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Potentially modifiable risk factors for dementia: Evidence from identical twins
Abstracts: Clinical Assessment / 1 (Suppl 1) (2005) O1-01-06
CORRELATIONS BETWEEN CHOLESTEROLRELATED GENETIC RISK SCORES AND LOWER BRAIN-IMAGING MEASUREMENTS OF REGIONAL GLUCOSE METABOLISM
Eric M. Reiman1, Kewei Chen1, Richard Caselli2, Daniel Bandy1, Wendy Lee1, Gene Alexander3, Dietrich Stephan4, Andreas Papassotiropoulos5; 1Banner Good Samaritan Medical Center, Phoenix, AZ, USA; 2Mayo Clinic Scottsdale, Scottsdale, AZ, USA; 3 Arizona State University, Tempe, AZ, USA; 4Translational Genomics Research Institute, Phoenix, AZ, USA; 5University of Zurich, Zurich, Switzerland Background: In a positron emission tomography (PET) study of cognitively normal, late-middle-aged persons, we demonstrated a correlation between apolipoprotein E (APOE) ⑀4 gene dose, an established contributor to the risk of late-onset Alzheimer’s disease (AD), and lower measurements of the cerebral metabolic rate for glucose (CMRgl) in AD-affected brain regions. We proposed the use of PET as a quantitative, pre-symptomatic endophenotype to evaluate the individual and aggregate effects of putative genetic and non-genetic modifiers of AD risk. In a genetic study of European AD cases and controls, Papassotiropoulos recently identified a cluster of single nucleotide polymorphisms (SNPs) in 7 cholesterolrelated genes (APOE, SOAT1, APOE 5’-untranslated region, OLR1, CYP46A1, LPL, LIPA, and APOA4) associated with the risk of AD. He proposed the calculation of a person’s cholesterol-related genetic AD risk scores from the risk-weighted summation of his or her implicated SNPs. Objective(s): To test the hypothesis that the proposed cholesterol-related AD genetic risk scores in cognitively normal, late-middle persons are correlated with lower CMRgl measurements in AD-affected brain regions. Methods: A brain mapping algorithm (SPM99) was used to compute significant correlations between cholesterol-related genetic risk scores and lower PET CMRgl measurements in 118 previously studied, cognitively normal, late-middle-aged persons. They included 25 APOE ⑀4 homozygotes, 35 ⑀4 heterozygotes, and 58 ⑀4 non-carriers and were 57⫾5 years of age. Conclusions: As predicted, significant correlations between cholesterol-related genetic risk scores and lower CMRgl were observed in each of the AD-affected brain regions; several of the correlations observed in the overall group were again observed in the aggregate APOE ⑀4 carrier group and in the ⑀4 homozygotes, heterozygotes, and non-carriers; significant correlations between the risk scores and higher CMRgl were not observed in any location. Furthermore, many of the observed correlations were again noted after excluding effects of APOE ⑀4 gene dose from the genetic risk scores. This study provides further support for the role of a cluster of cholesterol-related genes in the risk of AD, and it provides further support for the role of brain imaging in the pre-symptomatic assessment of putative modifiers of AD risk. O1-01-07
IS APOE PLASMA LEVEL ASSOCIATED WITH MCI? FINDINGS FROM THE FRAMINGHAM HEART STUDY
Michael Tocco1, Rhoda Au1, Howard Cabral2, Alexa Beiser2, Sanford H. Auerbach1, Robert C. Green1,2, Philip A. Wolf1; 1Boston University School of Medicine, Boston, MA, USA; 2Boston University School of Public Health, Boston, MA, USA Background: In-vitro studies suggest that the apoE3 isoform is associated with increased neuronal plasticity, reduced A neurotoxicity, and prevention of NFT formation relative to the apoE4 isoform. It has been reported that high apoE3 levels are related to greater neuronal growth; whereas high apoE4 levels have been shown to inhibit neuronal growth. Whether apoE plasma levels can differentiate between those with and without MCI in APOE-⑀3 and APOE-⑀4 positive individuals has not been explored. Objective: To determine if apolipoprotein E (apoE) isoform plasma level is associated with mild cognitive impairment (MCI). Methods: In this crosssectional study, 374 non-demented individuals (mean age ⫽ 72, SD ⫽ 4.4,
S79
range ⫽ 65-88) from the Framingham Heart Study were classified into MCI and non-MCI groups using the Petersen criteria of performance deficits of 1.5 SD below age and educated adjusted mean scores on memory (WAIS Logical Memory subtest) and non-memory tests (WAIS Similarities subtest, Trail-making test, Boston Naming Test, and the Hooper Visual Organization test). Four MCI categories were created: 1) Amnestic Single Domain MCI (impairment in memory only), 2) Amnestic Multiple Domain MCI (impairment in memory and one non-memory test) 3) Non-Amnestic Single Domain MCI (impairment on one non-memory test only), 4) Non-Amnestic Single Domain MCI (impairment on two or more non-memory measures). To assess the relationship between apoE isoform plasma level and MCI, individuals were divided into APOE-⑀3 (⑀3/⑀3, n ⫽ 287) and APOE-⑀4 (⑀4/⑀4, ⑀3/⑀4, n ⫽ 87) genotype groups. Conclusions: There were no significant differences in age, education, gender, and body mass index (BMI) between individuals with and without MCI in either the APOE-⑀3 and APOE-⑀4 groups. Among APOE-⑀3 individuals, an ANOVA, adjusted for age, education, and gender, revealed a significantly lower mean apoE3 plasma level in the Amnestic Single Domain MCI group (p ⫽ 0.05) compared to the non-MCI group (7.3 mg/dl and 10.3 mg/dl, respectively). There were no significant MCI group differences in apoE plasma level for APOE-⑀4 positive individuals. These findings suggest that higher apoE3 levels may offer protection from agerelated cognitive decline. O1-01-08
POTENTIALLY MODIFIABLE RISK FACTORS FOR DEMENTIA: EVIDENCE FROM IDENTICAL TWINS
Margaret Gatz1, James A. Mortimer2, Laura Fratiglioni3, Kecia Watari4; 1 Univ of Southern California, Los Angeles, CA, USA; 2Univ of South Florida, Tampa, FL, USA; 3Karolinska Institutet, Stockholm, Sweden; 4 Univ of California Los Angeles, Los Angeles, CA, USA Background: A variety of potentially modifiable risk factors over the lifespan have been shown to be associated with dementia in late life. Studying such factors in twins permits testing their importance while controlling for genetic influences. Objective: To test the following potentially modifiable risk factors among twin pairs discordant for dementia: level of education, relative height (as an index of early nutrition), periodontal disease experienced before early adulthood (as an index of inflammatory exposure), participation in mentally stimulating activities in middle adulthood, blue collar occupation, participation in physical exercise in middle adulthood, and history of stroke (as an index of vascular risk factors). Methods: All monozygotic (MZ) twin pairs in which one or both twins were demented were ascertained from the entire Swedish Twin Registry. There were 109 discordant pairs in which information was available from both members of the pair. Pairs were compared using matched t-tests for continuous variables and conditional logistic regression for categorical variables. Conclusion: The demented twins in discordant pairs had significantly fewer years of education (p⫽.04) and were three times more likely to be the twin with lower education; were four times more likely to have periodontal disease by midlife (p⫽.008); and were six times more likely to have had a stroke (p⫽.004). Fifty-six percent of the dementia cases in discordant pairs had one or more of these risk factors. None of the other variables added significantly. Multivariate analyses show that periodontal disease and stroke each contributed significantly to predicting dementia, while partially accounting for the effect of education. Because the analyses involve monozygotic twins, genetic influences are controlled; there were no significant interactions with whether the pair carried an apolipoprotein e4 allele. The results support the view that preventive measures earlier in the lifespan can contribute to lowering the risk of dementia. [Supported by grants from the National Institute on Aging (R01-AG08724) and the Alzheimer’s Association (ZEN-02-3895).]
CORRELATIONS BETWEEN CHOLESTEROLRELATED GENETIC RISK SCORES AND LOWER BRAIN-IMAGING MEASUREMENTS OF REGIONAL GLUCOSE METABOLISM
Eric M. Reiman1, Kewei Chen1, Richard Caselli2, Daniel Bandy1, Wendy Lee1, Gene Alexander3, Dietrich Stephan4, Andreas Papassotiropoulos5; 1Banner Good Samaritan Medical Center, Phoenix, AZ, USA; 2Mayo Clinic Scottsdale, Scottsdale, AZ, USA; 3 Arizona State University, Tempe, AZ, USA; 4Translational Genomics Research Institute, Phoenix, AZ, USA; 5University of Zurich, Zurich, Switzerland Background: In a positron emission tomography (PET) study of cognitively normal, late-middle-aged persons, we demonstrated a correlation between apolipoprotein E (APOE) ⑀4 gene dose, an established contributor to the risk of late-onset Alzheimer’s disease (AD), and lower measurements of the cerebral metabolic rate for glucose (CMRgl) in AD-affected brain regions. We proposed the use of PET as a quantitative, pre-symptomatic endophenotype to evaluate the individual and aggregate effects of putative genetic and non-genetic modifiers of AD risk. In a genetic study of European AD cases and controls, Papassotiropoulos recently identified a cluster of single nucleotide polymorphisms (SNPs) in 7 cholesterolrelated genes (APOE, SOAT1, APOE 5’-untranslated region, OLR1, CYP46A1, LPL, LIPA, and APOA4) associated with the risk of AD. He proposed the calculation of a person’s cholesterol-related genetic AD risk scores from the risk-weighted summation of his or her implicated SNPs. Objective(s): To test the hypothesis that the proposed cholesterol-related AD genetic risk scores in cognitively normal, late-middle persons are correlated with lower CMRgl measurements in AD-affected brain regions. Methods: A brain mapping algorithm (SPM99) was used to compute significant correlations between cholesterol-related genetic risk scores and lower PET CMRgl measurements in 118 previously studied, cognitively normal, late-middle-aged persons. They included 25 APOE ⑀4 homozygotes, 35 ⑀4 heterozygotes, and 58 ⑀4 non-carriers and were 57⫾5 years of age. Conclusions: As predicted, significant correlations between cholesterol-related genetic risk scores and lower CMRgl were observed in each of the AD-affected brain regions; several of the correlations observed in the overall group were again observed in the aggregate APOE ⑀4 carrier group and in the ⑀4 homozygotes, heterozygotes, and non-carriers; significant correlations between the risk scores and higher CMRgl were not observed in any location. Furthermore, many of the observed correlations were again noted after excluding effects of APOE ⑀4 gene dose from the genetic risk scores. This study provides further support for the role of a cluster of cholesterol-related genes in the risk of AD, and it provides further support for the role of brain imaging in the pre-symptomatic assessment of putative modifiers of AD risk. O1-01-07
IS APOE PLASMA LEVEL ASSOCIATED WITH MCI? FINDINGS FROM THE FRAMINGHAM HEART STUDY
Michael Tocco1, Rhoda Au1, Howard Cabral2, Alexa Beiser2, Sanford H. Auerbach1, Robert C. Green1,2, Philip A. Wolf1; 1Boston University School of Medicine, Boston, MA, USA; 2Boston University School of Public Health, Boston, MA, USA Background: In-vitro studies suggest that the apoE3 isoform is associated with increased neuronal plasticity, reduced A neurotoxicity, and prevention of NFT formation relative to the apoE4 isoform. It has been reported that high apoE3 levels are related to greater neuronal growth; whereas high apoE4 levels have been shown to inhibit neuronal growth. Whether apoE plasma levels can differentiate between those with and without MCI in APOE-⑀3 and APOE-⑀4 positive individuals has not been explored. Objective: To determine if apolipoprotein E (apoE) isoform plasma level is associated with mild cognitive impairment (MCI). Methods: In this crosssectional study, 374 non-demented individuals (mean age ⫽ 72, SD ⫽ 4.4,
S79
range ⫽ 65-88) from the Framingham Heart Study were classified into MCI and non-MCI groups using the Petersen criteria of performance deficits of 1.5 SD below age and educated adjusted mean scores on memory (WAIS Logical Memory subtest) and non-memory tests (WAIS Similarities subtest, Trail-making test, Boston Naming Test, and the Hooper Visual Organization test). Four MCI categories were created: 1) Amnestic Single Domain MCI (impairment in memory only), 2) Amnestic Multiple Domain MCI (impairment in memory and one non-memory test) 3) Non-Amnestic Single Domain MCI (impairment on one non-memory test only), 4) Non-Amnestic Single Domain MCI (impairment on two or more non-memory measures). To assess the relationship between apoE isoform plasma level and MCI, individuals were divided into APOE-⑀3 (⑀3/⑀3, n ⫽ 287) and APOE-⑀4 (⑀4/⑀4, ⑀3/⑀4, n ⫽ 87) genotype groups. Conclusions: There were no significant differences in age, education, gender, and body mass index (BMI) between individuals with and without MCI in either the APOE-⑀3 and APOE-⑀4 groups. Among APOE-⑀3 individuals, an ANOVA, adjusted for age, education, and gender, revealed a significantly lower mean apoE3 plasma level in the Amnestic Single Domain MCI group (p ⫽ 0.05) compared to the non-MCI group (7.3 mg/dl and 10.3 mg/dl, respectively). There were no significant MCI group differences in apoE plasma level for APOE-⑀4 positive individuals. These findings suggest that higher apoE3 levels may offer protection from agerelated cognitive decline. O1-01-08
POTENTIALLY MODIFIABLE RISK FACTORS FOR DEMENTIA: EVIDENCE FROM IDENTICAL TWINS
Margaret Gatz1, James A. Mortimer2, Laura Fratiglioni3, Kecia Watari4; 1 Univ of Southern California, Los Angeles, CA, USA; 2Univ of South Florida, Tampa, FL, USA; 3Karolinska Institutet, Stockholm, Sweden; 4 Univ of California Los Angeles, Los Angeles, CA, USA Background: A variety of potentially modifiable risk factors over the lifespan have been shown to be associated with dementia in late life. Studying such factors in twins permits testing their importance while controlling for genetic influences. Objective: To test the following potentially modifiable risk factors among twin pairs discordant for dementia: level of education, relative height (as an index of early nutrition), periodontal disease experienced before early adulthood (as an index of inflammatory exposure), participation in mentally stimulating activities in middle adulthood, blue collar occupation, participation in physical exercise in middle adulthood, and history of stroke (as an index of vascular risk factors). Methods: All monozygotic (MZ) twin pairs in which one or both twins were demented were ascertained from the entire Swedish Twin Registry. There were 109 discordant pairs in which information was available from both members of the pair. Pairs were compared using matched t-tests for continuous variables and conditional logistic regression for categorical variables. Conclusion: The demented twins in discordant pairs had significantly fewer years of education (p⫽.04) and were three times more likely to be the twin with lower education; were four times more likely to have periodontal disease by midlife (p⫽.008); and were six times more likely to have had a stroke (p⫽.004). Fifty-six percent of the dementia cases in discordant pairs had one or more of these risk factors. None of the other variables added significantly. Multivariate analyses show that periodontal disease and stroke each contributed significantly to predicting dementia, while partially accounting for the effect of education. Because the analyses involve monozygotic twins, genetic influences are controlled; there were no significant interactions with whether the pair carried an apolipoprotein e4 allele. The results support the view that preventive measures earlier in the lifespan can contribute to lowering the risk of dementia. [Supported by grants from the National Institute on Aging (R01-AG08724) and the Alzheimer’s Association (ZEN-02-3895).]