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Page 1: Intellectual Disability, Mild Cognitive Impairment, and Risk for Dementia

Intellectual Disability, Mild Cognitive Impairment,and Risk for DementiaWayne P. Silverman*, Warren B. Zigman†, Sharon J. Krinsky-McHale†, Robert Ryan†, and Nicole Schupf‡

*Kennedy Krieger Institute and Johns Hopkins University School of Medicine, Baltimore, MD; and †New York State Institute forBasic Research in Developmental Disabilities, Staten Island, NY, and ‡Columbia University Medical Center, New York, NY, USA

Abstract People with intellectual disability (ID) are living longer than ever before, raising concerns about old-age-associated disor-ders. Dementia is among the most serious of these disorders, and theories relating cognitive reserve to risk predict that older adultswith ID should be particularly vulnerable. Previous estimates of relative risk for dementia associated with ID have been inconsis-tent, and the present analyses examined the possible influence of variation in diagnostic criteria on findings. As expected, relaxationin the stringency of case definition for adults with ID increased relative risk, underscoring the importance of developing valid crite-ria for defining mild cognitive impairment and early dementia and distinguishing between the two in adults with ID. Once avail-able, these standards will contribute to more effective evidence-based planning.

Keywords: dementia, incidence, intellectual disability, mild cognitive impairment, relative risk

INTRODUCTION

People with intellectual disability (ID) are living longer andmore fulfilling lives than ever before, and for the vast majority ofindividuals, their life expectancy approaches that of the generalpopulation (e.g., Strauss & Eyman, 1996). Nevertheless, lifespandevelopment for adults with ID (and other neurodevelopmentaldisorders) is atypical by definition, and their primary etiology ofID, as well as the effects of their lifelong experiences, may influ-ence vulnerability to old-age-associated impairments.

Dementia is among the most serious concerns faced byelderly adults, potentially having devastating impacts on inde-pendence and quality of life. Dementia has many causes,Alzheimer’s disease being the most prevalent (see Jicha & Carr,2010), and increased risk associated with Down syndrome is welldocumented (see Zigman & Lott, 2007). However, the relation-ship between dementia risk and the presence/absence of ID perse is unclear and is the focus of the present set of analyses.

Dementia is defined in the Diagnostic and Statistical Manualof Mental Disorders (4th edition, text revision; DSM IV-TR;American Psychiatric Association, 2000), as “disorders . . . char-acterized by the development of multiple cognitive deficits(including memory impairment) that are due to the directphysiological effects of a general medical condition, to the per-sisting effects of a substance, or to multiple etiologies.” Diagnosisis determined by the presence of impaired cognition sufficientin severity to have consequences for occupational or social

functioning. In DSM V (American Psychiatric Association,2013), “dementia” has been replaced by “major neurocognitivedisorder,” but key features are largely unchanged in the reviseddefinition, requiring “evidence of significant cognitive decline. . . in one or more cognitive domains . . . based on: (1) concernof the individual, a knowledgeable informant, or the clinician . . .and (2) a substantial impairment in cognitive performance, pref-erably documented by standardized neuropsychological testing,or, in its absence, another quantified clinical assessment.” Whiledecline from a previously higher level of capability is a keyfeature that distinguishes dementia from ID, it is nevertheless thecase that preexisting cognitive impairments complicate diagno-sis. In fact, assessment methods and objective diagnostic criteriasuitable for the general population are typically uninformativefor adults with ID, and the need for consensus regarding evalua-tion methods and diagnostic criteria is now well recognizedwithin the developmental disabilities field (e.g., Burt & Aylward,1999; Janicki & Dalton, 2000; Silverman, Zigman, Kim,Krinsky-McHale, & Wisniewski, 1998).

Risk for aging-associated dementia within the typicallydeveloping population rarely occurs prior to 60 years of ageand increases thereafter, with approximately 30% of the popu-lation over 80 affected (see Zaccai, Ince, & Brayne, 2006).Obviously, there is substantial heterogeneity in individual risk,and considerable progress has been made in determining thegenetic as well as the environmental factors that may contributeto this variability (e.g., Barnes & Yaffe, 2011; McMurtray, Clark,Christine, & Mendez, 2006). A thorough review of this topic isbeyond the scope of this paper, but one factor that may con-tribute to increased risk associated with ID per se has beentermed “cognitive reserve” (Stern, 2009). This is a hypotheticalconstruct presumed to mitigate the effects of old-age-associatedbrain pathology caused by various underlying diseases (e.g.,

Received November 19, 2012; accepted July 3, 2013Correspondence: Wayne P. Silverman, PhD, Behavioral Psychology, KennedyKrieger Institute, 707 North Broadway, Suite 222s, Baltimore, MD 21205,USA. Tel: +1 443 923 2738; Fax: +1 443 923 2735; E-mail:[email protected]

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Alzheimer’s, Parkinson’s, and cerebrovascular disease). Stern(2009) argued persuasively that higher reserve, associated withhigh levels of cognitive capabilities, educational attainment,and literacy, should be protective and delay onset of dementia,while lower levels should increase vulnerability. If this is in factthe case, then ID should increase risk for old-age-associateddementia because of the lifelong presence of substantial cogni-tive and functional limitations that defines this diagnosis.

Only two large studies to date have examined relative riskfor dementia in adults with ID 65 years of age and older(Strydom, Hassiotis, King, & Livingston, 2009; Zigman et al.,2004), both of which omitted adults with Down syndrome,given the high risk for Alzheimer’s disease within this specificsubpopulation. Zigman et al. relied primarily on analyses ofcumulative incidence and found no evidence of increased riskcompared with the general population (Saunders et al., 1993).In contrast, Strydom et al. focused on prevalence and found anincreased standardized morbidity ratio of 2.8 associated withpresence of ID.

Strydom et al. considered several possible explanations forthis divergence in findings, including differences in sample size(Zigman et al. included 126 individuals with ID over 65, whileStrydom et al. had 142), bias in sampling method (enrollmentdid not consider dementia status in either study), and differencesin inclusion criteria (they suggested that Zigman et al. limiteddementia cases to Alzheimer’s disease, which was not actuallythe case). The two studies also employed different approachesto analyses of findings, were conducted in different countries(United States versus United Kingdom), and recruited partici-pants through two very different networks of services. Neverthe-less, these factors seem unlikely explanations for such aremarkable divergence in observed findings, and the presentanalysis focused on another possibility.

Strydom et al. and Zigman et al. employed different methodsto evaluate and classify cases, and this seemed to be an intuitivelylikely source of the differences in study outcomes. Although con-vergence in case classifications should be expected, given thatboth studies relied on the judgments of highly experienced pro-fessionals, both groups were working without an establishedconsensus regarding evaluation methods and, most significantly,criteria for defining dementia objectively. Strydom et al. basedtheir case classifications on a single assessment of capabilitiesand combined cases with “mild,” “moderate,” and “severe”dementia for analyses. Zigman et al. employed a substantiallydifferent method and based case classifications on individualprofiles of change over a period of up to 3 years. They also madea clear distinction between adults with dementia and their peersshowing milder declines comparable to mild cognitive impair-ment (MCI) within the general population (Petersen et al.,1999), while Strydom et al. made no mention of such a distinc-tion. This suggests that the difference in outcomes betweenStrydom et al. and Zigman et al. may have been caused by differ-ences in how they distinguished adults with mild dementia fromthose with MCI, a distinction that would be particularly difficultto make for adults with ID, especially without consideration ofobjective longitudinal findings. In fact, Strydom, Chan, Fenton,et al. (2013) recently reported a reexamination of the Strydomet al. (2009) cases approximately 3 years later. Using classifica-tion methods similar to their earlier study, they found that 33%

of the original dementia cases who survived were no longerdemented, and 48% of the original group redefined operation-ally as having MCI improved in status at follow-up. Both find-ings imply imprecision in classifications, as did the reportedinterrater reliability of κ = 0.68.

Conceptually, MCI is defined clearly enough as a state inter-mediate between “normal cognition” and dementia. Thus, adultswith MCI have experienced noticeable declines in cognition, butnot of sufficient severity to meet diagnostic criteria for dementia(Winblad et al., 2004). While explicit operationalization of thisdefinition remains in flux, even for older adults with typicallifespan development (e.g., Ganguli et al., 2011; Gauthier et al.,2006; Petersen et al., 1999; Winblad et al., 2004), there is clearconsensus that this condition often precedes old-age-associateddementia and can persist for an extended period of time. Withan estimated prevalence of between 8% and 42% for adults65 years of age and older (20.6% median prevalence in ninepopulation-based studies using various definitions of MCI;Ward, Arrighi, Michels, & Cedarbaum, 2012), approximatelythree times as many elderly adults have MCI as have frankdementia, the latter condition having an estimated prevalence of6.1% (Wimo, Winblad, Aquero-Torres, & von Strauss, 2003).

Unfortunately, standard practices for diagnosing MCI inadults experiencing typical lifespan development are ill-suitedfor situations where substantial preexisting cognitive impair-ments are present, as is the case for adults with ID. In fact, veryfew studies have focused on MCI among adults with ID, andnone have proposed explicit diagnostic criteria applicable to thispopulation, although several reports have emphasized the sig-nificance of this condition (Ball et al., 2006; Ball, Holland,Treppner, Watson, & Huppert, 2008; Holland, Hon, Huppert, &Stevens, 2000; Krinsky-McHale, Devenny, Kittler, & Silverman,2008; Krinsky-McHale, Devenny, & Silverman, 2002; Nelson,Orme, Osann, & Lott, 2001; Urv, Zigman, & Silverman, 2010).With adults with ID who develop old-age-associated dementiavery likely to experience a progression of underlying diseasesimilar to that of their typically developing peers, the degree towhich cases with ID and MCI are distinguished from those withdementia would affect estimates of relative risk. If prevalence forthese two distinct conditions is unrelated to presence of ID, theexpected relative risk for dementia associated with ID would beoverestimated to the extent that those actually having MCIwould be misclassified as having mild dementia. On the otherhand, relative risk would be underestimated to the extent thatindividuals with ID and mild dementia would be misclassified ashaving MCI.

The current study addressed this issue by reexamining thedementia classifications from the original Zigman et al. sample,employing operational definitions of dementia that varied instringency, and comparing estimates of cumulative incidencewith those for a sample representative of the general populationin one New York State county and matched for age and durationof surveillance. Importantly, these analyses were not intended todetermine the validity of any of the specific operational defini-tions of dementia or MCI under examination. While the presentresults may have implications for the eventual development ofbest-practice definitions of dementia and MCI for adults withID, the goals of these analyses are far more modest and arelimited to showing how varying the stringency of criteria

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defining dementia can impact estimates for age-specific inci-dence and therefore relative risk.

METHOD

All procedures involved reexamination of findings for thesample described in Zigman et al. (2004), and readers arereferred there for details of the evaluation procedures. In brief,149 adults with ID without Down syndrome 65 years of age orolder were enrolled in a longitudinal study of aging and demen-tia.1 They were assessed at baseline and then on up to two subse-quent occasions approximately 18 months apart. The finalsample included only the 101 individuals who were evaluated onall three occasions (to provide a surveillance period clearly suffi-cient to observe objective indications of declining status), whowere younger than 85.5 years of age at baseline (too few caseswere over 85 years of age or older at baseline to provide stableestimates of population incidence), whose lifelong impairmentswere not of such severity as to preclude objective evaluation ofdecline (the case for three individuals), and who did not experi-ence a significant health-related concern clearly unrelated to anunderlying neuropathology that could account for functionaldecline (the case for four individuals).

Assessments included informant interviews focused on adap-tive and maladaptive behaviors and neuropsychiatric problems,comprehensive reviews of clinical charts, and approximately2 h of cognitive assessments focused on both memory andnonmemory processes. Following each cycle of assessment, allfindings were examined during individual consensus case con-ferences, and the original dementia status for the cases includedin these analyses was determined as (1) not declining (other thanas expected with aging per se); (2) questionable/MCI, corre-sponding to presence of declines larger than expected with agingper se but of insufficient breadth or severity to be considereddementia; (3) possible dementia, corresponding to the presenceof substantial decline in multiple domains of cognition andfunctioning; or (4) definite dementia, where even more substan-tial declines are observed or with clear progression in decline.

For the current study, those original dementia classificationsmade following the third assessment cycle were redetermined,expanding upon the distinction between MCI and dementia toaddress the possibility that the Zigman et al. (2004) classificationdecisions may have characterized some cases of mild dementiaas MCI, thereby underestimating dementia risk. Each case wasnow rated independently by three investigators (S. K. M., W. P.S., W. B. Z.) based on complete profiles of performance overtime and blind to the original decisions, with dementia classifi-cations accompanied by a confidence rating using a seven-pointLikert scale (virtual certainty = 7, pure guess = 1). In all caseswhere certainty was less than 6, the investigator provided asecond-choice dementia classification to indicate if uncertaintyreflected greater or lesser severity of decline.

In cases where there was perfect agreement among raters,dementia status was determined based on the three independent

ratings. In cases where there was any disagreement, a full con-sensus conference including no fewer than five members of theresearch team was conducted, during which dementia status wasdetermined based on detailed consideration of all available data(see Zigman et al., 2004). These ratings of dementia status gen-erated seven first- and second-choice categories for analyses: (1)not declining with high confidence (n = 73), (2) not decliningbut possibly MCI (n = 7), (3) MCI but possibly not declining(n = 6), (4) MCI with high confidence (n = 7), (5) MCI but pos-sibly demented (n = 1), (6) demented but possibly MCI (n = 3),and (7) demented with high confidence (n = 4).

To allow a comparison with the general population, datawere obtained from the Washington Heights and InwoodColumbia Aging Project (WHICAP), which included a multira-cial representative sample of adults 65 years of age and olderliving in northern Manhattan, New York (Tang et al., 2001).Dementia status for these individuals was rated as either presentor absent based on a consensus process that considered physicaland neurological evaluations by physicians and performance ona battery of standardized neuropsychological assessments, con-sistent with DSM criteria (Stern et al., 1992).

Individuals within the WHICAP sample (n = 940) werescreened based on age at enrollment and duration of surveil-lance in order to match the sample with ID. A subgroup wasexcluded because they were followed either for less than 1.6 years(n = 125) or for longer than 4.0 years (n = 128). A final excludedsubgroup consisted of individuals over 85.5 years of age at base-line (n = 78), yielding a final sample of 609 individuals. Thegeneral characteristics of the ID and WHICAP samples aresummarized in Table 1.

1Except for ruling out Down syndrome based on phenotype, etiology of IDwas not determined.

TABLE 1Characteristics of participants with and without intellectualdisabilities

With (n = 101)Without

(n = 609)a

Age (years)Mean 73.2 75.2SD 5.1 4.9Range 64.9–85.4 65.1–85.4

Sex (%)Males 44 33Females 56 67

IQMean 41 —SD 12.5 —Range <20–71 —

Duration of follow-up (years)Mean 3.0 2.7SD 0.38 0.72Range 1.9–4.6 1.6–4.5

aDrawn from the Washington Heights and Inwood Columbia Aging Project.SD, standard deviation.

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Analytic Methods

Cumulative incidence was estimated employing life-tableanalyses, with individuals considered to be at risk from birthuntil their age at dementia onset (the point midway between ageat assessment when “dementia” was first detected and the imme-diately preceding assessment) or, if unaffected, age at their lastassessment. Here, as distinct from Zigman et al., cumulative inci-dence of dementia was compared for groups with and withoutID in a series of analyses, the only difference being the opera-tional case definition for adults with ID. An initial analysis classi-fied “dementia” conservatively as any case classified as “dementiawith high confidence.” Subsequent analyses relaxed that criterionstepwise, such that the dementia group was expanded to includecases as follows: (1) dementia but possible MCI, (2) MCI butpossible dementia, (3) definite MCI, (4) MCI but possibly notdeclining, and (5) not declining but possible MCI. Of course, asmore cases were added, the estimated risk for adults with IDincreased relative to the risk in the general population, and agoal of these analyses was to determine how relaxed the criterionfor “dementia” had to become within the Zigman et al. (2004)sample in order to replicate Strydom et al. (2009).

RESULTS

Hazard ratios (HRs) for five of the operationalized dementiacriteria for adults with ID are provided in Table 2. As can be seenin Table 2, there was no significant indication of increased riskof dementia associated with ID when only cases with a primaryclassification of dementia were considered (HRs = 1.1–1.6).When cases classified as MCI but possibly demented were added,relative risk increased further (HR = 1.9), but as indicated by theconfidence interval, the group with ID was still not significantlydifferent from the general population reference. Once cases withID classified as MCI without suspicion of dementia were added,however, the two samples differed significantly (HRs ≥ 3.2).

Figure 1a illustrates two cumulative incidence curves, one forthe WHICAP sample (controls) and a second for adults with IDwhen those cases were limited to individuals with consensus

classifications indicating dementia as the “primary” classification(dementia with high confidence or dementia but possibly MCI).Figure 1b compares cumulative incidence between the WHICAPand ID samples when cases in the latter group also includedindividuals having a primary consensus rating of MCI (MCI butpossibly demented, MCI with high confidence, or MCI but possiblynot declining). Figure 1a essentially replicates Zigman et al.(2004), while Figure 1b essentially replicates Strydom et al.(2009) (although omitting MCI cases with some doubt in thedirection of “not declining” is an even closer approximation—see Table 2).

DISCUSSION

The present analyses were able to reconcile the disparatefindings of Zigman et al. (2004) and Strydom et al. (2009)simply by varying the operational definition of dementia. Resultsshowed comparable risk for adults with and without ID, replicat-ing Zigman et al., when “dementia cases” were limited to indi-viduals classified as having possible or definite dementia duringconsensus conferences, even when some uncertainty existed inthe direction of MCI. Results indicated increased risk associatedwith ID, matching Strydom et al. (2009) and even Strydom,Chan, King, and Hassiotis (2013) when confidence intervals aretaken into consideration, when the case definition was expandedto include individuals with MCI as well as those with dementia.Thus, the present results tended to support the findings ofZigman et al. more strongly than Strydom et al., and this couldhave practical implications for program planning as well as theo-retical implications, suggesting that risk for dementia may be lessdependent on cognitive reserve than currently hypothesized.However, null findings always raise power concerns, and reason-able people could argue that even when the HR itself was consis-tent with Zigman et al., the confidence interval also overlappedwith the findings of Strydom et al. (2009). A slight increase inthe number of cases classified with dementia was observed com-pared with the original Zigman et al. results (seven versus five,respectively), and this also increases uncertainty regarding anull conclusion. Whatever that uncertainty may be, though,

TABLE 2Relationship between stringency of case definition and number of cases of dementia diagnosed among adults with intellectualdisabilities

Criterion to be exceeded Number of cases Hazard ratioa 95% confidence interval

Demented 4 1.1 0.4–2.8Demented but possibly with MCI 7 1.6 0.7–3.5MCI but possibly dementia 8 1.9 0.9–3.9MCI 15 3.2 1.7–6.0MCI but possibly not demented 21 4.3 2.4–7.8

aIndicates relative risk compared with typically developing population.MCI, mild cognitive impairment.

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the present results clearly illustrate that subtle differences incase definition can have substantial impacts on estimates ofincidence/prevalence.

For individuals with typical lifespan development, MCI isassociated with measurable declines in cognition and was origi-nally thought to leave functional abilities largely unaffected,providing a qualitative standard for ruling out dementia.However, subsequent research has shown that declines ininstrumental activities of daily living (IADLs) can be affected(see Winblad et al., 2004). Thus, the distinction between milddementia and MCI has shifted somewhat over time toward oneof degree of impairment rather than one of the presence ofdecline in any specific domain, broadly considered. Parallelingthe declines in IADLs accompanying MCI in the general popu-lation, it seems reasonable to suppose that some of the rela-tively more cognitively demanding functional skills assessed byadaptive behavior scales could be affected in adults with ID asMCI develops.

Currently, there is no consensus within the ID field regard-ing methods to assess dementia or objective criteria for diagno-sis (cf. Krinsky-McHale & Silverman, in press). In particular,the distinction between MCI and early/mild dementia hasattracted very little attention despite the dramatic increase ininterest in MCI within the broader fields of geriatric medicineand aging research. Objectively differentiating between MCIand dementia for older adults with ID is clearly complicated bythe presence of preexisting impairments and even more so bythe substantial variability in the severity of these impairmentscharacteristic of this population. As the present findings show,that distinction is critically important for determining if ID, inand of itself, is associated with increased risk for dementia.Because the prevalence of MCI within the general populationover 65 is approximately 20% and that of dementia is approxi-mately 6%, misclassifying adults with ID and MCI as dementedcould easily show the approximately threefold increase in riskreported by Strydom et al. (2009) when no such effect in factexists. The fact that Strydom, Chan, Fenton, et al. (2013) foundconsiderable divergence from their original classifications ofdementia status at follow-up some 3 years later reinforcesthis point. On the other hand, relative risk will be underesti-mated to the extent that individuals with mild dementia aremisclassified as having MCI. While the present findings seemmore supportive of the former alternative, they also suggestthat the original Zigman et al. (2004) criterion for dementiamay have leaned toward the conservative side. Given these dis-tinct possibilities, the most prudent conclusion to reach at thispoint is that the true relative risk for dementia associated withID remains uncertain.

Three strategies seem promising for resolving this uncer-tainty. The first is to develop evidence-based methods formaking the distinction between MCI and mild dementia, speci-fying empirically those features most useful for differentiatingbetween these conceptually distinct diagnoses. That can be animmediate focus of research, but a cautionary note seems appro-priate. Considerable time has elapsed since Burt and Aylward(1999) published recommendations for developing a consensusregarding diagnosis of dementia, yet the operationalization ofthose recommendations has not yet been realized. Given thecomplications inherent in the task of differentiating between

FIGURE 1

Cumulative incidence of dementia for adults with intellectualdisability (ID) (higher curves in each panel) compared withgeneral population controls (lower curves). Positive cases withID were restricted to individuals with a primary consensusclassification of “dementia” in Figure 1a, while Figure 1b showscomparable curves when cases with ID also included individualswith mild cognitive impairment.

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MCI and dementia for adults with ID, it seems unrealistic toexpect our field to develop and validate appropriate methodsand standards within the near future.

A second potential strategy might capitalize on currentefforts to identify biomarkers that can inform diagnosis of MCIor dementia within the general population. To date, these effortshave focused primarily on neuroimaging findings and assays ofblood and cerebrospinal fluid, but no definitive biomarker hasbeen found. Nevertheless, this is a very active area of presentresearch and promising directions for current and future workare being identified (cf. Hampel, Lista, & Khachaturian, 2012).In addition to physical biomarkers, behavioral changes distinctfrom declining performance, such as the emergence of problembehaviors or neuropsychiatric concerns, might indicate progres-sion of underlying progressive neuropathology, although find-ings to date suggest that only a minority of affected individualswould be expected to experience these changes (e.g., Urv,Zigman, & Silverman, 2010).

A third strategy seems more promising for determining if IDis associated with increased dementia risk. Rather than strug-gling with the task of distinguishing between MCI and milddementia, researchers can compare the combined incidence/prevalence of MCI and dementia across populations. Techni-cally, this would entail its own set of challenges, requiring casedefinitions of “substantial decline in cognition” for adults withID comparable to the standard of practice for MCI within thegeneral population. Obviously, the primary focus of such casedefinitions would need to be on declines in performance orabilities referenced to an individual’s established baseline. Whilethis seems as if it should be achievable in the near future, thetypes and magnitude of declines sufficient for defining “substan-tial declines” over and above those expected with aging per sewould still need to be determined empirically, and this goalneeds to be added to the research priorities within the field.Once that is accomplished, we will be in a better position todetermine whether ID, in and of itself, increases dementia riskand to anticipate more accurately the levels of supports that willbe needed by the increasing numbers of adults with ID reachingages at risk for the many causes of neuropathology underlyingold-age-associated dementia.

ACKNOWLEDGMENTS

Appreciation is extended to all our participants, theirfamilies, and the agencies serving the needs of individuals withintellectual and developmental disabilities for their invaluablesupport over many years. We acknowledge Deirdre Conlon, LisaKullman, Tracy Listwan, Catherine Marino, Giovanna Palma,David Swift, Anna Trzeciak, and Sheelagh Vietze for their dedica-tion and skills in data collection and processing, and DeborahPang, Robert Ryan, and Marcia Dabbene, our project coordina-tors, for their many contributions to our research program. Wethank Dr. Richard Mayeux and the WHICAP team of investiga-tors for the generous sharing of their incidence data. This workwas supported by NIH grants P01 HD035897, R01 AG037212,P01 AG007232, and P30 HD024061, as well as the New YorkState Office for People with Developmental Disabilities.

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