The overall goal of this project is to deepen our understanding of aging processes and the aging brain in a community-based population. Our projects are thematically linked to an overarching hypothesis based on previous results from our own studies and the literature: that microinfarcts are key pathophysiological processes in late life brain dysfunction.
Aims 1 &2 will test hypotheses regarding 4 late-life brain outcomes: 1) Development of dementia and AD;2) Trajectories of global cognitive decline incorporating sophisticated modern psychometric analyses;3) Standard microscopic neuropathological measures;and 4) Novel biochemical neuropathological markers, including soluble A(S oligomers, markers of regional oxidative damage, and inflammatory markers.
Aim 1. Exploit unique clinical records to test hypotheses about the association between mid- and late-life micro- and macro-vascular conditions and late-life brain outcomes.
Aim 1 will take advantage of the >117,000 person-years of medical record data available from the cohort.
Aim la. Test hypotheses related to type 2 diabetes (DM). We will identify the independent and joint contributions of mid-life and late-life insulin resistance and hyperglycemia on late-life brain outcomes to determine whether these outcomes are best explained by insulin resistance, hyperglycemia, or both.
Aim lb. Test hypotheses related to renal disease. We will determine whether mid-life and late-life renal function is associated with greater risk for late-life brain outcomes.
Aim 1 c. Test hypotheses related to atrial fibrillation (AF). We will determine whether AF is associated with higher risk for late-life brain outcomes, whether increased persistence and duration of AF convey additional increased risk, and the extent to which anticoagulation ameliorates risks associated with AF.
Aim 2. Exploit unique ACT study research data to test hypotheses about the association between late-life measures of physical performance, frailty, and late-life brain outcomes. We will follow-up our preliminary finding that timed walk during life is associated with the presence of microinfarcts among autopsied participants to more fully test the hypotheses that decrements in timed walk and the development of frailty precede late-life brain outcomes.
Aim 3. Continue to serve as a valuable scientific resource and improve infrastructure to facilitate external use of ACT data.
|Hohman, Timothy J; Bush, William S; Jiang, Lan et al. (2016) Discovery of gene-gene interactions across multiple independent data sets of late onset Alzheimer disease from the Alzheimer Disease Genetics Consortium. Neurobiol Aging 38:141-50|
|Cholerton, Brenna; Larson, Eric B; Quinn, Joseph F et al. (2016) Precision Medicine: Clarity for the Complexity of Dementia. Am J Pathol 186:500-6|
|Jackson, Michael L; Walker, Rod; Lee, Sei et al. (2016) Predicting 2-Year Risk of Developing Pneumonia in Older Adults without Dementia. J Am Geriatr Soc 64:1439-47|
|Crane, Paul K; Gibbons, Laura E; Dams-O'Connor, Kristen et al. (2016) Association of Traumatic Brain Injury With Late-Life Neurodegenerative Conditions and Neuropathologic Findings. JAMA Neurol 73:1062-9|
|Mez, Jesse; Mukherjee, Shubhabrata; Thornton, Timothy et al. (2016) The executive prominent/memory prominent spectrum in Alzheimer's disease is highly heritable. Neurobiol Aging 41:115-21|
|Flanagan, Margaret; Larson, Eric B; Latimer, Caitlin S et al. (2016) Clinical-pathologic correlations in vascular cognitive impairment and dementia. Biochim Biophys Acta 1862:945-51|
|Crane, Paul K; Walker, Rod L; Sonnen, Joshua et al. (2016) Glucose levels during life and neuropathologic findings at autopsy among people never treated for diabetes. Neurobiol Aging 48:72-82|
|Ridge, Perry G; Hoyt, Kaitlyn B; Boehme, Kevin et al. (2016) Assessment of the genetic variance of late-onset Alzheimer's disease. Neurobiol Aging 41:200.e13-20|
|Toledo, Jon B; Gopal, Pallavi; Raible, Kevin et al. (2016) Pathological Î±-synuclein distribution in subjects with coincident Alzheimer's and Lewy body pathology. Acta Neuropathol 131:393-409|
|Van Driest, Sara L; Wells, Quinn S; Stallings, Sarah et al. (2016) Association of Arrhythmia-Related Genetic Variants With Phenotypes Documented in Electronic Medical Records. JAMA 315:47-57|
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