PROJECT 2: METABOLIC FACTORS AND ALZHEIMER DISEASE Type 2 diabetes mellitus (T2DM) increases Alzheimer's disease (AD) risk by ~1.5 times, but the mechanisms are unclear. We focus on two metabolic risk-related mechanisms that may link early T2DM to AD: insulin & insulin-like growth factor 1 (IGF1) and cholesterol transport. In non-demented adults, we relate these metabolic factors to 1) cerebrospinal fluid (CSF) markers of AD pathology, 2) structural and functional brain connectivity and hippocampal subregion thickness in regions selectively vulnerable to AD, and 3) changes over 2 years in brain connectivity and memory. Our multimodal longitudinal project includes multi-shell diffusion tensor imaging analyzed with a novel fiber orientation distribution tool. These innovations improve our ability to measure brain connectivity even in the presence of crossed fibers and white matter lesions. We also will use resting state functional magnetic resonance imaging (rs-fMRI) to assess functional connectivity, and will evaluate entorhinal cortex and hippocampal CA1 thickness. We will examine 180 adults with no or mild cognitive impairment; aged 70-90 yrs. We will recruit subjects with low vascular risk, with hypertension, and those with elevated glycated hemoglobin and low HDL-C. Using continuous measures of insulin, IGF1, IGF binding proteins, and cholesterol efflux capacity derived from blood and CSF, we will evaluate: 1) How IGF1 and IGFBPs relate to neurodegeneration, mediated by CSF ptau181 levels and measured as atrophy in the entorhinal cortex and CA1 of the hippocampus and loss of functional and structural connectivity in AD-relevant regions; 2) How insulin and cholesterol efflux capacity relate to demyelination and functional connectivity deficits in AD-relevant regions, mediated by A?42 levels; and 3) How insulin signaling peptides and cholesterol efflux capacity are related to 2-year changes in cognition, and brain structure and function. We anticipate improved understanding of how T2DM and metabolic risk contribute to preclinical AD brain changes. This is crucial to enabling tailored treatment and prevention efforts to persons at specific risk.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
5P50AG005142-35
Application #
9692623
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
2021-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
35
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Southern California
Department
Type
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Brenowitz, Willa D; Han, Fang; Kukull, Walter A et al. (2018) Treated hypothyroidism is associated with cerebrovascular disease but not Alzheimer's disease pathology in older adults. Neurobiol Aging 62:64-71
Petok, Jessica R; Myers, Catherine E; Pa, Judy et al. (2018) Impairment of memory generalization in preclinical autosomal dominant Alzheimer's disease mutation carriers. Neurobiol Aging 65:149-157
Cruchaga, Carlos; Del-Aguila, Jorge L; Saef, Benjamin et al. (2018) Polygenic risk score of sporadic late-onset Alzheimer's disease reveals a shared architecture with the familial and early-onset forms. Alzheimers Dement 14:205-214
Davis, Jeremy J (2018) Performance validity in older adults: Observed versus predicted false positive rates in relation to number of tests administered. J Clin Exp Neuropsychol 40:1013-1021
Gallagher, Damien; Kiss, Alex; Lanctot, Krista L et al. (2018) Toward Prevention of Mild Cognitive Impairment in Older Adults With Depression: An Observational Study of Potentially Modifiable Risk Factors. J Clin Psychiatry 80:
Lin, Ming; Gong, Pinghua; Yang, Tao et al. (2018) Big Data Analytical Approaches to the NACC Dataset: Aiding Preclinical Trial Enrichment. Alzheimer Dis Assoc Disord 32:18-27
Weissberger, Gali H; Nation, Daniel A; Nguyen, Caroline P et al. (2018) Meta-analysis of cognitive ability differences by apolipoprotein e genotype in young humans. Neurosci Biobehav Rev 94:49-58
Kirson, Noam Y; Scott Andrews, J; Desai, Urvi et al. (2018) Patient Characteristics and Outcomes Associated with Receiving an Earlier Versus Later Diagnosis of Probable Alzheimer's Disease. J Alzheimers Dis 61:295-307
Barnes, Josephine; Bartlett, Jonathan W; Wolk, David A et al. (2018) Disease Course Varies According to Age and Symptom Length in Alzheimer's Disease. J Alzheimers Dis 64:631-642
Wang, Junyan; Aydogan, Dogu Baran; Varma, Rohit et al. (2018) Modeling topographic regularity in structural brain connectivity with application to tractogram filtering. Neuroimage 183:87-98

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