Prevención de la Enfermedad de Alzheimer y el deterioro cognitivo

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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.
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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.
http://consensus.nih.gov/aboutcdp.htmhttp://consensus.nih.gov/2010/alz.htmhttp://consensus.nih.gov/aboutcdp.htmhttp://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

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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

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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

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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


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


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

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