Sets of Co-regulated Serum Lipids are Associated with Alzheimer Disease Pathophysiology

Barupal, D. K.; Bailli, R.; Fan, S.; Saykin, A. J.; Meikle, P. J.; Nho, K.; Arnold, M.; Fiehn, O.; Kaddurah-Daouk, R.; Alzheimer Disease Neuroimaging Initiative,; Alzheimer Disease Metabolomics Consortium,

doi:10.1101/550723

bioRxiv · 10.1101/550723

Sets of Co-regulated Serum Lipids are Associated with Alzheimer Disease Pathophysiology

Barupal, D. K.·Bailli, R.·Fan, S.·Saykin, A. J.·Meikle, P. J.·Nho, K.·Arnold, M.·Fiehn, O.·Kaddurah-Daouk, R.·Alzheimer Disease Neuroimaging Initiative,·Alzheimer Disease Metabolomics Consortium,

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Abstract

INTRODUCTIONAltered regulation of lipid metabolism in Alzheimer disease (AD) can be characterized using lipidomic profiling. METHOD349 serum lipids were measured in 806 participants enrolled in the Alzheimer Disease Neuroimaging Initiative Phase 1 (ADNI1) cohort and analysed using lipid regression models and lipid set enrichment statistics. RESULTSAD diagnosis was associated with 7 of 28 lipid sets of which four also correlated with cognitive decline, including polyunsaturated fatty acids. CSF amyloid beta A{beta}1-42 correlated with glucosylceramides, lysophosphatidyl cholines and unsaturated triacylglycerides; CSF total tau and brain atrophy correlated with monounsaturated sphingomyelins and ceramides, in addition to EPA-containing lipids. DISCUSSIONLipid desaturation, elongation and acyl chain remodeling are dysregulated across the spectrum of AD pathogenesis. Monounsaturated lipids were important in early stages of AD, while polyunsaturated lipid metabolism was associated with later stages of AD. SIGNFICANCEBoth metabolic genes and co-morbidity with metabolic diseases indicate that lipid metabolism is critical in the etiology of Alzheimers disease (AD). For 800 subjects, we found that sets of blood lipids were associated with current AD-biomarkers and with AD clinical symptoms. Our study highlights the role of disturbed acyl chain lipid remodelling in several lipid classes. Our work has significant implications on finding a cure for AD. Depending on subject age, human blood lipids may have different effects on AD development. Remodelling of acyl chains needs to be studied in relation to genetic variants and environmental factors. Specifically, the impact of dietary supplements and drugs on lipid remodelling must be investigated.

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Barupal, D. K., Bailli, R., Fan, S., Saykin, A. J., Meikle, P. J., Nho, K., Arnold, M., Fiehn, O., Kaddurah-Daouk, R., Alzheimer Disease Neuroimaging Initiative,, Alzheimer Disease Metabolomics Consortium,. 2019-02-18. Sets of Co-regulated Serum Lipids are Associated with Alzheimer Disease Pathophysiology. https://doi.org/10.1101/550723

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