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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Arch Neurol. Author manuscript; available in PMC 2008 November 25.
Published in final edited form as:
PMCID: PMC2587094
NIHMSID: NIHMS57135

Elevated plasma amyloid β-peptide Aβ42, incident dementia and mortality in Down syndrome

Nicole Schupf, Ph.D.,1,3,5,6 Bindu Patel, M.P.H.,1,6 Deborah Pang, M.P.H.,1,6 Warren B. Zigman, Ph.D.,6 Wayne Silverman, Ph.D.,6,8 Pankaj D. Mehta, Ph.D.,7 and Richard Mayeux, M.D.1,2,4,5

Abstract

BACKGROUND

Deposition of the amyloid beta peptide, Aβ42, is thought to be an important initial step in the pathogenesis of Alzheimer’s disease. Individuals with Down syndrome have both increased levels of Aβ peptides and increased risk for Alzheimer’s disease.

OBJECTIVE

To examine the relation of plasma levels of Aβ42 and Aβ40 to risk of dementia in nondemented participants and to all-cause mortality in adults with Down syndrome.

DESIGN

Prospective, community-based longitudinal cohort study.

SETTING

State and voluntary service providers in New York State

PARTICIPANTS

Adults with Down syndrome (N=204).

MAIN OUTCOME MEASURE

Plasma Aβ42 and Aβ40 levels were measured at initial examination. Participants were assessed for cognitive and functional abilities, behavioral/psychiatric conditions, health and vital status at 14–18 month intervals over four cycles of data collection.

RESULTS

Among participants who were nondemented at baseline, those in the middle and highest tertiles of plasma Aβ42 levels were over 2 times as likely to develop AD as those in the lowest tertile. Compared with participants without AD, participants with prevalent AD had higher levels of plasma Aβ42 but not Aβ40. Among all participants, those in the highest tertile of plasma Aβ42 level at baseline were over twice as likely to die over the study period as those in the lowest tertile, while there was no difference in risk of death between those in the middle and lowest tertile of plasma Aβ42 level.

CONCLUSIONS

Elevations in plasma Aβ42 peptide are associated with earlier onset of AD and increased risk of death.

Keywords: Beta amyloid 1–42, Down syndrome, Alzheimer’s disease, blood plasma

INTRODUCTION

Alzheimer's disease (AD) is associated with deposition of extracellular beta amyloid (Aβ) in neuritic plaques and vessel walls, as well as intracellular accumulation of neurofibrillary tangles. Amyloid β peptides Aβ40 and Aβ42, the two major species of beta amyloid, are generated from the amyloid precursor protein (APP) by sequential proteolytic cleavage by β and δ secretases 1. Previous studies have demonstrated that brain levels of Aβ42 increase early in the development of dementia and decrease with cognitive decline 2. In CSF, Aβ42 is reduced in patients with AD. In the elderly with mild cognitive impairment (MCI), low CSF Aβ42 and high tau concentrations predict incipient AD3. However, the relation of plasma concentration of Aβ42 and Aβ40 is less consistent. While elevated plasma Aβ42 levels in nondemented participants have been associated with increased risk for AD, mild cognitive impairment and cognitive decline 2, 47, a recent large prospective study found that high levels of Aβ40 in conjunction with low levels of Aβ42 predicted the development of dementia8.

Individuals with Down syndrome have both increased levels of both Aβ40 and Aβ42 peptides in plasma and increased risk for AD917. The increased levels of Aβ peptides have been attributed to triplication and overexpression of the gene for beta amyloid precursor protein (APP), located on chromosome 2118. Previously, we reported that plasma Aβ42 levels in demented adults with DS were selectively increased compared with levels in nondemented adults with DS. We also found that Aβ42 levels were elevated in both demented and nondemented adults with the apolipoprotein E (APOE) ε4 allele12. However, all previous studies in adults with Down syndrome have used cross-sectional analyses to examine the relation of plasma Aβ peptides to prevalent dementia. In the present study, we expanded the sample employed in our previous cross sectional analysis and conducted a longitudinal study to examine the relation of plasma levels of Aβ42 and Aβ40 with incidence of dementia and to mortality risk over 5.5 years of follow-up.

MATERIALS AND METHODS

Subjects

A community-based sample of 207 adults with cytogenetically confirmed DS was studied. All individuals were 45 years of age and older, resided in New York State and were participating in a larger longitudinal study of aging in adults with mental retardation. Participants were recruited with the help of state and voluntary service provider agencies. Subjects were eligible to participate in the study if a family member or correspondent provided informed consent, and participants also signed a form acknowledging their willingness to participate. The participation rate was 74.6%. Recruitment, informed consent and study procedures were approved by the Institutional Review Boards of the New York State Institute for Basic Research in Developmental Disabilities and Columbia University Medical Center.

Clinical assessment

Assessments included evaluations of cognition, functional and vocational abilities, behavioral/psychiatric conditions and health status. Assessments were repeated at 14–18 months over four cycles of data collection. Cognitive function was evaluated with a test battery designed for use with individuals varying widely in their levels of intellectual functioning, as described previously 19. Participants showing declines in cognition or in adaptive behavior were evaluated by the study neurologist to confirm the presence of dementia and to determine the presence or absence of medical/psychiatric conditions other than AD that might result in or mimic dementia. Structured interviews were conducted with caregivers to collect information on changes in cognitive function, adaptive behavior and medical history. Past and current medical records were reviewed for all participants. Vital status was obtained from follow-up interviews and from the National Death Index and was collected through October 2005.

Diagnosis of Dementia

To determine the occurrence of dementia and dementia subtypes, information from all available sources was reviewed. Diagnosis was made in a consensus conference regarding the presence or absence of dementia and its cause. Following recommendations of the AAMR-IASSID Working Group for the Establishment of Criteria for the Diagnosis of Dementia in Individuals with Developmental Disability 20, we classified participants into two groups: (1) as demented if there was a history of progressive memory loss, disorientation, and functional decline over a period of at least one year, if no other medical or psychiatric conditions that might mimic dementia were present (e.g., untreated hypothyroidism, stroke) and if a clinical diagnosis of AD had been made by a neurologist or psychiatrist familiar with this population (n=77) and (2) as nondemented if they were without cognitive or functional decline (n=114), or if they showed some cognitive and/or functional decline but not of sufficient magnitude to meet criteria for dementia (n=16). Demented participants were characterized by a decline of at least 20% on a memory test, evidence of decline in one other area of cognition, and a decline of at least 15% on an adaptive behavior scale. Participants classified as demented showed substantial and consistent decline over the course of follow-up. In a few cases, there was caregiver concern about decline in function but only small declines in cognitive function or adaptive abilities and these participants were also classified as nondemented (n=3). Alzheimer’s disease was the predominant form of dementia, accounting for 96% of the cases. Participants with evidence of vascular or other forms of dementia, detected either during the neurological evaluations or from clinical histories, were excluded from the analysis (n=3), leaving 204 participants for analysis. Age at meeting criteria for dementia was used to estimate age at onset of AD, recognizing that it is difficult to document the onset of initial symptoms in this population with precision.

Plasma Aβ42 and Aβ40

A 10 ml venous blood sample (K3EDTA lavender-top tubes) was collected at baseline. Plasma levels of Aβ42 and Aβ40 levels were measured blind to dementia status using a combination of monoclonal antibody 6E10 (specific to an epitope present on 1–16 amino acid residues of Aβ) and rabbit antisera R165 (vs. Aβ42) and R162 (vs. Aβ40) in a double antibody sandwich ELISA as described previously 6, 11, 12. The detection limit for these assays was 5 pg/ml. Aβ1–42 and Aβ1–40 levels from each sample were measured twice using separate aliquots. The correlation between the repeat Aβ42 and Aβ40 measurements was substantial for both peptides (r= .86. and r= .96 for Aβ42 and Aβ40, respectively, p < .001) and we used the mean of the two measurements in statistical analyses.

Apolipoprotein E genotypes

APOE genotyping was carried out as described in a previous study21 employing standard PCR-RFLP methods using Hha1 (CfoI) digestion of an APOE genomic PCR product spanning the polymorphic (cys/arg) sites at codons 112 and 158. Acrylamide gel electrophoresis was used to assess and document the restriction fragment sizes 22. Participants were classified according to the presence or absence of an APOE ε4 allele.

Statistical analyses

In preliminary analyses, we used chi-square to analyze categorical variables and Student's t test and analysis of variance to compare characteristics of participants by tertiles of Aβ42 and Aβ40. We then used Student’s t test and analysis of variance to compare levels of Aβ42 and Aβ40 by dementia status, vital status and other demographic characteristics. Among those who were not demented at baseline, we used Kaplan-Meier life table methods and Cox proportional hazards models to estimate cumulative incidence and the hazard rate (HR) of dementia by tertile of Aβ peptides, first in univariate models (Model A) and then in models which adjusted for age, sex, level of mental retardation and the presence of the APOE ε4 allele (Model B). Among all participants, we also used Kaplan-Meier life table methods and Cox proportional hazards models to estimate cumulative survival and the hazard rate (HR) of death associated with tertiles of plasma Aβ42 and Aβ40. The time to event variable was time since baseline. Level of mental retardation was classified into two groups: mild/moderate (IQ 35–70) and severe/profound (IQ <34), based on IQ scores obtained before onset of dementia 23. Participants were also classified according to the presence or absence of an APOE ε4 allele.

RESULTS

Relation of demographic characteristics to tertiles of Aβ peptides

At the baseline assessment there were 30 participants with prevalent AD among the 204 individuals in the study. Over the course of follow-up (mean duration of 3.9 years ±1.1), 44 participants developed AD (27.8%). The mean time from baseline to onset of dementia was 2.1 (± 1.2) years. Baseline levels of plasma Aβ42 and Aβ40 were correlated with each other (r = .55, p=.001). In cross-sectional analyses, levels of Aβ42, but not Aβ40, were modestly related to age at baseline (r=.216, p = .002 and r=.097, p = .17, respectively). The relation of age and Aβ42 was similar among prevalent cases (r=.244, p=.195) and those who remained nondemented throughout the follow-up period (r=.158, p=.073), but was lower among incident cases (r=.083, p=.594). There was no substantial relation between age and Aβ40 in any group. Table 1 presents demographic characteristics by tertiles of Aβ42 peptide at baseline and Table 2 presents demographic characteristics by tertiles of Aβ40 peptide at baseline. Participants in the highest tertile of Aβ42 peptide were significantly older than those in the two lower tertiles, more likely to have prevalent dementia and more likely to have subsequently died (Table 1). Participants in the highest two tertiles of Aβ42 peptide were more likely to have developed AD than those in the lowest tertile (Table 1) (p < .05). Participants in the highest tertile of Aβ40 peptide were older than those in the lowest and middle tertiles, but the difference did not reach statistical significance (p= .18)(Table 2). Tertile of Aβ40 peptide was not related to dementia status or risk of death. (Table 2). Neither Aβ42 nor Aβ40 level differed by sex, level of mental retardation or presence of the APOE ε4 allele (Table 1 and Table 2).

Table 1
Demographic characteristics by tertiles of beta amyloid peptide Aβ42 at baseline
Table 2
Demographic characteristics by tertiles of beta amyloid peptide Aβ40 at baseline

Relation of Aβ level to demographic characteristics and risk of AD

Plasma Aβ42 levels were highest among those with prevalent dementia at baseline, followed by those who developed AD over the course of the study, and lowest among those who remained dementia free throughout the follow-up period (25.8 ± 7.5 pg/ml vs. 24.1 ± 5.9 pg/ml vs. 22.7 ± 6.1 pg/ml, respectively, p =.042). In contrast, plasma Aβ40 levels did not differ by dementia status (153.1 ± 50.7 pg/ml vs. 162.5 ± 55.1 pg/ml vs. 171.5 ± 54.3 pg/ml, respectively, p = .18). Plasma Aβ42 levels were also higher at baseline in those who died during the course of follow-up than in those who survived (25.8 ± 7.6 pg/ml vs. 22.8 ± 5.7 pg/ml, respectively, p= .01), but plasma Aβ40 did not differ between those who died and those who survived (164.7 ± 56.6 pg/ml vs. 155.9 ± 51.0 pg/ml, respectively, p = .69).

Among participants who were nondemented at baseline, those in the middle and highest tertiles of plasma Aβ42 levels were over 2.0 times as likely to develop AD as those in the lowest tertile, after adjustment for age at baseline, sex, level of mental retardation and the presence of the APOE ε4 allele (HR= 2.6, 95% CI: 1.2–5.9, p=.02 for those in the middle tertile of Aβ42 level, and HR = 2.0, 95% CI: 0.9–4.6, p = .10 for those in the highest tertile of Aβ42 level) (Table 3)(Figure 1). Although participants in the middle tertile of Aβ42 level had the highest risk of developing AD (HR=2.6), the effect of the middle and highest tertiles was similar. Therefore we repeated the analysis combining the middle and highest tertiles. The HR for AD in the combined middle and highest tertiles compared with the lowest tertile was 2.3 (95% CI: 1.1–4.8, p=.02). In contrast, there was no relation between plasma Aβ40 level and risk of incident AD (Table 3).

Figure 1
Cumulative Incidence of Alzheimer’s disease by tertiles of Aβ42 peptides An external file that holds a picture, illustration, etc.
Object name is nihms57135ig1.jpg Lowest tertile: An external file that holds a picture, illustration, etc.
Object name is nihms57135ig2.jpg Middle tertile: An external file that holds a picture, illustration, etc.
Object name is nihms57135ig3.jpg Highest tertile
Table 3
Risk of Alzheimer's disease (AD) by plasma Aβ peptide levels among participants who were not demented at baseline.

Relation of Aβ peptides to mortality

Among all participants, those in the highest tertile of plasma Aβ42 level were more likely to die during follow-up than those in the lowest tertile (HR=2.4 for the highest vs. the lowest tertile of Aβ42 level , 95% CI: 1.1–5.1, p=.02), while risk of death did not differ for those in the middle tertile of Aβ42 level and those in the lowest tertile (HR= 1.2 , 95% CI: 0.5–2.8) (Table 4)(Figure 2). Because dementia is associated with increased risk of death, we repeated this analysis including only individuals who never demented and found a comparable result, although the result was not statistically significant due to a loss of power (HR for mortality in those with the highest tertile of Aβ42 level = 2.7, 95% CI: 0.5–15.6)(not shown).

Figure 2
Cumulative Mortality by tertiles of Aβ42 peptide An external file that holds a picture, illustration, etc.
Object name is nihms57135ig4.jpg Lowest tertile: An external file that holds a picture, illustration, etc.
Object name is nihms57135ig5.jpg Middle tertile: An external file that holds a picture, illustration, etc.
Object name is nihms57135ig6.jpg Highest tertile
Table 4
Risk of death by plasma Aβ peptide levels among all participants

DISCUSSION

In adults with DS, plasma levels of Aβ42, but not Aβ40, were related to risk of both AD and death. However, we also found elevated plasma Aβ42 levels in participants with prevalent AD, while in the population without DS, plasma levels of Aβ42 have been found to be highest in the preclinical state, declining shortly after onset of dementia 4, 5, 2426. The association between elevated Aβ and prevalent dementia may be mediated, at least in part, by increasing age. Aβ42 levels increased with age in adults with DS, and this relationship was strongest for those with prevalent dementia, who were also older, on average, than their nondemented peers. Increasing Aβ species in plasma with age may be a peripheral reflection of the balance between AB production and clearance that in the brain contributes to age-related Aβ deposition and AD risk. However, there was no relation between age and Aβ42 levels in nondemented participants who developed dementia over the follow-up period, suggesting an independent effect of elevated Aβ42 levels on risk for dementia. Seventy-five percent of our prevalent cases had reported onset of dementia within three years of the baseline assessment. This suggests the possibility that high preclinical levels of Aβ42 peptide might decline more slowly among affected adults with DS. It will require longitudinal measurement of Aβ peptide levels over more extended periods of follow-up to determine the pattern of change with disease progression in this population.

Among participants without dementia at baseline, those in the highest two tertiles of plasma Aβ42 were more than twice as likely to develop AD over the study period than those in the lowest tertile of plasma Aβ42. Figure 1 shows that increased incidence of AD was apparent after approximately 1.5 years of follow-up but did not show further increases after 4.5 years of follow-up. Earlier age at onset and increased risk of AD was similar for participants in the two highest Aβ42 tertiles, suggesting a threshold effect. For adults with DS, these findings, together with the striking lack of effects for Aβ40, support the hypothesis that individual differences in Aβ processing or deposition, distinct from overexpression of APP, may influence the pathogenesis of AD.

Our findings are similar to those showing plasma levels of Aβ42 that are higher in nondemented elderly individuals without DS who subsequently developed late onset sporadic AD than in those who remained free of dementia 5, 6. Among nondemented elderly individuals, plasma levels of Aβ42 were also increased in women with mild cognitive impairment who are at high risk of progression to AD 4, and high baseline levels and greater reductions in plasma levels of Aβ42 during follow-up have been associated with greater cognitive decline 7. In contrast, a recent prospective study with 10 years of follow-up found that high levels of Aβ40, in conjunction with low levels of Aβ42 predicted the development of dementia 8. Differences between study results may be related to sampling, assay methods or timing of the sample collection in relation to the preclinical period or to stage of disease progression, and further work with longitudinal cohorts is needed to resolve this issue.

Among all participants, those in the highest tertile of plasma Aβ42 at baseline were at more than twice the risk of dying over the study period compared with those in the lowest tertile, while those in the middle tertile of Aβ42 level did not have increased risk of death. The increased risk of death for those in the highest tertile may be related, at least in part, to increased mortality in demented participants. Cognitive impairment has been shown to be strongly associated with mortality in both nondemented and demented elderly 2730, and dementia is also associated with increased risk of death among adults with DS 3133. Among elderly individuals without DS, baseline plasma Aβ42 levels were higher in participants with recent onset of AD who died compared with those who survived or those without AD 5. The investigators suggested that higher levels of Aβ42 may reflect a more advanced disease or a more aggressive form of AD 5. However, in this study, the increased risk of death appeared to be unrelated to the presence of frank dementia. An alternative hypothesis is that high Aβ42 levels are related to poorer overall health status. Therefore, we examined the frequency of seizures, stroke, cancer, hypothyroidism, diabetes, hypertension, osteoporosis, heart disease (all heart and, separately, myocardial infarction, coronary artery disease, atrial fibrillation, congestive heart failure) by tertile of Aβ42 among all participants. Only the frequency of congestive heart failure (CHF) was significantly higher among those in the highest tertile of Aβ42 (lowest tertile = 1.5%, middle tertile=2.9% and highest tertile = 10.3%, p=.038). Also, the highest frequency of CHF was found in those with prevalent dementia (nondemented=3.1%, incident dementia=2.3% and prevalent dementia= 16.7%). However, when we repeated the Cox models for mortality including the presence or absence of CHF as a covariate, we found that this had no substantive effect on results (HR without CHF= 2.4, 95% CI; 1.1–5.1; HR with CHF as a covariate= 2.2, 95% CI: 1,02–4.7) (not shown). ). Thus, the relation of Aβ42 levels to the declines associated with dementia and death is unlikely to be due to differences among our groups in health status.

The relation of the APOE ε4 allele to plasma Aβ peptides in individuals with DS seems less clear. In a previous study, we found that mean plasma levels of Aβ42 were higher in adults with DS with an APOE e4 allele than in those without, and were highest when both dementia and an e4 allele were present 12. Another study found that plasma levels of Aβ42 and Aβ40 peptides in adults with DS were independent of the presence of an ε4 allele 9, and this was the case in this present study. Both previous studies used cross sectional samples with younger participants. With continued follow-up, the relation of APOE to dementia and to plasma Aβ peptides may become attenuated, as older individuals without the ε4 allele and with lower levels of plasma Aβ peptides develop dementia.

Because adults with Down syndrome overexpress APP and have onset of dementia 10–20 years before the elderly without DS, the argument can be made that our findings may have limited generalizability to the general population. However, studies of DS and AD have suggested that underlying biological mechanisms of interest are consistent in the DS and other elderly populations 34.

It is worthwhile to consider whether elevated plasma Aβ42 peptide level may serve in clinical settings as a biological marker sensitive to the development and progression of AD. However, the substantial overlap in the distribution of Aβ42 levels between demented and nondemented groups , together with changes in levels that may be associated with disease progression, would make interpretation of individual results difficult5. The origin of Aβ in plasma is unknown, and deposition of Aβ42 in brain tissue is unlikely to result directly from increased plasma levels. While diagnostic applications are not evident, it seems clear that both brain and plasma levels of Aβ42 are sensitive to alterations in Aβ processing that contribute to Alzheimer’s disease pathogenesis5, and it will be important to gain a thorough understanding of the molecular mechanisms involved.

Acknowledgements

Supported by NIH grants AG014673, HD35897, HD37425, AG07232, the National Down Syndrome Society, and by funds provided by New York State through its Office of Mental Retardation and Developmental Disabilities. The first author, Dr. Schupf, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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