title: What success can teach us about failure: the plasma metabolome of older adults with superior memory and lessons for Alzheimer's disease.
abstract: As the world population ages, primary prevention of age-related cognitive decline and disability will become increasingly important. Prevention strategies are often developed from an understanding of disease pathobiology, but models of biological success may provide additional useful insights. Here, we studied 224 older adults, some with superior memory performance (n = 41), some with normal memory performance (n = 109), and some with mild cognitive impairment or Alzheimer's disease (AD; n = 74) to understand metabolomic differences which might inform future interventions to promote cognitive health. Plasma metabolomics revealed significant differential abundance of 12 metabolites in those with superior memory relative to controls (receiver operating characteristic area under the curve [AUC] = 0.89) and the inverse abundance pattern in the mild cognitive impairment, AD (AUC = 1.0) and even preclinical AD groups relative to controls (AUC = 0.97). The 12 metabolites are components of key metabolic pathways regulating oxidative stress, inflammation, and nitric oxide bioavailability. These findings from opposite ends of the cognitive continuum highlight the role of these pathways in superior memory abilities and whose failure may contribute to age-related memory impairment. These pathways may be targeted to promote successful cognitive aging.
authors.affiliation: Department of Neurology, University of California, Irvine, Irvine, CA, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Mapstone
authors.affiliation: School of Nursing and Department of Psychiatry, University of Rochester, Rochester, NY, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Lin
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Mike A
authors.initials: MA
authors.lastname: Nalls
authors.affiliation: Department of Biochemistry, Georgetown University, Washington, DC, USA; Department of Oncology, Georgetown University, Washington, DC, USA.
authors.forename: Amrita K
authors.initials: AK
authors.lastname: Cheema
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Singleton
authors.affiliation: Department of Neurology, University of California, Irvine, Irvine, CA, USA; Department of Neurological Surgery, University of California, Irvine, Irvine, CA, USA.
authors.forename: Massimo S
authors.initials: MS
authors.lastname: Fiandaca
authors.affiliation: Department of Neurology, University of California, Irvine, Irvine, CA, USA. Electronic address: Federoff@uci.edu.
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Federoff
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis* / Q000209:etiology; D001120:Arginine / Q000097:blood / Q000378:metabolism; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D060825:Cognitive Dysfunction / Q000175:diagnosis* / Q000209:etiology; D005260:Female; D006801:Humans; D007249:Inflammation; D008297:Male; D008568:Memory / Q000502:physiology*; D055442:Metabolome; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D015415:Biomarkers; D009569:Nitric Oxide; D001120:Arginine
keywords: Alzheimer's disease; Arginine metabolism; Memory; Metabolomics; Nitric oxide; Oxidative stress