A Metabolomics Analysis of a Novel Phenotype of Older Adults at Higher Risk of Dementia

Issue title: Omics Approaches in Alzheimer’s Disease Research

Guest editors: Sudeshna Das

Article type: Research Article

Authors: Sultana, Munira^{a; *} | Camicioli, Richard^b | Dixon, Roger A.^c | Whitehead, Shawn^d | Pieruccini-Faria, Frederico^e | Petrotchenko, Evgeniy^f | Speechley, Mark^g | Borchers, Christoph H.^f | Montero-Odasso, Manuel^{g; h}

Affiliations: [a] Western University, London, ON, Canada | [b] Department of Medicine, University of Alberta, Edmonton, AB, Canada | [c] Psychology Science, University of Alberta, Edmonton, AB, Canada | [d] Department of Anatomy and Cell Biology, Western University, London, ON, Canada | [e] Gait and Brain Lab, London, ON, Canada | [f] Segal Cancer Proteomics Centre, Montreal, QC, Canada | [g] Department of Epidemiology and Biostatistics, Western University, London, ON, Canada | [h] Department of Medicine, Western University, London, ON, Canada

Correspondence: [*] Correspondence to: Munira Sultana, MBBS, MPH, PhD, Western University, 1151 Richmond Street, London, Ontario N6A 3K7, Canada. Tel.: +1 226 224 7704; E-mail: msulta@uwo.ca.

Abstract: Background:Older adults presenting with dual-decline in cognition and walking speed face a 6-fold higher risk for dementia compared with those showing no decline. We hypothesized that the metabolomics profile of dual-decliners would be unique even before they show signs of decline in cognition and gait speed. Objective:The objective of this study was to determine if plasma metabolomics signatures can discriminate dual-decliners from no decliners, purely cognitive decliners, and purely motor decliners prior to decline. Methods:A retrospective cross-sectional study using baseline plasma for untargeted metabolomics analyses to investigate early signals of later dual-decline status in study participants (n = 76) with convenient sampling. Dual-decline was operationalized as decline in gait speed (>10 cm/s) and cognition (>2 points decline in Montreal Cognitive Assessment score) on at least two consecutive 6-monthly assessments. The participants’ decliner status was evaluated 3 years after the blood sample was collected. Pair-wise comparison of detected compounds was completed using principal components and hierarchical clustering analyses. Results:Analyses did not detect any cluster separation in untargeted metabolomes across baseline groups. However, follow-up analyses of specific molecules detected 4 compounds (17-Hydroxy-12-(hydroxymethyl)-10-oxo-8 oxapentacyclomethyl hexopyranoside, Fleroxacin, Oleic acid, and 5xi-11,12-Dihydroxyabieta-8(14),9(11),12-trien-20-oic acid) were at significantly higher concentration among the dual-decliners compared to non-decliners. The pure cognitive decliner group had significantly lower concentration of six compounds (1,3-nonanediol acetate, 4-(2-carboxyethyl)-2-methoxyphenyl beta-D-glucopyranosiduronic acid, oleic acid, 2E-3-[4-(sulfo-oxy)phenyl] acrylic acid, palmitelaidic acid, and myristoleic acid) compared to the non-decliner group. Conclusions:The unique metabolomics profile of dual-decliners warrants follow-up metabolomics analysis. Results may point to modifiable pathways.

Keywords: Aging, Alzheimer’s disease, cognition, diagnosis, gait, metabolomics

DOI: 10.3233/JAD-230683

Journal: Journal of Alzheimer's Disease, vol. 99, no. s2, pp. S317-S325, 2024