Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY The major features of Alzheimer’s Disease and Alzheimer’s Disease Related Dementias (AD/ADRD) include elevations in amyloid beta (Aβ) and tau that result in the formation of neuritic plaques, neurofibrillary tangles and cerebral atrophy. These processes begin decades before the onset of the cognitive deficits that characterize the early clinical manifestation of AD/ADRD. However, the pathophysiology of AD/ADRD remains incompletely understood and additional molecular processes may give rise to either Aβ and tau accumulation or to other neurotoxic processes that have yet to be identified. This proposal will investigate proteomic biomarkers for cognitive and brain changes in the Lothian Birth Cohort 1936 (LBC1936), one of the best- characterised longitudinal studies in the world. It will also combine data from other world-class prospective studies of cognitive and brain aging to create the largest study of protein biomarkers and longitudinal cognitive and brain changes, prior to clinical ADRD diagnosis, to date. This project aims to measure 7,000 (SomaScan7K) proteins and the already established AD/ADRD biomarkers NfL, p-tau181, p-tau217, GFAP and Aβ42/Aβ40 in the LBC1936, at ages 73 (N~800), 76 (N~650), 82 (N~400) and 85 (N~300) years. Growth curve and survival models will be used to test associations between biomarkers and pre-dementia cognitive decline/brain changes AND hazard of clinically-ascertained dementia. Downstream analyses will be performed to identify biological pathways associated with cognitive and brain changes in older age. DNA methylation proxies of proteins (epigenetic scores-EpiScores), which may have more stable longitudinal profiles than the proteins themselves, will be generated and tested as predictors of cognitive and brain structural changes and dementia onset. LBC1936 data will be combined with other world-class prospective studies of cognitive and brain aging (sample N>20,000), and dementia to create the largest study of protein biomarkers and longitudinal cognitive and brain changes to date. This will allow us to expand our analysis by using the power of the large sample sizes available through a consortium to generate more precise estimates in a more limited range of phenotypes that can be used for generating more predictive scores in other cohorts. Blood-based biomarkers will be validated in brain tissue. Downstream analyses will investigate biological pathways associated with cognitive and brain changes. Polygenic indices for identified proteins will be created to see if they predict AD/ADRD in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohorts. Mendelian randomization methods will be used to investigate if levels of proteins identified in the proteomics association studies cause cognitive decline/brain changes/MCI/AD OR if cognitive decline/brain changes/MCI/AD cause protein level changes.
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