There are many active research projects accessing and applying shared ADNI data. Use the search above to find specific research focuses on the active ADNI investigations. This information is requested annually as a requirement for data access.
| Principal Investigator | |
| Principal Investigator's Name: | Joy Stradford |
| Institution: | University of Southern California |
| Department: | Neuroimaging and Informatics |
| Country: | |
| Proposed Analysis: | Gender Imaging Genetics Project: This project will examine the effects of gender and APOE4 on brain, cognition, and clinical progression towards Alzheimer’s dementia using a large-scale, existing data approach. Women are more than twice as likely than men to develop Alzheimer’s disease (AD)15. Indeed, 2/3 of AD cases in the US are women20 despite an equal incidence of apolipoprotein-ε4 genotype (APOE4), the major genetic AD risk factor, across genders. Epidemiological studies show that single vs. double APOE4 dose confers AD risk differently in men and women21, suggesting a synergistic effect of gender and APOE4 on clinical progression to Alzheimer’s dementia22. One contributing factor may involve APOE4 and brain structure, as APOE4 carriers have greater shape deformations and volumetric loss in the hippocampus compared to non-carriers23-26. However, the interactions between gender and APOE4 (single and double APOE4 dose) on brain morphometry, cognitive decline, and clinical conversion to AD have not been investigated. We will leverage existing longitudinal cohorts from the National Alzheimer’s Coordinating Centers (NACC)33-35, Alzheimer’s Disease Neuroimaging Initiative (ADNI)36,37, Australian Imaging Biomarkers and Lifestyle (AIBL)40-44, Parkinson’s Progressive Markers Initiative (PPMI)45, and Banner Alzheimer Institute/Mayo Clinic APOE4/4 study (BAI/Mayo)46-48 to increase statistical power and sensitivity to discover meaningful gender and APOE4 interactions. Using state-of-the-art neuroimaging analyses and robust, longitudinal statistical models of cognition and clinical conversion, we will evaluate hippocampal shapes, our primary region of interest, along with other AD-specific regions, in relation to cognitive function and clinical progression in our cohorts of cognitively normal (CN), mild cognitive impairment (MCI), and Alzheimer’s disease (AD). This project will aggregate and harmonize imaging, cognitive, and clinical data from ~2800 participants (1061 APOE4-single allele, 288 APOE4-double allele, and 1489 non-carriers) with longitudinal follow-up visits (mean: 4.2 timepoints) to evaluate gender X APOE4 (single, double dose) interactions on changes in brain morphometry, cognitive function, and clinical diagnosis (see Table 1 for aggregated variables across cohorts). For assessment of cognition, we will harmonize the cognitive variables across cohorts to examine tests of global cognition, episodic memory and executive function. We will also leverage our independent cohorts to perform 4-fold cross-validation of selected cognitive tests. Critically, we already conducted manual quality control of 3300 structural T1 MRIs and segmented hippocampi across cohorts, resulting in a clean, preliminary dataset of participants for proof of concept (See Pilot data). All participant datasets include: 1) structural T1 MRIs for gray matter shape, volume, 2) APOE4 genotype, 3) cognitive assessments, and 4) demographics and clinical status. A subset of participants will have CSF Aβ42, tau levels (n=759) or amyloid PET (n=1099), which will be included in a sub-analysis of preclinical AD28,49. We will pursue a gender X APOE4 dose-dependent interaction in the following 3 aims: Aim 1: Analyze brain deformation and cognitive decline Hypothesis 1a: Hippocampal shape changes will be different between men and women based on APOE4 dose, such that APOE4 homozygote women will have the most deformation and cognitive loss over time. Hippocampal shape will be more sensitive to differences than hippocampal volume. Hypothesis 1b: Women who have the APOE4 allele and abnormal CSF Aβ, tau or amyloid PET will have the most shape deformation and cognitive decline over time. Aim 2: Examine the predictive utility of brain morphometry on future cognitive decline. Hypothesis 2a: Hippocampal shape morphometry will predict different rates of cognitive decline between men and women, with accelerated cognitive decline in APOE4 homozygote women. Hypothesis 2b: Women who have the APOE4 allele, brain deformation, and abnormal CSF Aβ, tau or amyloid PET will have the most cognitive decline in memory, executive function, and global cognition over time. Aim 3: Assess clinical progression in the AD continuum Hypothesis 3a: Clinical progression, defined as conversion from CNÆMCI and MCIÆAD, will be greater for women than men and accelerated in APOE4 homozygote women with hippocampal deformation. Hypothesis 3b: Women who have the APOE4 allele, brain deformation, and abnormal CSF Aβ, tau or amyloid PET will have accelerated clinical progression to MCI and clinical AD over time. Overall Impact: This project will provide new, critical information on how gender, a commonly overlooked and underpowered variable in Alzheimer’s disease research, interacts with APOE4 to confer brain deformation, cognitive decline, and clinical progression. Findings from this study will inform clinical trials on how individuals with specific genetic profiles (gender, APOE4) have meaningful decline in imaging and cognitive biomarkers that predict clinical progression to MCI and AD. Furthermore, results from this study will aid in refining therapeutic targets for individuals with specific phenotypes of Alzheimer’s disease risk. |
| Additional Investigators | |
| Investigator's Name: | Chris Patterson |
| Proposed Analysis: | This project will examine the effects of gender and APOE4 on brain, cognition, and clinical progression towards Alzheimer’s dementia using a large-scale, existing data approach. Women are more than twice as likely than men to develop Alzheimer’s disease (AD)15. Indeed, 2/3 of AD cases in the US are women20 despite an equal incidence of apolipoprotein-ε4 genotype (APOE4), the major genetic AD risk factor, across genders. Epidemiological studies show that single vs. double APOE4 dose confers AD risk differently in men and women21, suggesting a synergistic effect of gender and APOE4 on clinical progression to Alzheimer’s dementia22. One contributing factor may involve APOE4 and brain structure, as APOE4 carriers have greater shape deformations and volumetric loss in the hippocampus compared to non-carriers23-26. However, the interactions between gender and APOE4 (single and double APOE4 dose) on brain morphometry, cognitive decline, and clinical conversion to AD have not been investigated. We will leverage existing longitudinal cohorts from the National Alzheimer’s Coordinating Centers (NACC)33-35, Alzheimer’s Disease Neuroimaging Initiative (ADNI)36,37, Australian Imaging Biomarkers and Lifestyle (AIBL)40-44, Parkinson’s Progressive Markers Initiative (PPMI)45, and Banner Alzheimer Institute/Mayo Clinic APOE4/4 study (BAI/Mayo)46-48 to increase statistical power and sensitivity to discover meaningful gender and APOE4 interactions. Using state-of-the-art neuroimaging analyses and robust, longitudinal statistical models of cognition and clinical conversion, we will evaluate hippocampal shapes, our primary region of interest, along with other AD-specific regions, in relation to cognitive function and clinical progression in our cohorts of cognitively normal (CN), mild cognitive impairment (MCI), and Alzheimer’s disease (AD). This project will aggregate and harmonize imaging, cognitive, and clinical data from ~2800 participants (1061 APOE4-single allele, 288 APOE4-double allele, and 1489 non-carriers) with longitudinal follow-up visits (mean: 4.2 timepoints) to evaluate gender X APOE4 (single, double dose) interactions on changes in brain morphometry, cognitive function, and clinical diagnosis (see Table 1 for aggregated variables across cohorts). For assessment of cognition, we will harmonize the cognitive variables across cohorts to examine tests of global cognition, episodic memory and executive function. We will also leverage our independent cohorts to perform 4-fold cross-validation of selected cognitive tests. Critically, we already conducted manual quality control of 3300 structural T1 MRIs and segmented hippocampi across cohorts, resulting in a clean, preliminary dataset of participants for proof of concept (See Pilot data). All participant datasets include: 1) structural T1 MRIs for gray matter shape, volume, 2) APOE4 genotype, 3) cognitive assessments, and 4) demographics and clinical status. A subset of participants will have CSF Aβ42, tau levels (n=759) or amyloid PET (n=1099), which will be included in a sub-analysis of preclinical AD28,49. We will pursue a gender X APOE4 dose-dependent interaction in the following 3 aims: Aim 1: Analyze brain deformation and cognitive decline Hypothesis 1a: Hippocampal shape changes will be different between men and women based on APOE4 dose, such that APOE4 homozygote women will have the most deformation and cognitive loss over time. Hippocampal shape will be more sensitive to differences than hippocampal volume. Hypothesis 1b: Women who have the APOE4 allele and abnormal CSF Aβ, tau or amyloid PET will have the most shape deformation and cognitive decline over time. Aim 2: Examine the predictive utility of brain morphometry on future cognitive decline. Hypothesis 2a: Hippocampal shape morphometry will predict different rates of cognitive decline between men and women, with accelerated cognitive decline in APOE4 homozygote women. Hypothesis 2b: Women who have the APOE4 allele, brain deformation, and abnormal CSF Aβ, tau or amyloid PET will have the most cognitive decline in memory, executive function, and global cognition over time. Aim 3: Assess clinical progression in the AD continuum Hypothesis 3a: Clinical progression, defined as conversion from CNÆMCI and MCIÆAD, will be greater for women than men and accelerated in APOE4 homozygote women with hippocampal deformation. Hypothesis 3b: Women who have the APOE4 allele, brain deformation, and abnormal CSF Aβ, tau or amyloid PET will have accelerated clinical progression to MCI and clinical AD over time. Overall Impact: This project will provide new, critical information on how gender, a commonly overlooked and underpowered variable in Alzheimer’s disease research, interacts with APOE4 to confer brain deformation, cognitive decline, and clinical progression. Findings from this study will inform clinical trials on how individuals with specific genetic profiles (gender, APOE4) have meaningful decline in imaging and cognitive biomarkers that predict clinical progression to MCI and AD. Furthermore, results from this study will aid in refining therapeutic targets for individuals with specific phenotypes of Alzheimer’s disease risk. |
| Investigator's Name: | Vahan Aslanyan |
| Proposed Analysis: | This project will examine the effects of gender and APOE4 on brain, cognition, and clinical progression towards Alzheimer’s dementia using a large-scale, existing data approach. Women are more than twice as likely than men to develop Alzheimer’s disease (AD)15. Indeed, 2/3 of AD cases in the US are women20 despite an equal incidence of apolipoprotein-ε4 genotype (APOE4), the major genetic AD risk factor, across genders. Epidemiological studies show that single vs. double APOE4 dose confers AD risk differently in men and women21, suggesting a synergistic effect of gender and APOE4 on clinical progression to Alzheimer’s dementia22. One contributing factor may involve APOE4 and brain structure, as APOE4 carriers have greater shape deformations and volumetric loss in the hippocampus compared to non-carriers23-26. However, the interactions between gender and APOE4 (single and double APOE4 dose) on brain morphometry, cognitive decline, and clinical conversion to AD have not been investigated. We will leverage existing longitudinal cohorts from the National Alzheimer’s Coordinating Centers (NACC)33-35, Alzheimer’s Disease Neuroimaging Initiative (ADNI)36,37, Australian Imaging Biomarkers and Lifestyle (AIBL)40-44, Parkinson’s Progressive Markers Initiative (PPMI)45, and Banner Alzheimer Institute/Mayo Clinic APOE4/4 study (BAI/Mayo)46-48 to increase statistical power and sensitivity to discover meaningful gender and APOE4 interactions. Using state-of-the-art neuroimaging analyses and robust, longitudinal statistical models of cognition and clinical conversion, we will evaluate hippocampal shapes, our primary region of interest, along with other AD-specific regions, in relation to cognitive function and clinical progression in our cohorts of cognitively normal (CN), mild cognitive impairment (MCI), and Alzheimer’s disease (AD). This project will aggregate and harmonize imaging, cognitive, and clinical data from ~2800 participants (1061 APOE4-single allele, 288 APOE4-double allele, and 1489 non-carriers) with longitudinal follow-up visits (mean: 4.2 timepoints) to evaluate gender X APOE4 (single, double dose) interactions on changes in brain morphometry, cognitive function, and clinical diagnosis (see Table 1 for aggregated variables across cohorts). For assessment of cognition, we will harmonize the cognitive variables across cohorts to examine tests of global cognition, episodic memory and executive function. We will also leverage our independent cohorts to perform 4-fold cross-validation of selected cognitive tests. Critically, we already conducted manual quality control of 3300 structural T1 MRIs and segmented hippocampi across cohorts, resulting in a clean, preliminary dataset of participants for proof of concept (See Pilot data). All participant datasets include: 1) structural T1 MRIs for gray matter shape, volume, 2) APOE4 genotype, 3) cognitive assessments, and 4) demographics and clinical status. A subset of participants will have CSF Aβ42, tau levels (n=759) or amyloid PET (n=1099), which will be included in a sub-analysis of preclinical AD28,49. We will pursue a gender X APOE4 dose-dependent interaction in the following 3 aims: Aim 1: Analyze brain deformation and cognitive decline Hypothesis 1a: Hippocampal shape changes will be different between men and women based on APOE4 dose, such that APOE4 homozygote women will have the most deformation and cognitive loss over time. Hippocampal shape will be more sensitive to differences than hippocampal volume. Hypothesis 1b: Women who have the APOE4 allele and abnormal CSF Aβ, tau or amyloid PET will have the most shape deformation and cognitive decline over time. Aim 2: Examine the predictive utility of brain morphometry on future cognitive decline. Hypothesis 2a: Hippocampal shape morphometry will predict different rates of cognitive decline between men and women, with accelerated cognitive decline in APOE4 homozygote women. Hypothesis 2b: Women who have the APOE4 allele, brain deformation, and abnormal CSF Aβ, tau or amyloid PET will have the most cognitive decline in memory, executive function, and global cognition over time. Aim 3: Assess clinical progression in the AD continuum Hypothesis 3a: Clinical progression, defined as conversion from CNÆMCI and MCIÆAD, will be greater for women than men and accelerated in APOE4 homozygote women with hippocampal deformation. Hypothesis 3b: Women who have the APOE4 allele, brain deformation, and abnormal CSF Aβ, tau or amyloid PET will have accelerated clinical progression to MCI and clinical AD over time. Overall Impact: This project will provide new, critical information on how gender, a commonly overlooked and underpowered variable in Alzheimer’s disease research, interacts with APOE4 to confer brain deformation, cognitive decline, and clinical progression. Findings from this study will inform clinical trials on how individuals with specific genetic profiles (gender, APOE4) have meaningful decline in imaging and cognitive biomarkers that predict clinical progression to MCI and AD. Furthermore, results from this study will aid in refining therapeutic targets for individuals with specific phenotypes of Alzheimer’s disease risk. |
