprehensively promising preventivestrategies suggested by previous studies, such asomega-3 atty acids intake, physical exercise, andcognitive training and engagement.
Studies should include women and men romsocioeconomically and ethnically diverse populations
to examine the incidence and prevalence o Alzheimersdisease and cognitive decline in these groups. Based
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on the successes to date o the existing collaborativeeorts, it is clear that a collaborative research inrastructure(at both the national and international level) will be critical
in advancing our research goals.Research is necessary to identiy specifc populationsubgroups that may be at higher risk o developing cognitiveimpairment or Alzheimers disease, based on nonmodifableactors such as age, ethnicity, or gene variation (or example,ApoE). Long-term studies on high-risk populations(particularly treatment-seeking individuals with symptomso mild cognitive impairment) should be conductedto delineate risk actors or and natural progressionto Alzheimers disease and to identiy the long-termoutcomes and actors associated with improvement,decline, and stabilization o cognitive unction.
Building on the existing research inrastructure, additionalresearch resources and platorms that acilitate longitudinallong-term assessments o the risk o cognitive decline
and the risk o progression rom cognitive decline toAlzheimers disease need to be leveraged. For example,a large, multicenter Alzheimers disease registry, ollowingthe models o cancer, would greatly expand opportunitiesor research and surveillance. In addition, observationalstudies within large healthcare delivery systems withdefned populations and well-developed electronic healthrecords could serve as a cost-eective research platorm
or studies o cognitive decline and Alzheimers disease.
A web site should be established to continually updatethe American public in an ongoing way about preventiveinterventions or Alzheimers disease and cognitive declinewith proven efcacy.
Future research into the basic mechanisms o normal andpathological aging is critical to identiy additional targetsor prevention.
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Conclusions
Cognitive decline and Alzheimers disease are majorcauses o morbidity and mortality worldwide and aresubstantially burdensome to the aected persons, theircaregivers, and society in general. Extensive researchover the past 20 years has provided important insights onthe nature o Alzheimers disease and cognitive declineand the magnitude o the problem. Nevertheless, thereremain important and ormidable challenges in conductingresearch on these diseases, particularly in the area o
prevention. Currently, frm conclusions cannot be drawnabout the association o any modifable risk actor withcognitive decline or Alzheimers disease. Highly reliableconsensus-based diagnostic criteria or cognitive decline,mild cognitive impairment, and Alzheimers disease arelacking, and available criteria have not been uniormlyapplied. Evidence is insufcient to support the use opharmaceutical agents or dietary supplements to prevent
cognitive decline or Alzheimers disease. We recognizethat a large amount o promising research is under way;these eorts need to be increased and added to bynew understandings and innovations (as noted in ourrecommendations or uture research).
For example, ongoing studies including (but not limitedto) studies on antihypertensive medications, omega-3atty acids, physical activity, and cognitive engagementmay provide new insights into the prevention or delay ocognitive decline or Alzheimers disease. This importantresearch needs to be supplemented by urther studies.Large-scale population-based studies and RCTs arecritically needed to investigate strategies to maintaincognitive unction in individuals at risk or decline, toidentiy actors that may delay the onset o Alzheimersdisease among persons at risk, and to identiy actors thatmay slow the progression o Alzheimers disease amongpersons in whom the condition is already diagnosed.
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State-o-the-Science Panel
Martha L. Daviglus, M.D.,Ph.D., M.P.H.
Panel and ConerenceChairperson
Proessor o PreventiveMedicine and Medicine
Department oPreventive Medicine
Feinberg School o MedicineNorthwestern University
Chicago, Illinois
Carl C. Bell, M.D.DirectorInstitute or Juvenile ResearchProessorDepartment o Psychiatry and
School o Public HealthUniversity o Illinois at ChicagoPresident and Chie
Executive OfcerCommunity Mental Health
Council, Inc.Chicago, Illinois
Wade Berrettini, M.D., Ph.D.Karl E. Rickels Proessor
o PsychiatryDepartment o PsychiatryDirector
Center or Neurobiologyand Behavior
The University o PennsylvaniaPhiladelphia, Pennsylvania
Phyllis E. Bowen, Ph.D.Proessor Emerita o
Human NutritionDepartment o Kinesiology
and Nutrition
University o Illinois at ChicagoChicago, Illinois
E. Sander Connolly, Jr., M.D.Bennett M. Stein Proessor
o Neurological SurgeryVice Chairperson o
NeurosurgeryColumbia University
Medical CenterNew York-Presbyterian HospitalNew York, New York
Nancy Jean Cox, Ph.D.ProessorGenetic Medicine
The University o ChicagoChicago, Illinois
Jacqueline M. Dunbar-Jacob,Ph.D., R.N., FAAN
Dean and ProessorSchool o Nursing
University o PittsburghPittsburgh, Pennsylvania
Evelyn C. Granieri, M.D.,M.P.H., M.S.Ed.
ChieDivision o Geriatric Medicine
and AgingCollege o Physicians
and Surgeons
Columbia UniversityNew York-Presbyterian HospitalNew York, New York
Gail HuntPresident and Chie
Executive OfcerNational Alliance or CaregivingBethesda, Maryland
23
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Kathleen McGarry, Ph.D.Proessor o EconomicsDepartment o EconomicsUniversity o Caliornia,
Los AngelesLos Angeles, Caliornia
Dinesh Patel, M.D.Senior GeriatricianCharles E. Smith
Lie CommunitiesAssistant Clinical Proessor
o MedicineGeorge Washington University
School o MedicineRockville, Maryland
Arnold L. Potosky, Ph.D.Proessor o OncologyDirector o Health
Services ResearchGeorgetown University
Medical CenterLombardi Comprehensive
Cancer CenterCancer Control ProgramWashington, District o Columbia
Speakers
Paul S. Aisen, M.D.ProessorDepartment o NeurosciencesUniversity o Caliornia,
San DiegoSchool o Medicine
La Jolla, Caliornia
Marilyn S. Albert, Ph.D.Proessor o NeurologyDivision o Cognitive
NeuroscienceThe Johns Hopkins University
School o MedicineBaltimore, Maryland
Elaine Sanders-Bush, Ph.D.Proessor o Pharmacology
and PsychiatryVanderbilt University
Medical CenterNashville, Tennessee
Donald Silberberg, M.D.ProessorDepartment o Neurology
The University o PennsylvaniaMedical Center
Philadelphia, Pennsylvania
Maurizio Trevisan, M.D., M.S.Executive Vice Chancellor andChie Executive Ofcer
Health Sciences SystemNevada System o
Higher EducationProessor o MedicineUniversity o Nevada
School o MedicineLas Vegas, Nevada
David A. Bennett, M.D.Robert C. Borwell Proessor
o Neurological SciencesDirectorDepartment o
Neurological SciencesRush University Alzheimers
Disease CenterRush University Medical CenterChicago, Illinois
24
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James Burke, M.D., Ph.D.Associate Proessor o
Medicine-NeurologyAssociate Director
Bryan Alzheimers DiseaseResearch CenterDirectorDuke Memory Disorders ClinicDuke UniversityDurham, North Carolina
Carl W. Cotman, Ph.D.ProessorInstitute or Brain Aging
and DementiaUniversity o Caliornia, IrvineIrvine, Caliornia
Charles S. DeCarli, M.D.Proessor o NeurologyDepartment o NeurologyCenter or NeuroscienceDirector
Alzheimers Disease Center
and Imaging o Dementiaand Aging LaboratoryUniversity o Caliornia, DavisSacramento, Caliornia
Laura Fratiglioni, M.D., Ph.D.Proessor o
Geriatric EpidemiologyDirector
Aging Research Center
Department o Neurobiology,Care Sciences and SocietyKarolinska InstituteStockholm, Sweden
Mary Ganguli, M.D., M.P.H.Department o PsychiatryWestern Psychiatric
Institute and ClinicUniversity o Pittsburgh
Medical CenterPittsburgh, Pennsylvania
Hugh Hendrie, D.Sc., M.B., Ch.B.ProessorDepartment o PsychiatryIndiana University
School o MedicineScientistIndiana University Center
or Aging ResearchResearch ScientistRegenstrie Institute, Inc.Indianapolis, Indiana
Tracey Holsinger, M.D.Assistant Proessor
Department oGeriatric PsychiatryDuke UniversityDurham, North Carolina
Arthur F. Kramer, Ph.D.Proessor o Psychology
and NeuroscienceBeckman InstituteUniversity o Illinois
Urbana, Illinois
Constantine Lyketsos, M.D., M.H.S.The Elizabeth Plank
Althouse ProessorThe Johns Hopkins UniversityChairperson o PsychiatryJohns Hopkins Bayview
Medical CenterBaltimore, Maryland
Jennier J. Manly, Ph.D.Associate ProessorDepartment o NeurologySergievsky CenterColumbia University College
o Physicians and SurgeonsNew York, New York
25
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Martha Clare Morris, Sc.D.DirectorSections o Nutrition and
Nutritional Epidemiology
Department o InternalMedicineRush University Medical CenterChicago, Illinois
Dan M. Mungas, Ph.D.Adjunct ProessorDepartment o NeurologyUniversity o Caliornia, Davis
School o Medicine
Sacramento, Caliornia
Ronald C. Petersen, Ph.D., M.D.Cora Kanow Proessor
o AlzheimersDisease Research
DirectorAlzheimers Disease
Research CenterMayo Clinic College o Medicine
Rochester, Minnesota
Joseph F. Quinn, M.D.Associate ProessorDepartment o NeurologyOregon Health &
Science UniversityPortland Veterans Aairs
Medical CenterPortland, Oregon
Yaakov Stern, Ph.D.ProessorDepartments o Neurology,
Psychiatry, and Psychology
Sergievsky Center andTaub InstituteColumbia University College
o Physicians and SurgeonsNew York, New York
Frederick W. Unverzagt, Ph.D.Proessor o PsychiatryDepartment o PsychiatryIndiana University School
o MedicineIndianapolis, Indiana
John W. Williams, Jr., M.D., M.H.S.ProessorDepartment o General
Internal MedicineDuke UniversityDurham, North Carolina
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Planning Committee
Neil Buckholtz, Ph.D.Planning ChairpersonChieDementias o Aging BranchNeuroscience and
Neuropsychologyo Aging Program
National Institute on AgingNational Institutes o HealthBethesda, Maryland
Lisa Ahramjian, M.S.Communications SpecialistOfce o Medical Applications
o ResearchOfce o the DirectorNational Institutes o HealthBethesda, Maryland
Shilpa Amin, M.D., M.Bsc., FAAFP
Medical OfcerEvidence-based Practice
Centers ProgramCenter or Outcomes
and EvidenceAgency or Healthcare
Research and QualityRockville, Maryland
Lynda A. Anderson, Ph.D.
DirectorHealthy Aging ProgramDivision o Adult and
Community HealthNational Center or Chronic
Disease Prevention andHealth Promotion
Coordinating Center orHealth Promotion
Centers or Disease Control
and PreventionAtlanta, Georgia
Nancy C. Andreasen, M.D., Ph.D.Conerence and Panel
Chairperson*DirectorMental Health Clinical
Research CenterDirectorPsychiatric Iowa
Neuroimaging ConsortiumAndrew H. Woods Chair
and Proessor o PsychiatryUniversity o IowaIowa City, Iowa
Sanjay Asthana, M.D., FRCP-CDuncan G. and Lottie H. Ballantine
Chair in GeriatricsProessor and Head, Section o
Geriatrics and GerontologyUniversity o Wisconsin-Madison
Medical SchoolDirector, Geriatric Research,
Education and Clinical CenterWilliam S. Middleton Memorial
Veterans HospitalAssociate DirectorWisconsin Alzheimers InstituteMadison, Wisconsin
Stephanie Chang, M.D., M.P.H.
Medical OfcerEvidence-based Practice
Centers ProgramCenter or Outcomes
and EvidenceAgency or Healthcare
Research and QualityRockville, Maryland
Planning Committee members provided their input at a meeting held August 1921, 2008. The inormation provided here was accurate at thetime o that meeting.*Dr. Nancy Andreasen stepped down as panel chair on January 20, 2010, due to a relationship that was unoreseen to be a possible conict o
interest; we thank her or her invaluable service in this process.27
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Charles S. DeCarli, M.D.Proessor o NeurologyDepartment o NeurologyCenter or Neuroscience
DirectorAlzheimers Disease Centerand Imaging o Dementiaand Aging Laboratory
University o Caliornia, DavisSacramento, Caliornia
Emmeline M. Edwards, Ph.D.Deputy DirectorDivision o Extramural Research
National Institute o NeurologicalDisorders and StrokeNational Institutes o HealthBethesda, Maryland
Jovier D. Evans, Ph.D.ChieGeriatric Translational
Neuroscience and GeriatricPharmacologic Intervention
Research ProgramsGeriatrics Research BranchNational Institute o
Mental HealthNational Institutes o HealthBethesda, Maryland
Steven Fox, M.D., M.P.H., S.M.Center or Outcomes
and Evidence
Agency or HealthcareResearch and QualityRockville, Maryland
Hugh C. Hendrie, D.Sc., M.B., Ch.B.ProessorDepartment o PsychiatryIndiana University
School o Medicine CenterScientistIndiana University Center
or Aging ResearchResearch ScientistRegenstrie Institute, Inc.Indianapolis, Indiana
Jonathan W. King, Ph.D.Division o Behavioral
and Social ResearchNational Institute on AgingNational Institutes o HealthBethesda, Maryland
Kathy Mann Koepke, Ph.D.Program Director, NeuroscienceNINR Centers and Program
Projects CoordinatorDivision o Extramural Activities
National Institute oNursing ResearchNational Institutes o HealthBethesda, Maryland
Barnett S. Kramer, M.D., M.P.H.Associate Director or
Disease PreventionDirectorOfce o Medical Applications
o ResearchOfce o the DirectorNational Institutes o HealthBethesda, Maryland
Kelli K. Marciel, M.A.Communications DirectorOfce o Medical Applications
o ResearchOfce o the Director
National Institutes o HealthBethesda, Maryland
Planning Committee members provided their input at a meeting heldAugust 1921, 2008. The inormation provided here was accurate at thetime o that meeting.28
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Arthur A. Meltzer, Ph.D.Ofce o Clinical Standards
and QualityCenters or Medicare &
Medicaid ServicesBaltimore, Maryland
Martha Clare Morris, Sc.D.DirectorSections o Nutrition and
Nutritional EpidemiologyDepartment o
Internal MedicineRush University Medical Center
Chicago, Illinois
Marcelle Morrison-Bogorad, Ph.D.DirectorNeuroscience and
Neuropsychology oAging Program
National Institute on AgingNational Institutes o HealthBethesda, Maryland
Richard Nahin, Ph.D., M.P.H.National Center or
Complementary andAlternative Medicine
National Institutes o HealthBethesda, Maryland
Lata S. Nerurkar, Ph.D.Senior Advisor or
the ConsensusDevelopment ProgramOfce o Medical Applications
o ResearchOfce o the DirectorNational Institutes o HealthBethesda, Maryland
Susan C. Rossi, Ph.D., M.P.H.Deputy DirectorOfce o Medical Applications
o Research
Ofce o the DirectorNational Institutes o HealthBethesda, Maryland
Yaakov Stern, Ph.D.ProessorDepartments o Neurology,
Psychiatry, and PsychologySergievsky Center and
Taub Institute
Columbia University College oPhysicians and SurgeonsNew York, New York
Christine A. Swanson, Ph.D.Ofce o Dietary SupplementsOfce o the DirectorNational Institutes o HealthBethesda, Maryland
Frederick W. Unverzagt, Ph.D.Proessor o PsychiatryDepartment o PsychiatryIndiana University
School o MedicineIndianapolis, Indiana
Molly V. Wagster, Ph.D.ChieBehavioral and Systems
Neuroscience BranchDivision o NeuroscienceNational Institute on AgingNational Institutes o HealthBethesda, Maryland
Planning Committee members provided their input at a meeting heldAugust 1921, 2008. The inormation provided here was accurate at thetime o that meeting. 29
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Conerence Sponsor
National Institute on Aging
Richard Hodes, M.D.Director
Ofce o Medical Applications
o ResearchJennier M. Croswell, M.D., M.P.H.
Acting Director
Conerence Cosponsors
Eunice Kennedy Shriver NationalInstitute o Child Health andHuman Development
Alan Guttmacher, M.D.Acting Director
National Center or Complementaryand Alternative Medicine
Josephine P. Briggs, M.D.Director
National Institute o Mental HealthThomas Insel, M.D.Director
Conerence Partners
Centers or Disease Controland Prevention
Janet Collins, Ph.D.Director
National Institute o NeurologicalDisorders and StrokeStory C. Landis, Ph.D.Director
National Institute o NursingResearch
Patricia Grady, Ph.D., R.N.,FAAN
Director
Ofce o Dietary SupplementsPaul Coates, Ph.D.Director
Centers or Medicare &Medicaid Services
Barry M. Straube, M.D.Chie Medical OfcerDirectorOfce o Clinical Standards
and Quality
30
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31
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