- Email: [email protected]
Effects of the Apolipoprotein E genotype on memory performance and brain morphology in young healthy adults
Poster Presentations P1 P1-376
EFFECTS OF THE APOLIPOPROTEIN E GENOTYPE ON MEMORY PERFORMANCE AND BRAIN MORPHOLOGY IN YOUNG HEALTHY ADULTS
Harald Hampel1, Julia Miller2, Monika Scheibe2, Fabian Fusser2, Silke Matura2, Viola Oertel-Kn€ochel2, Tarik Karakaya2, J€org Magerkurth2, David Prvulovic2, 1Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Frankfurt, Germany; 2University of Frankfurt, Frankfurt, Germany. Background: The apolipoprotein E e4 (ApoE4) genotype is the highest single genetic risk factor for sporadic Alzheimer’s disease (AD) and has been associated with an increased risk of memory decline in healthy elderly subjects. Moreover, regional brain volume reductions have been observed in e4- carriers relative to non-carriers in brain areas that are known to be affected by AD pathology, such as the medial temporal lobe and the posterior cingulate cortex. However, results from studies on the effects of the ApoE4 genotype in young healthy subjects have been conflicting. The aim of the present study was to assess grey matter volume, microstructural white matter fiber tract integrity as well as various memory performance indices in young healthy ApoE4 carriers compared with non-carriers. Methods: 15 ApoE4 carriers, aged 27.4 6 5.8 years and 15 non-carriers, matched in age and education underwent high-resolution 3D-anatomical MRI imaging, diffusion tensor imaging (DTI), and neuropsychological assessment including the California Verbal Learning Test (CVLT) and the working memory subtests of the MATRICS Consensus Cognitive Battery. Voxel-Based Morphometry (VBM) was used to identify areas of ApOE4-related differences in brain volume. Additionally, DTI data was analysed with Tract-Based Spatial Statistics (TBSS) to reveal possible differences in fractional anisotropy (FA) between groups. Results: Compared to controls, APOE e4 carriers showed impaired delayed recall (p ¼ 0.04) of verbal material (CVLT word list). Working memory and visual memory performance, however were not affected. Structural analysis with VBM and DTI did not reveal any significant differences in gray matter and white matter volume or in FA between groups. Conclusions: The results indicate impaired performance in delayed recall of verbal material associated with APOE e4 in the absence of underlying brain morphological changes. Further investigations on functional dynamic biomarkers are required in order to test for possible aberrant functional activation patterns and for potential functional network connectivity alterations underlying impaired episodic memory performance in young genetic risk carriers. P1-377
INTERACTIVE EFFECTS OF A SEDENTARY LIFESTYLE AND THE APOE E4 ALLELE ON AMYLOID DEPOSITION
Denise Head, Julie Bugg, Alison Goate, Anne Fagan, Mark Mintun, Tammie Benzinger, David Holtzman, John Morris, Washington University, St. Louis, Missouri, United States. Background: The presence of an APOE e4 allele is one of the most established genetic risk factors for Alzheimer’s disease (AD). Furthermore, APOE e4+ status has been associated with greater amyloid deposition even in cognitively normal adults. In contrast, physical exercise has been associated with less amyloid deposition. The primary objective of the current study was to examine whether exercise engagement influences the association between APOE genotype and amyloid deposition in cognitively normal adults. Methods: 201 adults (135 females, 66 males) aged 45-88 were recruited and confirmed to be cognitively normal based on the Clinical Dementia Rating scale. A self-report questionnaire on physical exercise engagement over the last decade was administered to all of the participants in conjunction with APOE genotyping. Cerebrospinal fluid (CSF) samples were collected from 165 participants, whereas amyloid imaging with PET-PIB was performed on 163 participants. Participants were categorized into low and high exercise engagement groups based on whether reported exercise levels were at or above the levels recommended by the American Heart Association. Results: APOE e4 carriers evidenced higher PIB binding with increased mean cortical binding potential (p < .001) and lower
S233
CSF Aß42 levels (p < .001). In addition, a more sedentary lifestyle was associated with higher PIB binding (p ¼ .005) and lower CSF Aß42 levels (p ¼ .009). Most importantly, we observed a novel interaction between APOE status and exercise engagement for PIB binding (p ¼ .008). Specifically, a more sedentary lifestyle was significantly associated with higher PIB binding for e4 carriers (p ¼ .013) but not for e4 non-carriers (p ¼ .208). These findings were robust to controlling for age, gender, education, hypertension, body mass index, diabetes, heart problems and history of depression. Conclusions: Collectively, these results are suggestive that sedentary APOE e4+ individuals may be at augmented risk for cortical amyloid deposition. P1-378
AGE, APOE E4, AND ETHNIC EFFECT ON [C-11] PIB IN MULTINATIONAL ADNI STUDIES: DIRECT COMPARISON OF J-ADNI, US-ADNI AND AIBL DATA
Kenji Ishii1, Muneyuki Sakata1, Keiichi Oda1, Jun Toyohara1, Kiichi Ishiwata1, Michio Senda2, Kengo Ito3, Ryozo Kuwano4, Takeshi Iwatsubo5 THE JAPANESE ALZHEIMER’S DISEASE NEUROIMAGING INITIATIVE6, THE ALZHEIMER’S DISEASE NEUROIMAGING INITIATIVE7, AIBL RESEARCH GROUP81Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan; 2Institute of Biomedical Research and Innovation, Kobe, Japan; 3 National Center for Geriatrics and Gerontology, Obu, Japan; 4Brain Research Institute, Niigata University, Niigata, Japan; 5Graduate School of Medicine, University of Tokyo, Tokyo, Japan; 6Tokyo, Japan; 7Los Angeles, California, United States; 8Melboume, Australia. Background: It has not been established whether the association between apolipoprotein E (APOE) e4 allele, age, and amyloid deposition is similar or different between ethnic groups. In this study, we evaluated the influence of APOE e4 and age on the cortical accumulation of 11C-Pittsburgh compound B (PiB) in three multi-center studies of Alzheimer’s disease (AD) with harmonized protocol; Alzheimer’s Disease Neuroimaging Initiative (US-ADNI, U), Australian Imaging Biomarker and Lifestyle Flagship Study of Aging (AIBL, A), and Japanese Alzheimer’s Disease Neuroimaging Initiative (J-ADNI, J). Methods: We analyzed the initial 11C-PiB scan data from US-ADNI: 19 cognitively normal (NL), 64 mild cognitive impairment (MCI) subjects, and 19 AD patients, AIBL: 119 NL, 41 MCI, 27 AD, and J-ADNI: 46 NL, 32 MCI, and 21 AD. All the 11C-PiB PET images were acquired 50-70 min post-injection. The mean cortical standardized uptake value ratio (mcSUVR) in reference to cerebellar cortex was measured with the same platform of data analysis. The cut-off mcSUVR value for PiB-positivity was set at 1.5 for all the studies. Results: The PiB-positive rate (%) in each group with or without e4 allele (e4+/e4-)were; NL (80/ 57), MCI (83/52), AD (100/88) in US-ADNI; NL (56/23), MCI (88/31), AD (100/100) in AIBL; and NL (59/7), MCI (100/44), AD (100/80) in JADNI. General linear model and logistic regression model were constructed to predict the mcSUVR and PiB positivity based on age, gene dose of e4 allele (0, 1, 2), and study (U, A, or J) as explanatory variables. Significant positive contribution (p<0.001) was estimated in age and e4, but no significant effect of the study group was observed for either mcSUVR value or PiB positivity in the data set of NL category and overall subjects. A single dose of e4 has equivalent contribution to 11.8 years of age for PiB positivity in NL group (Table1). Conclusions: Our results suggest that the three multi-national ADNI data are feasible for combined analysis. Study effect or ethnic effect was estimated to be limited, however, age and e4 effect on amyloid deposition is similar in Japanese population to those in Caucasians, despite the lower e4 allele frequency in the Japanese population. PiB (+) rate in Normals by age and e4 allele J-ADNI + US-ADNI + AIBL (n ¼ 182) 60s e4 (-/-) e4 (+/-) e4 (+/+)
5% 37% 67%
70s 2/41 11/30 4/6
28% 65% 100%
80s 14/50 13/20 1/1
49% 91% –
11/23 10/11 –
EFFECTS OF THE APOLIPOPROTEIN E GENOTYPE ON MEMORY PERFORMANCE AND BRAIN MORPHOLOGY IN YOUNG HEALTHY ADULTS
Harald Hampel1, Julia Miller2, Monika Scheibe2, Fabian Fusser2, Silke Matura2, Viola Oertel-Kn€ochel2, Tarik Karakaya2, J€org Magerkurth2, David Prvulovic2, 1Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Frankfurt, Germany; 2University of Frankfurt, Frankfurt, Germany. Background: The apolipoprotein E e4 (ApoE4) genotype is the highest single genetic risk factor for sporadic Alzheimer’s disease (AD) and has been associated with an increased risk of memory decline in healthy elderly subjects. Moreover, regional brain volume reductions have been observed in e4- carriers relative to non-carriers in brain areas that are known to be affected by AD pathology, such as the medial temporal lobe and the posterior cingulate cortex. However, results from studies on the effects of the ApoE4 genotype in young healthy subjects have been conflicting. The aim of the present study was to assess grey matter volume, microstructural white matter fiber tract integrity as well as various memory performance indices in young healthy ApoE4 carriers compared with non-carriers. Methods: 15 ApoE4 carriers, aged 27.4 6 5.8 years and 15 non-carriers, matched in age and education underwent high-resolution 3D-anatomical MRI imaging, diffusion tensor imaging (DTI), and neuropsychological assessment including the California Verbal Learning Test (CVLT) and the working memory subtests of the MATRICS Consensus Cognitive Battery. Voxel-Based Morphometry (VBM) was used to identify areas of ApOE4-related differences in brain volume. Additionally, DTI data was analysed with Tract-Based Spatial Statistics (TBSS) to reveal possible differences in fractional anisotropy (FA) between groups. Results: Compared to controls, APOE e4 carriers showed impaired delayed recall (p ¼ 0.04) of verbal material (CVLT word list). Working memory and visual memory performance, however were not affected. Structural analysis with VBM and DTI did not reveal any significant differences in gray matter and white matter volume or in FA between groups. Conclusions: The results indicate impaired performance in delayed recall of verbal material associated with APOE e4 in the absence of underlying brain morphological changes. Further investigations on functional dynamic biomarkers are required in order to test for possible aberrant functional activation patterns and for potential functional network connectivity alterations underlying impaired episodic memory performance in young genetic risk carriers. P1-377
INTERACTIVE EFFECTS OF A SEDENTARY LIFESTYLE AND THE APOE E4 ALLELE ON AMYLOID DEPOSITION
Denise Head, Julie Bugg, Alison Goate, Anne Fagan, Mark Mintun, Tammie Benzinger, David Holtzman, John Morris, Washington University, St. Louis, Missouri, United States. Background: The presence of an APOE e4 allele is one of the most established genetic risk factors for Alzheimer’s disease (AD). Furthermore, APOE e4+ status has been associated with greater amyloid deposition even in cognitively normal adults. In contrast, physical exercise has been associated with less amyloid deposition. The primary objective of the current study was to examine whether exercise engagement influences the association between APOE genotype and amyloid deposition in cognitively normal adults. Methods: 201 adults (135 females, 66 males) aged 45-88 were recruited and confirmed to be cognitively normal based on the Clinical Dementia Rating scale. A self-report questionnaire on physical exercise engagement over the last decade was administered to all of the participants in conjunction with APOE genotyping. Cerebrospinal fluid (CSF) samples were collected from 165 participants, whereas amyloid imaging with PET-PIB was performed on 163 participants. Participants were categorized into low and high exercise engagement groups based on whether reported exercise levels were at or above the levels recommended by the American Heart Association. Results: APOE e4 carriers evidenced higher PIB binding with increased mean cortical binding potential (p < .001) and lower
S233
CSF Aß42 levels (p < .001). In addition, a more sedentary lifestyle was associated with higher PIB binding (p ¼ .005) and lower CSF Aß42 levels (p ¼ .009). Most importantly, we observed a novel interaction between APOE status and exercise engagement for PIB binding (p ¼ .008). Specifically, a more sedentary lifestyle was significantly associated with higher PIB binding for e4 carriers (p ¼ .013) but not for e4 non-carriers (p ¼ .208). These findings were robust to controlling for age, gender, education, hypertension, body mass index, diabetes, heart problems and history of depression. Conclusions: Collectively, these results are suggestive that sedentary APOE e4+ individuals may be at augmented risk for cortical amyloid deposition. P1-378
AGE, APOE E4, AND ETHNIC EFFECT ON [C-11] PIB IN MULTINATIONAL ADNI STUDIES: DIRECT COMPARISON OF J-ADNI, US-ADNI AND AIBL DATA
Kenji Ishii1, Muneyuki Sakata1, Keiichi Oda1, Jun Toyohara1, Kiichi Ishiwata1, Michio Senda2, Kengo Ito3, Ryozo Kuwano4, Takeshi Iwatsubo5 THE JAPANESE ALZHEIMER’S DISEASE NEUROIMAGING INITIATIVE6, THE ALZHEIMER’S DISEASE NEUROIMAGING INITIATIVE7, AIBL RESEARCH GROUP81Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan; 2Institute of Biomedical Research and Innovation, Kobe, Japan; 3 National Center for Geriatrics and Gerontology, Obu, Japan; 4Brain Research Institute, Niigata University, Niigata, Japan; 5Graduate School of Medicine, University of Tokyo, Tokyo, Japan; 6Tokyo, Japan; 7Los Angeles, California, United States; 8Melboume, Australia. Background: It has not been established whether the association between apolipoprotein E (APOE) e4 allele, age, and amyloid deposition is similar or different between ethnic groups. In this study, we evaluated the influence of APOE e4 and age on the cortical accumulation of 11C-Pittsburgh compound B (PiB) in three multi-center studies of Alzheimer’s disease (AD) with harmonized protocol; Alzheimer’s Disease Neuroimaging Initiative (US-ADNI, U), Australian Imaging Biomarker and Lifestyle Flagship Study of Aging (AIBL, A), and Japanese Alzheimer’s Disease Neuroimaging Initiative (J-ADNI, J). Methods: We analyzed the initial 11C-PiB scan data from US-ADNI: 19 cognitively normal (NL), 64 mild cognitive impairment (MCI) subjects, and 19 AD patients, AIBL: 119 NL, 41 MCI, 27 AD, and J-ADNI: 46 NL, 32 MCI, and 21 AD. All the 11C-PiB PET images were acquired 50-70 min post-injection. The mean cortical standardized uptake value ratio (mcSUVR) in reference to cerebellar cortex was measured with the same platform of data analysis. The cut-off mcSUVR value for PiB-positivity was set at 1.5 for all the studies. Results: The PiB-positive rate (%) in each group with or without e4 allele (e4+/e4-)were; NL (80/ 57), MCI (83/52), AD (100/88) in US-ADNI; NL (56/23), MCI (88/31), AD (100/100) in AIBL; and NL (59/7), MCI (100/44), AD (100/80) in JADNI. General linear model and logistic regression model were constructed to predict the mcSUVR and PiB positivity based on age, gene dose of e4 allele (0, 1, 2), and study (U, A, or J) as explanatory variables. Significant positive contribution (p<0.001) was estimated in age and e4, but no significant effect of the study group was observed for either mcSUVR value or PiB positivity in the data set of NL category and overall subjects. A single dose of e4 has equivalent contribution to 11.8 years of age for PiB positivity in NL group (Table1). Conclusions: Our results suggest that the three multi-national ADNI data are feasible for combined analysis. Study effect or ethnic effect was estimated to be limited, however, age and e4 effect on amyloid deposition is similar in Japanese population to those in Caucasians, despite the lower e4 allele frequency in the Japanese population. PiB (+) rate in Normals by age and e4 allele J-ADNI + US-ADNI + AIBL (n ¼ 182) 60s e4 (-/-) e4 (+/-) e4 (+/+)
5% 37% 67%
70s 2/41 11/30 4/6
28% 65% 100%
80s 14/50 13/20 1/1
49% 91% –
11/23 10/11 –