The Association Between Plasma Ceramides and Sphingomyelins and Risk of Alzheimer’s Disease Differs by Sex and APOE in the Baltimore Longitudinal Study of Aging

Issue title: Mini-Forum on Sphingolipids in Alzheimer’s Disease and Related Disorders

Guest editors: Michelle Mielke and Pilar Martinez

Article type: Research Article

Authors: Mielke, Michelle M.^{a; b; *} | Haughey, Norman J.^{c; d} | Han, Dingfen^d | An, Yang^e | Bandaru, Veera Venkata Ratnam^c | Lyketsos, Constantine G.^d | Ferrucci, Luigi^e | Resnick, Susan M.^f

Affiliations: [a] Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA | [b] Department of Neurology, Mayo Clinic, Rochester, MN, USA | [c] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA | [d] Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA | [e] Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA | [f] Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA

Correspondence: [*] Correspondence to: Michelle M. Mielke, PhD, Department of Health Sciences Research, Division of Epidemiology, and Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Tel.: +1 507 293 1069; Fax: +1 507 284 1516; E-mail: [email protected].

Abstract: Background:Cellular and animal studies demonstrated relationships between sphingolipid metabolism and Alzheimer’s disease (AD) pathology. High blood ceramide levels have been shown to predict cognitive impairment and AD, but these studies had small sample sizes and did not assess differences in risk by sex or APOE genotype. Objective:To determine whether plasma ceramides and sphingomyelins were associated with risk of AD, and whether the association varied by sex and APOE genotype. Methods:Participants included 626 men and 366 women, aged 55 years and older, enrolled in the Baltimore Longitudinal Study of Aging. Plasma ceramides and sphingomyelins were determined using quantitative analyses performed on a high-performance liquid chromatography coupled electrospray ionization tandem mass spectrometer. Cox proportional hazards models, stratified by sex, were used to examine the relationship of plasma ceramides and sphingomyelins with risk of AD over a mean (SD) follow-up of 15.0 (7.0) years for men and 13.1 (5.9) years for women. Results:Among men, the highest tertile of most ceramides and sphingomyelins were associated with an increased risk of AD. Among women, there were no associations between any of the ceramides and risk of AD. In contrast, women in the highest tertile of most sphingomyelins had a reduced risk of AD, which was most pronounced among APOE ɛ4 carriers. Conclusion:These results provide further evidence for the role of sphingolipid metabolism in AD and highlight the importance of considering sex and APOE genotype in assessing this relationship.

Keywords: Alzheimer’s disease, ceramides, cohort study, Epidemiology, lipids, longitudinal, sex differences

DOI: 10.3233/JAD-160925

Journal: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 819-828, 2017