0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Contribution |

Hypometabolism in Alzheimer-Affected Brain Regions in Cognitively Healthy Latino Individuals Carrying the Apolipoprotein E ε4 Allele FREE

Jessica B. S. Langbaum, PhD; Kewei Chen, PhD; Richard J. Caselli, MD; Wendy Lee, MS; Cole Reschke, BS; Daniel Bandy, MS; Gene E. Alexander, PhD; Christine M. Burns, BA; Alfred W. Kaszniak, PhD; Stephanie A. Reeder, BA; Jason J. Corneveaux, BS; April N. Allen, BS; Jeremy Pruzin, BS, BA; Matthew J. Huentelman, PhD; Adam S. Fleisher, MD; Eric M. Reiman, MD
[+] Author Affiliations

Author Affiliations: Banner Alzheimer's Institute (Drs Langbaum, Chen, Fleisher, and Reiman, Mss Lee and Reeder, and Messrs Reschke and Bandy), Neurogenomics Division, Translational Genomics Research Institute (Messrs Corneveaux and Pruzin, Ms Allen, and Drs Huentelman and Reiman), and Arizona Alzheimer's Consortium (Drs Langbaum, Chen, Caselli, Alexander, Kaszniak, Huentelman, Fleisher, and Reiman, Mss Lee, Burns, Reeder, and Allen and Messrs Reschke, Bandy, Corneveaux, and Pruzin), Phoenix, Department of Mathematics, Arizona State University, Tempe (Dr Chen), Department of Neurology, Mayo Clinic Arizona, Scottsdale (Dr Caselli), and Departments of Psychology (Drs Alexander and Kaszniak and Ms Burns) and Psychiatry (Dr Reiman), and Evelyn F. McKnight Brain Institute (Drs Alexander and Kaszniak), University of Arizona, Tucson; and Department of Neurosciences, University of California San Diego, La Jolla (Dr Fleisher).


Arch Neurol. 2010;67(4):462-468. doi:10.1001/archneurol.2010.30.
Text Size: A A A
Published online

Objective  To investigate with fluorodeoxyglucose positron emission tomography whether regional reductions in the cerebral metabolic rate for glucose (CMRgl) previously found in cognitively healthy late-middle-aged apolipoprotein E (APOE) ε4 carriers extend to members of the Latino Mexican American community.

Design  Prospective cohort study.

Setting  Banner Alzheimer's Institute, Phoenix, Arizona.

Patients or Other Participants  Eleven APOE ε4 carriers and 16 noncarriers from Arizona's Latino community (mean [SD] age, 54.6 [6.4] years) matched for sex, mean age, and educational level and who were predominantly of self-designated Mexican origin.

Main Outcome Measure  A brain mapping algorithm was used to compare cross-sectional regional CMRgl in Latino APOE ε4 carriers vs noncarriers.

Results  Participant groups had similar distributions for age, sex, education, family history of dementia, clinical ratings, and neuropsychological test scores. Latino APOE ε4 carriers had lower CMRgl than the noncarriers in the posterior cingulate, precuneus, and parietal regions previously found to be preferentially affected in patients with Alzheimer disease (AD) and cognitively healthy non-Latino APOE ε4 carriers. Additionally, the Latino APOE ε4 carriers had lower CMRgl in the middle and anterior cingulate cortex, hippocampus, and thalamus.

Conclusions  This study provides support for the relationship between APOE ε4 and risk of AD in Latino individuals. It illustrates the role of positron emission tomography as a presymptomatic endophenotype for the assessment of AD risk factors and supports the inclusion of Latino APOE ε4 carriers in proof-of-concept studies using fluorodeoxyglucose PET to evaluate promising presymptomatic treatments in cognitively healthy carriers of this common AD susceptibility gene.

Figures in this Article

Alzheimer disease (AD) is the most common form of dementia in elderly individuals.1 Over the next few decades, it is projected that there will be dramatic increases in the number of elderly individuals, their racial and ethnic diversity,2 and the number of patients with AD.3 Latino individuals appear to have a higher incidence of AD,4 which may be partly attributable to suggested AD risk factors including diabetes mellitus, obesity, cardiovascular disease, and hypertension, coupled with an earlier mean age at onset5 and a longer postdiagnosis survival time.6

Next to age, the apolipoprotein E (APOE) ε4 allele is the best established risk factor for late-onset AD.7 While this association has been confirmed in numerous case-control studies in Europe and the Americas, the association in different Latino groups continues to be clarified.812 For instance, the association between AD and APOE ε4 is inconsistent for individuals from the Caribbean, perhaps because of differing levels of African admixture among these populations.10,1216

Moreover, some studies suggest that the strength of the association in Latino individuals is weaker compared with that in non-Latino white individuals.8,17 The differences could be due to a multitude of factors, including whether there are differences in the frequency of APOE alleles by ethnic group,10 whether only APOE ε4 homozygosity increases the risk for AD in certain ethnicities or races,13 or whether APOE ε4 is only associated with late-onset familial AD rather than sporadic AD in certain populations.11 Additionally, the accuracy of the self-designated origin, racial, or ethnic classifications and the homogeneity of the Latino groupings may be factors, as some Latino individuals are of African origin and the association between APOE ε4 and AD is inconsistent in Nigerian and African American individuals.10,18,19 Lastly, other genetic variants, including variants in SORL1, may be associated with AD in certain Latino populations as well as non-Latino white individuals.20,21

Fluorodeoxyglucose (FDG) positron emission tomography (PET) studies find that patients with AD have preferential and progressive reductions in the cerebral metabolic rate for glucose (CMRgl) in the posterior cingulate, precuneus, parietal, temporal, and prefrontal brain regions.2229 We and others have found that cognitively healthy APOE ε4 carriers exhibit CMRgl reductions in these AD-affected regions,3034 leading us to propose that FDG PET could be used as a promising biomarker (but not yet validated surrogate end point) for the evaluation of promising presymptomatic AD treatments in cognitively healthy APOE ε4 carriers.33,35 Based on the finding that the CMRgl reductions in AD-affected regions are associated with the number of ε4 alleles in a person's APOE genotype (ie, 3 levels of genetic risk for AD),36 we proposed using FDG PET to provide a quantitative presymptomatic endophenotype, a measurable feature that is more closely related to disease susceptibility than the clinical syndrome itself, to help assess the individual and aggregate effects of putative modifiers of AD risk.33

This study compared FDG PET measurements of regional CMRgl in cognitively healthy late-middle-aged APOE ε4 carriers and noncarriers from the rapidly growing US Latino community.2 In particular, it sought to determine whether cognitively healthy Latino APOE ε4 carriers have lower CMRgl than noncarriers in AD-affected regions, provide presymptomatic endophenotypic evidence for the role of the APOE ε4 allele as a late-onset AD susceptibility gene in this population, and support the inclusion of Latino ε4 carriers in our proposed presymptomatic AD treatment trials. Moreover, to address the potential heterogeneity within the Latino cohort, the cohort was tested for stratification between APOE ε4 carriers and noncarriers.

PARTICIPANTS

To identify Latino APOE ε4 carriers, a newspaper article about AD research and an accompanying advertisement, as well as other outreach activities, permitted us to recruit 81 (68 women and 13 men) cognitively healthy volunteers from Arizona's English-speaking Latino community, 47 to 68 years of age, irrespective of their reported family history of AD. Nearly all respondents were the result of the newspaper article and accompanying advertisement. Respondents understood that they would not receive any information about their APOE genotype, provided their informed consent, and were studied under guidelines approved by the human subjects committees at Banner Good Samaritan Medical Center and the Mayo Clinic. Venous blood samples were drawn and APOE genotypes characterized with analysis involving restriction fragment length polymorphisms.37

The distribution of APOE genotypes in the Latino respondents is noted in Table 1. While 22 APOE ε4 carriers were identified, 8 declined to participate in the imaging studies and 3 did not meet our selection criteria for imaging study enrollment because of comorbid medical conditions (diabetes, stroke, and cancer). Of the 59 noncarriers, 14 declined to participate in the imaging studies and 11 did not meet our selection criteria because of diabetes or stroke. The 11 APOE ε4 carriers who agreed to participate in the imaging studies (1 with the ε4/ε4 allele, 1 with the ε2/ε4 allele, and 9 with the ε3/ε4 allele) were matched to 16 APOE ε4 noncarriers (1 with the ε2/ε3 allele and 15 with the ε3/ε3 allele) for sex, mean age, and educational level. Investigators who were unaware of the participants' APOE genotypes obtained data from medical and family histories as previously described,31 including a neurological examination, a structured psychiatric interview, the Mini- Mental State Examination,38 the Hamilton Depression Rating Scale,39 a battery of neuropsychological tests, and brain imaging studies.

Table Graphic Jump LocationTable 1. Distribution of Apolipoprotein E Genotypes in 81 Latino Respondents 47 to 68 Years of Age

The 27 participants in the imaging portion of the study were predominantly self-designated Mexican American (1 participant self-designated being of South American origin [Peru] and 2 self-designated being of Puerto Rican origin) and 10 reported a first-degree family history of dementia. At the time of their initial visit, all participants denied having impairment in memory or other cognitive skills, did not satisfy criteria for a current psychiatric disorder other than depression or anxiety, had no known cardiovascular or cerebrovascular disease, had scores of at least 28 on the Mini-Mental State Examination, had normal neurological examination results, and identified English as their primary language. To allow for inclusion of this underrepresented cohort into a study of this nature, we broadened our usual criteria to allow for self-reported depression or anxiety and pharmaceutical treatments of these disorders and did not require a first-degree family history of AD. Five participants reported using medication to treat depression or anxiety; however, all Hamilton Depression Rating Scale scores were within normal limits. In addition, 6 participants reported a history of hypertension or hypercholesterolemia.

BRAIN IMAGING

Volumetric T1-weighted magnetic resonance imaging (MRI), performed to rule out structural lesions, and FDG PET were performed as previously described.31,36 For 6 participants (2 APOE ε4 carriers and 4 noncarriers), PET was performed with an older 951/31 scanner (Siemens, Knoxville, Tennessee). This scanner records in 2-dimensional mode with intravenous injection of about 3.7 × 108 Bq of FDG. The remaining 21 participants (9 APOE ε4 carriers and 12 noncarriers) were studied with an HR+ scanner (Siemens). The HR+ scanner simultaneously records data in a 3-dimensional mode with the intravenous injection of 1.85 × 108 to 2.96 × 108 Bq of FDG and permits the reconstruction of images consisting of 63 horizontal slices with a center-to-center slice separation of 2.46 mm, an axial field of view of 15.5 cm, an in-plane resolution of 4.2 to 5.1 mm full width at half maximum (FWHM), and an axial resolution of 4.6 to 6.0 mm FWHM. Regardless of scanner type, a 60-minute dynamic sequence of emission scans was acquired from each participant, who had fasted for at least 4 hours and was instructed to lay quietly with eyes closed in a darkened room. The emission image was reconstructed with measured attenuation correction and a 0.40-cycle per pixel Hanning filter, resulting in a final in-plane resolution of 10.5 mm FWHM. Regional analyses were performed using the PET images (counts relative to the whole-brain uptake) acquired during the last 30 minutes.

PET DATA ANALYSIS

An automated algorithm (SPM5; Wellcome Department of Cognitive Neurology, London, England) was used to linearly and nonlinearly deform each person's PET image into the coordinates of a standard brain atlas. Images were further smoothed using a 3-dimensional gaussian filter to a spatial resolution of 12 mm FWHM. The images were normalized for the variation in whole-brain measurements by using proportionate scaling. Two-sample t tests were used to examine the differences in CMRgl between the Latino APOE ε4 carriers and noncarriers (P < .005, uncorrected for multiple comparisons) on a voxel by voxel basis. The statistical map was superimposed onto a map of CMRgl reductions in previously studied patients with AD22 and a spatially standardized, volume-rendered MRI. Significance levels were then adjusted for the number of resolution elements in the AD-affected posterior cingulate, precuneus, parietotemporal, and frontal brain regions using the small-volume correction procedure in SPM (P < .05, corrected fo multiple comparisons). Findings in other brain regions were not corrected for multiple comparisons and are considered exploratory. The statistical analysis was first performed using all data, covarying for the coding of the 2 scanners. A post hoc analysis was conducted using only the data (n = 21) from the HR+ scanner to confirm findings independent of any potential confounds associated with the use of the 2 different scanners. Post hoc voxel-based analysis was conducted using data from a predominately non-Latino white cohort40 (11 APOE ε4 heterozygotes and 22 noncarriers) to confirm findings independent of an interaction between APOE ε4 carrier/noncarrier status and Latino/non-Latino status. Additional post hoc analyses were conducted. First, voxelwise post hoc analyses were conducted to determine the effect of positive first-degree family history of dementia on CMRgl reductions, given that this may impart additional risk above APOE.4143 Second, an analysis was conducted to examine whether the observed CMRgl reductions were associated with performance on the Rey Auditory Verbal Learning Test–Long-Term Memory,44 a measure we have shown to be the most sensitive to age-related memory decline in APOE ε4 carriers.45 For the later, data from the voxel with the most significant reduction of CMRgl (1 AD-predicted region and 1 additional region) were extracted from each subject and used to calculate Pearson correlation coefficients.

POPULATION STRUCTURE ANALYSIS

Twenty-five of the 27 Latino samples were successfully genotyped with the Affymetrix 6.0 array (Affymetrix Inc, Santa Clara, California) using standard methods and Birdsuite46 was used to call single-nucleotide polymorphism (SNP) genotypes from CEL files. The Latino cohort was tested for stratification between APOE ε4 carriers and noncarriers in PLINK version 1.0647 using a clustering approach with pairwise identity-by-state distance measures. For this analysis, we removed SNPs with Hardy-Weinberg equilibrium of P ≤ .001, missing genotypes more than 10%, and minor allele frequencies less than 1% for a total of 764 108 SNPs used for stratification analysis. Ten thousand label-swapping permutations were performed between APOE ε4 carriers and noncarriers and similarity P values were calculated.

The distribution of APOE genotypes in the 81 subjects is shown in Table 1. The APOE genotype frequencies are similar to those found in other samples of Mexican American individuals,48,49 and the percentage of APOE ε4 homozygotes is similar to that found in the general population.50 The characteristics of the APOE ε4 carriers and noncarriers enrolled in the imaging study are shown in Table 2. The APOE ε4 carriers and noncarrier groups did not differ significantly in their sex, reported family history of dementia, mean age, educational level, Mini-Mental State Examination score, other clinical ratings and neuropsychological test scores, or in the scanners used to acquire their FDG PET data.

Table Graphic Jump LocationTable 2. Characteristics, Clinical Ratings, and Neuropsychological Scores of the Subjects Studied With PET

As predicted, Latino APOE ε4 carriers had significantly lower CMRgl relative to the noncarriers bilaterally in brain regions previously found to be preferentially affected by AD, including the posterior cingulate (P < .05, corrected for multiple comparisons using small-volume correction), precuneus, and parietal cortex (P < .005, uncorrected for multiple comparisons) (Table 3) (Figure). In addition, compared with noncarriers, the APOE ε4 carriers had CMRgl reductions in the middle and anterior cingulate, hippocampus, and thalamus (P < .005, uncorrected for multiple comparisons) (Table 3) (Figure). The latter findings should be considered exploratory since the findings were not predicted and were not subject to small-volume correction. For each of the locations specified in Table 3, the mean CMRgl was 6.9% to 16.0% lower in the APOE ε4 carriers than in the noncarriers.

Place holder to copy figure label and caption
Figure.

Significantly lower cerebral metabolic rate for glucose in cognitively healthy Latino apolipoprotein E ε4 carriers than noncarriers (shown in blue, P < .005, uncorrected). Reductions are shown in relationship to brain regions preferentially affected in an earlier positron emission tomography study of patients with Alzheimer disease22 (shown in purple).

Graphic Jump Location
Table Graphic Jump LocationTable 3. Location and Magnitude of Most Significant CMRgl Reductions Among Latino APOE ε4 Carriers Compared With Noncarriersa

A post hoc voxel-based analysis failed to identify an interaction between APOE ε4 carrier/noncarrier status and Latino/non-Latino status, as the CMRgl reductions observed in the Latino APOE ε4 carriers compared with noncarriers were not significantly different from CMRgl reductions in non-Latino white APOE ε4 heterozygotes compared with noncarriers. Findings from the post hoc analysis of the data from the 21 participants scanned with the HR+ scanner were nearly identical to the results obtained from all 27 participants who were scanned on either the HR+ scanner or 951/31 scanner, indicating that the findings are not attributable to any confounds associated with the use of 2 scanners. Similarly, the post hoc voxel-based analyses that controlled for first-degree family history of dementia were nearly identical to those shown in Table 3 and the Figure, indicating that the findings are not solely attributable to this confound (data not shown). Lastly, reduction in CMRgl was not correlated with Rey Auditory Verbal Learning Test–Long-Term Memory score, nor was there a significant interaction with APOE ε4 carrier status.

Pairwise identity-by-state clustering across 764 108 SNPs showed no significant similarity or difference between APOE ε4 carriers and noncarriers (P = .17 less similar and P = .83 more similar). Additionally, using the identity-by-state approach, we confirmed the 25 genotyped Latino individuals clustered into a single cluster with no significant outliers based on nearest neighbor calculations.

In our previous FDG PET studies, we found that cognitively healthy late-middle-aged APOE ε4 carriers have significantly lower CMRgl than noncarriers in brain regions preferentially affected by AD.31,33,36 The present study extends our findings to a cohort of Latino Mexican American individuals and supports the relationship between the APOE ε4 allele and the risk of AD in this rapidly growing North American community. Furthermore, the genetic findings confirmed the relative homogeneity of our Latino cohort, with no stratification between the APOE ε4 carriers and noncarriers.

Among certain Latino groups, the association between the APOE ε4 allele and AD continues to be clarified, particularly for those of Caribbean origin.10,1214 Some studies suggest that the strength of the association in Latino individuals is weaker compared with that in non-Latino white individuals8,17 or that the degree of association among Latino individuals may be intermediate between that in African American and non-Latino white individuals,12,52 consistent with the African admixture in Latino individuals of Caribbean origin.53 If inconsistent findings persist, they may be attributable to AD-related environmental and genetic differences (eg, dietary differences or African vs European origin) within the heterogeneous characterization of “Latino,” perhaps warranting the use of genome-wide genetic analyses in future studies, with the caveat that there may be cultural sensitivities to the issue specific to different ethnic groups.

In addition to the predicted CMRgl reductions in AD-related brain regions, the Latino APOE ε4 carriers exhibited hypometabolism in the middle and anterior cingulate cortex, hippocampus, and thalamus. This pattern of hypometabolism is somewhat different than what we previously observed in a predominately non-Latino cohort of APOE ε4 carriers.31,40 However, in a post hoc comparison of the interaction between Latino/non-Latino status and APOE ε4 carrier/noncarrier status, these CMRgl reductions in Latino individuals were not significantly greater than those in the predominately non-Latino cohort and so are of uncertain significance. Accordingly, there is a need for additional studies with a larger Latino sample size to confirm that the more extensive regional findings remain significant. If they do, there are other differences besides Latino status that may account for the findings. For instance, there is no requirement for family history of AD in our Latino cohort as there is in our predominately non-Latino cohort, thereby potentially causing us to slightly underestimate changes related to AD risk in the non-Latino cohort.

This study has some limitations. First, since our findings are restricted to participants who identified English as their primary language, were predominately self-designated Mexican American, were recruited using targeted outreach efforts, and had relatively high levels of education and included only 11 APOE ε4 carriers and more women than men, additional population-based studies are needed to determine the extent to which they are generalizable to other Latino subjects and communities. Still, our findings are likely to be relevant to those Mexican American individuals who express interest in proof-of-concept presymptomatic AD treatment studies, discussed later. Second, we have not yet sought to determine the extent to which our findings are solely attributable to the combined effects of atrophy and partial-volume averaging, MRI white matter intensities, or vascular risk factors. Still, we previously demonstrated that APOE ε4–related CMRgl reductions are not solely attributable to brain atrophy, subjects in our imaging studies do not have clinically significant MRI abnormalities, and the carriers and noncarriers did not differ significantly in their reported vascular risk factors.

We have proposed how FDG PET and other brain imaging measurements could be used in cognitively healthy APOE ε4 carriers as quantitative presymptomatic endophenotypes, measurable features that are more closely related to disease susceptibility than the clinical syndrome itself, to help evaluate the individual and aggregate effects of putative genetic and nongenetic modifiers of AD risk.36 We are currently investigating the possibility of using multivariate statistical methods, including partial least squares and our recently reported multimodal partial least squares method,54 to characterize the patterns of FDG PET and other imaging changes associated with APOE ε4 gene dose, characterize the presymptomatic brain imaging phenotype in a single-subject score that reflects this pattern, and use them to evaluate suggested genetic and nongenetic modifiers of AD risk using our presymptomatic brain imaging phenotype with superior statistical power and freedom from the type I error associated with multiple comparisons.

We have also proposed how FDG PET and other brain imaging measurements could be used to evaluate the effectiveness of putative presymptomatic AD therapies to slow down the progressive regional CMRgl declines in proof-of-concept studies without having to study thousands of healthy late-middle-aged persons or wait many years to determine whether or when persons in the clinical trial develop symptoms.35 As a complement to observational studies of older patients with AD and controls, our proposed endophenotype could provide prospective evaluation of putative risk modifiers, help address the potentially confounding effects of differential survival related to the risk modifiers, provide information about the individual or aggregate effects of risk factors, and permit the accurate measurement and real-time evaluation of a putative risk factor years before the onset of symptoms. As a complement to prospective cohort studies, this imaging endophenotype could potentially be used as a surrogate marker for presymptomatic AD treatment development, decreasing the number of healthy participants needed or length of treatment needed to observe drug effects.

The present study illustrates the use of this endophenotype by showing an AD-related pattern of hypometabolism in APOE ε4 carriers from Arizona's Latino community. Consistent with previous findings in non-Latino white individuals, the predominately Mexican American APOE ε4 carriers have reduced glucose metabolism in AD-related brain regions, which, coupled with the projected rapid increase in the racial and ethnic diversity of older adults,2 supports the inclusion of Latino APOE ε4 carriers in proof-of-concept studies using FDG PET to evaluate promising presymptomatic treatments in cognitively healthy people at increased risk for AD.

Correspondence: Jessica B. S. Langbaum, PhD, Banner Alzheimer's Institute, 901 E Willetta St, Phoenix, AZ 85006 (jessica.langbaum@bannerhealth.com).

Accepted for Publication: September 9, 2009.

Author Contributions:Study concept and design: Langbaum, Caselli, Huentelman, Fleisher, and Reiman. Acquisition of data: Bandy, Burns, Kaszniak, Reeder, Corneveaux, Allen, Pruzin, and Reiman. Analysis and interpretation of data: Langbaum, Chen, Lee, Reschke, Alexander, Kaszniak, Corneveaux, Huentelman, Fleisher, and Reiman. Drafting of the manuscript: Langbaum, Bandy, Corneveaux, and Reiman. Critical revision of the manuscript for important intellectual content: Langbaum, Chen, Caselli, Lee, Reschke, Alexander, Burns, Kaszniak, Reeder, Allen, Pruzin, Huentelman, Fleisher, and Reiman. Statistical analysis: Langbaum, Chen, Lee, Reschke, Alexander, Kaszniak, and Corneveaux. Obtained funding: Caselli and Reiman. Administrative, technical, and material support: Caselli, Reschke, Bandy, Burns, Kaszniak, Reeder, Allen, Pruzin, Fleisher, and Reiman. Study supervision: Langbaum, Bandy, Burns, Huentelman, Fleisher, and Reiman.

Financial Disclosure: None reported.

Funding/Support: This work was supported by National Institute of Mental Health grant R01MH57899 (Dr Reiman), National Institute on Aging grants R01AG031581 and P30AG19610 (Dr Reiman), the Evelyn G. McKnight Brain Institute (Dr Alexander), the state of Arizona (Drs Reiman, Caselli, Alexander, and Chen), and contributions from the Banner Alzheimer's Foundation and Mayo Clinic Foundation.

Previous Presentation: Portions of this study were presented at the 11th International Conference on Alzheimer's Disease; July 27, 2008; Chicago, Illinois.

Additional Contributions: We thank Richard Gerkin, MD, MS, Napatkamon Ayutyanont, PhD, Patti Aguilar, David Branch, AAS, CNMT, ARRT, Sandra Goodwin, CNMT, NMTCB(PET), ARRT, CRT, Bruce Henslin, BA, Debbie Intorcia, Jennifer Keppler, CNMT, MBA, Xiaofen Liu, MS, Anita Prouty, BS, Oded Smilovici, MS, Desiree Van Egmond, AS, Justin Venditti, BA, and Sandra Yee-Benedetto, BA, for assistance.

Evans  DAFunkenstein  HHAlbert  MS  et al.  Prevalence of Alzheimer's disease in a community population of older persons: higher than previously reported. JAMA 1989;262 (18) 2551- 2556
PubMed Link to Article
Day  JC  Population Projections of the United States by Age, Sex, Race, and Hispanic Origin: 1995 to 2050.  Washington, DC US Government Printing Office1996;US Bureau of the Census Current Population Reports P25-1130
Hebert  LEScherr  PABienias  JLBennett  DAEvans  DA Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch Neurol 2003;60 (8) 1119- 1122
PubMed Link to Article
Tang  MXCross  PAndrews  H  et al.  Incidence of AD in African-Americans, Caribbean Hispanics, and Caucasians in northern Manhattan. Neurology 2001;56 (1) 49- 56
PubMed Link to Article
Clark  CMDeCarli  CMungas  D  et al.  Earlier onset of Alzheimer disease symptoms in Latino individuals compared with Anglo individuals. Arch Neurol 2005;62 (5) 774- 778
PubMed Link to Article
Helzner  EPScarmeas  NCosentino  STang  MXSchupf  NStern  Y Survival in Alzheimer disease: a multiethnic, population-based study of incident cases. Neurology 2008;71 (19) 1489- 1495
PubMed Link to Article
Corder  EHSaunders  AMStrittmatter  WJ  et al.  Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 1993;261 (5123) 921- 923
PubMed Link to Article
Farrer  LA Cupples  LAHaines  JL  et al. APOE and Alzheimer Disease Meta Analysis Consortium, Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA 1997;278 (16) 1349- 1356
PubMed Link to Article
Harwood  DGBarker  WWOwnby  RLMullan  MDuara  R Apolipoprotein E polymorphism and cognitive impairment in a bi-ethnic community-dwelling elderly sample. Alzheimer Dis Assoc Disord 2002;16 (1) 8- 14
PubMed Link to Article
Tang  MXStern  YMarder  K  et al.  The APOE-epsilon4 allele and the risk of Alzheimer disease among African Americans, whites, and Hispanics. JAMA 1998;279 (10) 751- 755
PubMed Link to Article
Romas  SNSantana  VWilliamson  J  et al.  Familial Alzheimer disease among Caribbean Hispanics: a reexamination of its association with APOE. Arch Neurol 2002;59 (1) 87- 91
PubMed Link to Article
Maestre  GOttman  RStern  Y  et al.  Apolipoprotein E and Alzheimer's disease: ethnic variation in genotypic risks. Ann Neurol 1995;37 (2) 254- 259
PubMed Link to Article
Tang  MXMaestre  GTsai  WY  et al.  Relative risk of Alzheimer disease and age-at-onset distributions, based on APOE genotypes among elderly African Americans, Caucasians, and Hispanics in New York City. Am J Hum Genet 1996;58 (3) 574- 584
PubMed
Olarte  LSchupf  NLee  JH  et al.  Apolipoprotein E epsilon4 and age at onset of sporadic and familial Alzheimer disease in Caribbean Hispanics. Arch Neurol 2006;63 (11) 1586- 1590
PubMed Link to Article
Arboleda  GHYunis  JJPardo  R  et al.  Apolipoprotein E genotyping in a sample of Colombian patients with Alzheimer's disease. Neurosci Lett 2001;305 (2) 135- 138
PubMed Link to Article
Sevush  SPeruyera  GCrawford  FMullan  M Apolipoprotein-E epsilon 4 allele frequency and conferred risk for Cuban Americans with Alzheimer's disease. Am J Geriatr Psychiatry 2000;8 (3) 254- 256
PubMed
Harwood  DGBarker  WWOwnby  RLSt George-Hyslop  PMullan  MDuara  R Apolipoprotein E polymorphism and age of onset for Alzheimer's disease in a bi-ethnic sample. Int Psychogeriatr 2004;16 (3) 317- 326
PubMed Link to Article
Hendrie  HCHall  KSHui  S  et al.  Apolipoprotein E genotypes and Alzheimer's disease in a community study of elderly African Americans. Ann Neurol 1995;37 (1) 118- 120
PubMed Link to Article
Osuntokun  BOSahota  AOgunniyi  AO  et al.  Lack of an association between apolipoprotein E epsilon 4 and Alzheimer's disease in elderly Nigerians. Ann Neurol 1995;38 (3) 463- 465
PubMed Link to Article
Tycko  BLee  JHCiappa  A  et al.  APOE and APOC1 promoter polymorphisms and the risk of Alzheimer disease in African American and Caribbean Hispanic individuals. Arch Neurol 2004;61 (9) 1434- 1439
PubMed Link to Article
Lee  JHCheng  RSchupf  N  et al.  The association between genetic variants in SORL1 and Alzheimer disease in an urban, multiethnic, community-based cohort. Arch Neurol 2007;64 (4) 501- 506
PubMed Link to Article
Alexander  GEChen  KPietrini  PRapoport  SIReiman  EM Longitudinal PET evaluation of cerebral metabolic decline in dementia: a potential outcome measure in Alzheimer's disease treatment studies. Am J Psychiatry 2002;159 (5) 738- 745
PubMed Link to Article
Minoshima  SFrey  KAKoeppe  RAFoster  NLKuhl  DE A diagnostic approach in Alzheimer's disease using three-dimensional stereotactic surface projections of fluorine-18-FDG PET. J Nucl Med 1995;36 (7) 1238- 1248
PubMed
Silverman  DHSmall  GWChang  CY  et al.  Positron emission tomography in evaluation of dementia: regional brain metabolism and long-term outcome. JAMA 2001;286 (17) 2120- 2127
PubMed Link to Article
Chase  TNFoster  NLFedio  PBrooks  RMansi  LDi Chiro  G Regional cortical dysfunction in Alzheimer's disease as determined by positron emission tomography. Ann Neurol 1984;15(suppl)S170- S174
PubMed Link to Article
Foster  NLChase  TNMansi  L  et al.  Cortical abnormalities in Alzheimer's disease. Ann Neurol 1984;16 (6) 649- 654
PubMed Link to Article
Jagust  WJFriedland  RPBudinger  TFKoss  EOber  B Longitudinal studies of regional cerebral metabolism in Alzheimer's disease. Neurology 1988;38 (6) 909- 912
PubMed Link to Article
Mosconi  LTsui  WHHerholz  K  et al.  Multicenter standardized 18F-FDG PET diagnosis of mild cognitive impairment, Alzheimer's disease, and other dementias. J Nucl Med 2008;49 (3) 390- 398
PubMed Link to Article
Langbaum  JBSChen  KLee  W  et al. Alzheimer's Disease Neuroimaging Initiative, Categorical and correlational analyses of baseline fluorodeoxyglucose positron emission tomography images from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Neuroimage 2009;45 (4) 1107- 1116
PubMed Link to Article
Small  GWMazziotta  JCCollins  MT  et al.  Apolipoprotein E type 4 allele and cerebral glucose metabolism in relatives at risk for familial Alzheimer disease. JAMA 1995;273 (12) 942- 947
PubMed Link to Article
Reiman  EMCaselli  RJYun  LS  et al.  Preclinical evidence of Alzheimer's disease in persons homozygous for the ε4 allele for apolipoprotein E. N Engl J Med 1996;334 (12) 752- 758
PubMed Link to Article
Reiman  EMChen  KAlexander  GE  et al.  Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia. Proc Natl Acad Sci U S A 2004;101 (1) 284- 289
PubMed Link to Article
Reiman  EMCaselli  RJChen  KAlexander  GEBandy  DFrost  J Declining brain activity in cognitively normal apolipoprotein E ε4 heterozygotes: a foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer's disease. Proc Natl Acad Sci U S A 2001;98 (6) 3334- 3339
PubMed Link to Article
Rimajova  MLenzo  NPWu  JS  et al.  Fluoro-2-deoxy-D-glucose (FDG)-PET in APOE epsilon4 carriers in the Australian population. J Alzheimers Dis 2008;13 (2) 137- 146
PubMed
Reiman  EMLangbaum  JBS Brain imaging in the evaluation of putative Alzheimer's disease slowing, risk-reducing and prevention therapies. Jagust  WJD'Esposito  MImaging the Aging Brain. New York, NY Oxford University Press2009;319- 350
Reiman  EMChen  KAlexander  GE  et al.  Correlations between apolipoprotein E ε4 gene dose and brain-imaging measurements of regional hypometabolism. Proc Natl Acad Sci U S A 2005;102 (23) 8299- 8302
PubMed Link to Article
Crook  RHardy  JDuff  K Single-day apolipoprotein E genotyping. J Neurosci Methods 1994;53 (2) 125- 127
PubMed Link to Article
Folstein  MFFolstein  SE McHugh  PR “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12 (3) 189- 198
PubMed Link to Article
Hamilton  M A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;2356- 62
PubMed Link to Article
Reiman  EMCaselli  RJAlexander  GEChen  K Tracking the decline in cerebral glucose metabolism in persons and laboratory animals at genetic risk for Alzheimer's disease. Clin Neurosci Res 2001;1 (3) 194- 206
Link to Article
Mosconi  LMistur  RSwitalski  R  et al.  Declining brain glucose metabolism in normal individuals with a maternal history of Alzheimer disease. Neurology 2009;72 (6) 513- 520
PubMed Link to Article
Johnson  SCSchmitz  TWTrivedi  MA  et al.  The influence of Alzheimer disease family history and apolipoprotein E epsilon4 on mesial temporal lobe activation. J Neurosci 2006;26 (22) 6069- 6076
PubMed Link to Article
Xu  G McLaren  DGRies  ML  et al.  The influence of parental history of Alzheimer's disease and apolipoprotein E epsilon4 on the BOLD signal during recognition memory. Brain 2009;132 (pt 2) 383- 391
PubMed Link to Article
Rey  A L'examen psychologique dans les cas d'encephalopathie tramatique. Arch de Psychologie 1941;28215- 285
Caselli  RJDueck  ACOsborne  D  et al.  Longitudinal modeling of age-related memory decline and the APOE ε4 effect. N Engl J Med 2009;361 (3) 255- 263
PubMed Link to Article
McCarroll  SAKuruvilla  FKorn  J  et al.  Integrated detection and population-genetic analysis of SNPs and copy number variation. Nat Genet 2008;40 (10) 1166- 1174
PubMed Link to Article
Purcell  SNeale  BTodd-Brown  K  et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007;81 (3) 559- 575
PubMed Link to Article
Haffner  SMStern  MPMiettinen  HRobbins  DHoward  BV Apolipoprotein E polymorphism and LDL size in a biethnic population. Arterioscler Thromb Vasc Biol 1996;16 (9) 1184- 1188
PubMed Link to Article
Shriver  MDBoerwinkle  EHewett-Emmett  DHanis  CL Frequency and effects of apolipoprotein E polymorphism in Mexican-American NIDDM subjects. Diabetes 1991;40 (3) 334- 337
PubMed Link to Article
Mahley  RW Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science 1988;240 (4852) 622- 630
PubMed Link to Article
Talairach  JTournoux  P Co-Planar Stereotaxic Atlas of the Human Brain.  New York, NY Thieme Medical Publishers1988;
Mayeux  RStern  YOttman  R  et al.  The apolipoprotein epsilon 4 allele in patients with Alzheimer's disease. Ann Neurol 1993;34 (5) 752- 754
PubMed Link to Article
Osborne  LCMason  JM HLA-A/B haplotype frequencies among US Hispanic and African-American populations. Hum Genet 1993;91 (4) 326- 332
PubMed Link to Article
Chen  KReiman  EMHuan  Z  et al.  Linking functional and structural brain images with multivariate network analyses: a novel application of the partial least square method. Neuroimage 2009;47 (2) 602- 610
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure.

Significantly lower cerebral metabolic rate for glucose in cognitively healthy Latino apolipoprotein E ε4 carriers than noncarriers (shown in blue, P < .005, uncorrected). Reductions are shown in relationship to brain regions preferentially affected in an earlier positron emission tomography study of patients with Alzheimer disease22 (shown in purple).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Distribution of Apolipoprotein E Genotypes in 81 Latino Respondents 47 to 68 Years of Age
Table Graphic Jump LocationTable 2. Characteristics, Clinical Ratings, and Neuropsychological Scores of the Subjects Studied With PET
Table Graphic Jump LocationTable 3. Location and Magnitude of Most Significant CMRgl Reductions Among Latino APOE ε4 Carriers Compared With Noncarriersa

References

Evans  DAFunkenstein  HHAlbert  MS  et al.  Prevalence of Alzheimer's disease in a community population of older persons: higher than previously reported. JAMA 1989;262 (18) 2551- 2556
PubMed Link to Article
Day  JC  Population Projections of the United States by Age, Sex, Race, and Hispanic Origin: 1995 to 2050.  Washington, DC US Government Printing Office1996;US Bureau of the Census Current Population Reports P25-1130
Hebert  LEScherr  PABienias  JLBennett  DAEvans  DA Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch Neurol 2003;60 (8) 1119- 1122
PubMed Link to Article
Tang  MXCross  PAndrews  H  et al.  Incidence of AD in African-Americans, Caribbean Hispanics, and Caucasians in northern Manhattan. Neurology 2001;56 (1) 49- 56
PubMed Link to Article
Clark  CMDeCarli  CMungas  D  et al.  Earlier onset of Alzheimer disease symptoms in Latino individuals compared with Anglo individuals. Arch Neurol 2005;62 (5) 774- 778
PubMed Link to Article
Helzner  EPScarmeas  NCosentino  STang  MXSchupf  NStern  Y Survival in Alzheimer disease: a multiethnic, population-based study of incident cases. Neurology 2008;71 (19) 1489- 1495
PubMed Link to Article
Corder  EHSaunders  AMStrittmatter  WJ  et al.  Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 1993;261 (5123) 921- 923
PubMed Link to Article
Farrer  LA Cupples  LAHaines  JL  et al. APOE and Alzheimer Disease Meta Analysis Consortium, Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA 1997;278 (16) 1349- 1356
PubMed Link to Article
Harwood  DGBarker  WWOwnby  RLMullan  MDuara  R Apolipoprotein E polymorphism and cognitive impairment in a bi-ethnic community-dwelling elderly sample. Alzheimer Dis Assoc Disord 2002;16 (1) 8- 14
PubMed Link to Article
Tang  MXStern  YMarder  K  et al.  The APOE-epsilon4 allele and the risk of Alzheimer disease among African Americans, whites, and Hispanics. JAMA 1998;279 (10) 751- 755
PubMed Link to Article
Romas  SNSantana  VWilliamson  J  et al.  Familial Alzheimer disease among Caribbean Hispanics: a reexamination of its association with APOE. Arch Neurol 2002;59 (1) 87- 91
PubMed Link to Article
Maestre  GOttman  RStern  Y  et al.  Apolipoprotein E and Alzheimer's disease: ethnic variation in genotypic risks. Ann Neurol 1995;37 (2) 254- 259
PubMed Link to Article
Tang  MXMaestre  GTsai  WY  et al.  Relative risk of Alzheimer disease and age-at-onset distributions, based on APOE genotypes among elderly African Americans, Caucasians, and Hispanics in New York City. Am J Hum Genet 1996;58 (3) 574- 584
PubMed
Olarte  LSchupf  NLee  JH  et al.  Apolipoprotein E epsilon4 and age at onset of sporadic and familial Alzheimer disease in Caribbean Hispanics. Arch Neurol 2006;63 (11) 1586- 1590
PubMed Link to Article
Arboleda  GHYunis  JJPardo  R  et al.  Apolipoprotein E genotyping in a sample of Colombian patients with Alzheimer's disease. Neurosci Lett 2001;305 (2) 135- 138
PubMed Link to Article
Sevush  SPeruyera  GCrawford  FMullan  M Apolipoprotein-E epsilon 4 allele frequency and conferred risk for Cuban Americans with Alzheimer's disease. Am J Geriatr Psychiatry 2000;8 (3) 254- 256
PubMed
Harwood  DGBarker  WWOwnby  RLSt George-Hyslop  PMullan  MDuara  R Apolipoprotein E polymorphism and age of onset for Alzheimer's disease in a bi-ethnic sample. Int Psychogeriatr 2004;16 (3) 317- 326
PubMed Link to Article
Hendrie  HCHall  KSHui  S  et al.  Apolipoprotein E genotypes and Alzheimer's disease in a community study of elderly African Americans. Ann Neurol 1995;37 (1) 118- 120
PubMed Link to Article
Osuntokun  BOSahota  AOgunniyi  AO  et al.  Lack of an association between apolipoprotein E epsilon 4 and Alzheimer's disease in elderly Nigerians. Ann Neurol 1995;38 (3) 463- 465
PubMed Link to Article
Tycko  BLee  JHCiappa  A  et al.  APOE and APOC1 promoter polymorphisms and the risk of Alzheimer disease in African American and Caribbean Hispanic individuals. Arch Neurol 2004;61 (9) 1434- 1439
PubMed Link to Article
Lee  JHCheng  RSchupf  N  et al.  The association between genetic variants in SORL1 and Alzheimer disease in an urban, multiethnic, community-based cohort. Arch Neurol 2007;64 (4) 501- 506
PubMed Link to Article
Alexander  GEChen  KPietrini  PRapoport  SIReiman  EM Longitudinal PET evaluation of cerebral metabolic decline in dementia: a potential outcome measure in Alzheimer's disease treatment studies. Am J Psychiatry 2002;159 (5) 738- 745
PubMed Link to Article
Minoshima  SFrey  KAKoeppe  RAFoster  NLKuhl  DE A diagnostic approach in Alzheimer's disease using three-dimensional stereotactic surface projections of fluorine-18-FDG PET. J Nucl Med 1995;36 (7) 1238- 1248
PubMed
Silverman  DHSmall  GWChang  CY  et al.  Positron emission tomography in evaluation of dementia: regional brain metabolism and long-term outcome. JAMA 2001;286 (17) 2120- 2127
PubMed Link to Article
Chase  TNFoster  NLFedio  PBrooks  RMansi  LDi Chiro  G Regional cortical dysfunction in Alzheimer's disease as determined by positron emission tomography. Ann Neurol 1984;15(suppl)S170- S174
PubMed Link to Article
Foster  NLChase  TNMansi  L  et al.  Cortical abnormalities in Alzheimer's disease. Ann Neurol 1984;16 (6) 649- 654
PubMed Link to Article
Jagust  WJFriedland  RPBudinger  TFKoss  EOber  B Longitudinal studies of regional cerebral metabolism in Alzheimer's disease. Neurology 1988;38 (6) 909- 912
PubMed Link to Article
Mosconi  LTsui  WHHerholz  K  et al.  Multicenter standardized 18F-FDG PET diagnosis of mild cognitive impairment, Alzheimer's disease, and other dementias. J Nucl Med 2008;49 (3) 390- 398
PubMed Link to Article
Langbaum  JBSChen  KLee  W  et al. Alzheimer's Disease Neuroimaging Initiative, Categorical and correlational analyses of baseline fluorodeoxyglucose positron emission tomography images from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Neuroimage 2009;45 (4) 1107- 1116
PubMed Link to Article
Small  GWMazziotta  JCCollins  MT  et al.  Apolipoprotein E type 4 allele and cerebral glucose metabolism in relatives at risk for familial Alzheimer disease. JAMA 1995;273 (12) 942- 947
PubMed Link to Article
Reiman  EMCaselli  RJYun  LS  et al.  Preclinical evidence of Alzheimer's disease in persons homozygous for the ε4 allele for apolipoprotein E. N Engl J Med 1996;334 (12) 752- 758
PubMed Link to Article
Reiman  EMChen  KAlexander  GE  et al.  Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia. Proc Natl Acad Sci U S A 2004;101 (1) 284- 289
PubMed Link to Article
Reiman  EMCaselli  RJChen  KAlexander  GEBandy  DFrost  J Declining brain activity in cognitively normal apolipoprotein E ε4 heterozygotes: a foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer's disease. Proc Natl Acad Sci U S A 2001;98 (6) 3334- 3339
PubMed Link to Article
Rimajova  MLenzo  NPWu  JS  et al.  Fluoro-2-deoxy-D-glucose (FDG)-PET in APOE epsilon4 carriers in the Australian population. J Alzheimers Dis 2008;13 (2) 137- 146
PubMed
Reiman  EMLangbaum  JBS Brain imaging in the evaluation of putative Alzheimer's disease slowing, risk-reducing and prevention therapies. Jagust  WJD'Esposito  MImaging the Aging Brain. New York, NY Oxford University Press2009;319- 350
Reiman  EMChen  KAlexander  GE  et al.  Correlations between apolipoprotein E ε4 gene dose and brain-imaging measurements of regional hypometabolism. Proc Natl Acad Sci U S A 2005;102 (23) 8299- 8302
PubMed Link to Article
Crook  RHardy  JDuff  K Single-day apolipoprotein E genotyping. J Neurosci Methods 1994;53 (2) 125- 127
PubMed Link to Article
Folstein  MFFolstein  SE McHugh  PR “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12 (3) 189- 198
PubMed Link to Article
Hamilton  M A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;2356- 62
PubMed Link to Article
Reiman  EMCaselli  RJAlexander  GEChen  K Tracking the decline in cerebral glucose metabolism in persons and laboratory animals at genetic risk for Alzheimer's disease. Clin Neurosci Res 2001;1 (3) 194- 206
Link to Article
Mosconi  LMistur  RSwitalski  R  et al.  Declining brain glucose metabolism in normal individuals with a maternal history of Alzheimer disease. Neurology 2009;72 (6) 513- 520
PubMed Link to Article
Johnson  SCSchmitz  TWTrivedi  MA  et al.  The influence of Alzheimer disease family history and apolipoprotein E epsilon4 on mesial temporal lobe activation. J Neurosci 2006;26 (22) 6069- 6076
PubMed Link to Article
Xu  G McLaren  DGRies  ML  et al.  The influence of parental history of Alzheimer's disease and apolipoprotein E epsilon4 on the BOLD signal during recognition memory. Brain 2009;132 (pt 2) 383- 391
PubMed Link to Article
Rey  A L'examen psychologique dans les cas d'encephalopathie tramatique. Arch de Psychologie 1941;28215- 285
Caselli  RJDueck  ACOsborne  D  et al.  Longitudinal modeling of age-related memory decline and the APOE ε4 effect. N Engl J Med 2009;361 (3) 255- 263
PubMed Link to Article
McCarroll  SAKuruvilla  FKorn  J  et al.  Integrated detection and population-genetic analysis of SNPs and copy number variation. Nat Genet 2008;40 (10) 1166- 1174
PubMed Link to Article
Purcell  SNeale  BTodd-Brown  K  et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007;81 (3) 559- 575
PubMed Link to Article
Haffner  SMStern  MPMiettinen  HRobbins  DHoward  BV Apolipoprotein E polymorphism and LDL size in a biethnic population. Arterioscler Thromb Vasc Biol 1996;16 (9) 1184- 1188
PubMed Link to Article
Shriver  MDBoerwinkle  EHewett-Emmett  DHanis  CL Frequency and effects of apolipoprotein E polymorphism in Mexican-American NIDDM subjects. Diabetes 1991;40 (3) 334- 337
PubMed Link to Article
Mahley  RW Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science 1988;240 (4852) 622- 630
PubMed Link to Article
Talairach  JTournoux  P Co-Planar Stereotaxic Atlas of the Human Brain.  New York, NY Thieme Medical Publishers1988;
Mayeux  RStern  YOttman  R  et al.  The apolipoprotein epsilon 4 allele in patients with Alzheimer's disease. Ann Neurol 1993;34 (5) 752- 754
PubMed Link to Article
Osborne  LCMason  JM HLA-A/B haplotype frequencies among US Hispanic and African-American populations. Hum Genet 1993;91 (4) 326- 332
PubMed Link to Article
Chen  KReiman  EMHuan  Z  et al.  Linking functional and structural brain images with multivariate network analyses: a novel application of the partial least square method. Neuroimage 2009;47 (2) 602- 610
PubMed Link to Article

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 24

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles
JAMAevidence.com


Allele