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: | Meg Mihalache |
| Institution: | Georgetown University |
| Department: | Cancer Prevention and Control |
| Country: | |
| Proposed Analysis: | As the population ages, it is important to understand heterogeneity in cognitive aging. One of the most common cognitive aging pathologies is late-onset Alzheimer’s disease (AD), with a large body of evidence about its risk factors and clinical-pathologic features. There is also growing recognition that cancer and its treatments can affect cognitive aging (cancer-related cognitive decline, or CRCD). CRCD typically involves more subtle declines than seen in AD, but some older breast cancer survivors have substantial decline over time. While the etiology of CRCD is unknown, some data indicates similar cognitive aging features as AD, including reduced hippocampal and prefrontal brain volume, increases in inflammatory markers, and shared risk factors, such as the APOE genotype. We were the first group to report steeper cognitive decline in ε4+ vs. ε4- older breast cancer survivors after chemotherapy. These observations may indicate that some survivors with cognitive decline were already on the path to developing AD, despite exclusions for cognitive impairment. It is also possible that some or all CRCD involves non-AD processes. To address this question, we will test hypotheses to determine whether breast cancer survivors with CRCD show plasma AD-pathology biomarker abnormalities and cognitive, imaging, and risk profiles similar to those reported in AD. To accomplish this goal, we will use existing de-identified data and specimens from the Thinking and Living with Cancer (TLC) study, a multi-site prospective cohort originally designed to study CRCD, quality of life, and physical activity. TLC includes female breast cancer survivors ages 60-98 assessed pre-treatment and annually for up to 60 months until study end in 2020 and age-, race-, education-, and site-frequency matched non-cancer controls meeting the same eligibility criteria (n~700/group). Studying older breast cancer survivors is important since they are already facing cognitive aging, the survivors are in the age range where non-cancer populations with APOE-ɛ4 develop AD, AD rates are highest in women, and 35% of survivors already have significantly more global cognitive decline than seen in non-cancer controls (i.e., reliable change). Our primary measure of CRCD for this project will be based on reliable change in composite scores for global cognition, and memory, executive functioning, language, and visuospatial abilities. In secondary analyses, we will use age- and education-population norms and TLC non-cancer control scores to create z-scores to facilitate comparison with studies using this latter approach. TLC includes longitudinal data on genetic (APOE, COMT, BDNF) and non-genetic AD risk factors and pro- and anti-inflammation markers (IL-6, TNF-α, IL-8, IL-10, IFNg, CRP). New data to be added for this study are plasma AD-pathology markers (Aβ1-42, tau, p-tau, and neurofilament light chain [NFL]) and danger-associated molecular patterns (DAMPs: Aβ, S100 proteins, and HMBG1) using banked TLC post-treatment specimens. A sub-set of TLC survivors at Indiana University has baseline and 12-month MRI data using the NIA-funded Indiana Alzheimer’s Disease Center (IADC) protocol; we will complete 24-month imaging (n=75) in this project to assess post-acute effects. We will compare the pattern of TLC results to published AD data, particularly those for women. The aims are: 1. To test hypotheses about the relationship between clinical-pathological features of CRCD and AD. H1a: Survivors who have more (vs. less) longitudinal cognitive decline or incident impairment will show greater AD pathology abnormalities (lower Aβ1-42, higher tau, p-tau, and NFL) and more persistent changes in gray matter volume and episodic and working memory function on MRI (“brain alterations”). H1b: These associations will be strongest for survivors who had chemotherapy (+/- hormonal) vs. hormonal therapy only. 2. To test hypotheses about associations between CRCD and AD-risk factors (genotype, family history of dementia, sleep problems, obesity, activity level, menopause age and hormone use, and comorbidity). H2. Survivors who have a higher number of AD risk factors will have lower Aβ1-42, higher tau, p-tau, and NFL, more cognitive decline and higher rates of impairment, and greater brain alterations. 3. To test hypotheses about the association between AD-related inflammation markers and AD clinical-pathological features in CRCD and explore if inflammation mediates CRCD risk. H3a: Survivors with increased inflammation will have lower Aβ1-42, higher tau, p-tau, and NFL, more cognitive decline and impairment, and greater brain alterations; H3b: Inflammatory DAMPs will mediate the relationship between AD-risk factors and AD pathology biomarkers, cognitive decline, and brain alterations in survivors. This geroscience research is particularly relevant to NIA because: 1) we are looking at aging-related inflammatory mechanisms for two important cognitive aging processes: CRCD and AD, 2) cognitive aging is the most feared condition affecting the health and function of older individuals, and 3) we will advance AD and cognitive aging research goals by elucidating the impact of genetic and inflammatory processes on cognitive aging. This research is clinically significant because cognitive aging has clinically important effects on daily life. Our established collaboration of cancer, geriatrics, and Alzheimer’s researchers will facilitate innovations in cognitive aging research by determining potential bidirectional mechanisms between CRCD and AD. Insights about commonalities between CRCD and AD could move the AD field forward by suggesting novel early AD therapies based on those effective in CRCD; information about differences will suggest new pathways. Overall, this study will efficiently provide important new data about cognitive aging. |
| Additional Investigators | |
| Investigator's Name: | Jeanne Mandelblatt |
| Proposed Analysis: | As the population ages, it is important to understand heterogeneity in cognitive aging. One of the most common cognitive aging pathologies is late-onset Alzheimer’s disease (AD), with a large body of evidence about its risk factors and clinical-pathologic features. There is also growing recognition that cancer and its treatments can affect cognitive aging (cancer-related cognitive decline, or CRCD). CRCD typically involves more subtle declines than seen in AD, but some older breast cancer survivors have substantial decline over time. While the etiology of CRCD is unknown, some data indicates similar cognitive aging features as AD, including reduced hippocampal and prefrontal brain volume, increases in inflammatory markers, and shared risk factors, such as the APOE genotype. We were the first group to report steeper cognitive decline in ε4+ vs. ε4- older breast cancer survivors after chemotherapy. These observations may indicate that some survivors with cognitive decline were already on the path to developing AD, despite exclusions for cognitive impairment. It is also possible that some or all CRCD involves non-AD processes. To address this question, we will test hypotheses to determine whether breast cancer survivors with CRCD show plasma AD-pathology biomarker abnormalities and cognitive, imaging, and risk profiles similar to those reported in AD. To accomplish this goal, we will use existing de-identified data and specimens from the Thinking and Living with Cancer (TLC) study, a multi-site prospective cohort originally designed to study CRCD, quality of life, and physical activity. TLC includes female breast cancer survivors ages 60-98 assessed pre-treatment and annually for up to 60 months until study end in 2020 and age-, race-, education-, and site-frequency matched non-cancer controls meeting the same eligibility criteria (n~700/group). Studying older breast cancer survivors is important since they are already facing cognitive aging, the survivors are in the age range where non-cancer populations with APOE-ɛ4 develop AD, AD rates are highest in women, and 35% of survivors already have significantly more global cognitive decline than seen in non-cancer controls (i.e., reliable change). Our primary measure of CRCD for this project will be based on reliable change in composite scores for global cognition, and memory, executive functioning, language, and visuospatial abilities. In secondary analyses, we will use age- and education-population norms and TLC non-cancer control scores to create z-scores to facilitate comparison with studies using this latter approach. TLC includes longitudinal data on genetic (APOE, COMT, BDNF) and non-genetic AD risk factors and pro- and anti-inflammation markers (IL-6, TNF-α, IL-8, IL-10, IFNg, CRP). New data to be added for this study are plasma AD-pathology markers (Aβ1-42, tau, p-tau, and neurofilament light chain [NFL]) and danger-associated molecular patterns (DAMPs: Aβ, S100 proteins, and HMBG1) using banked TLC post-treatment specimens. A sub-set of TLC survivors at Indiana University has baseline and 12-month MRI data using the NIA-funded Indiana Alzheimer’s Disease Center (IADC) protocol; we will complete 24-month imaging (n=75) in this project to assess post-acute effects. We will compare the pattern of TLC results to published AD data, particularly those for women. The aims are: 1. To test hypotheses about the relationship between clinical-pathological features of CRCD and AD. H1a: Survivors who have more (vs. less) longitudinal cognitive decline or incident impairment will show greater AD pathology abnormalities (lower Aβ1-42, higher tau, p-tau, and NFL) and more persistent changes in gray matter volume and episodic and working memory function on MRI (“brain alterations”). H1b: These associations will be strongest for survivors who had chemotherapy (+/- hormonal) vs. hormonal therapy only. 2. To test hypotheses about associations between CRCD and AD-risk factors (genotype, family history of dementia, sleep problems, obesity, activity level, menopause age and hormone use, and comorbidity). H2. Survivors who have a higher number of AD risk factors will have lower Aβ1-42, higher tau, p-tau, and NFL, more cognitive decline and higher rates of impairment, and greater brain alterations. 3. To test hypotheses about the association between AD-related inflammation markers and AD clinical-pathological features in CRCD and explore if inflammation mediates CRCD risk. H3a: Survivors with increased inflammation will have lower Aβ1-42, higher tau, p-tau, and NFL, more cognitive decline and impairment, and greater brain alterations; H3b: Inflammatory DAMPs will mediate the relationship between AD-risk factors and AD pathology biomarkers, cognitive decline, and brain alterations in survivors. This geroscience research is particularly relevant to NIA because: 1) we are looking at aging-related inflammatory mechanisms for two important cognitive aging processes: CRCD and AD, 2) cognitive aging is the most feared condition affecting the health and function of older individuals, and 3) we will advance AD and cognitive aging research goals by elucidating the impact of genetic and inflammatory processes on cognitive aging. This research is clinically significant because cognitive aging has clinically important effects on daily life. Our established collaboration of cancer, geriatrics, and Alzheimer’s researchers will facilitate innovations in cognitive aging research by determining potential bidirectional mechanisms between CRCD and AD. Insights about commonalities between CRCD and AD could move the AD field forward by suggesting novel early AD therapies based on those effective in CRCD; information about differences will suggest new pathways. Overall, this study will efficiently provide important new data about cognitive aging. |
