Metabolomic signatures of dual decline in memory and gait: An aging phenotype of high risk of dementia

Abstract

AbstractBackgroundOur recent meta‐analysis of 6 geographically and culturally diverse aging studies has shown that older adults with dual gait and memory decline had a synergistically greater hazard of dementia than those with memory decline or gait decline only. Mechanisms underlying this increased risk are unknown. We hypothesize that those with dual decline have specific pathophysiological pathways to dementia.MethodIn the Baltimore Longitudinal Study of Aging, we compared rates of change in 455 plasma metabolites from 26 biochemical classes among dementia‐free participants aged 50 and older who experienced dual decline (n=114), gait decline only (n=167), memory decline only (n=168), and no decline (n=406) using linear mixed‐effects models. Longitudinal data on gait, memory, and Biocrates p500 metabolomics were collected simultaneously over an average of 6.6 years. Analyses were adjusted for batch, demographics, baseline memory and gait, education, and APOE e4 carrier status. We further performed enrichment analysis.ResultAfter covariate adjustment, rates of change in 18 metabolites significantly differed among four groups (q<0.05). Top 10 ranked metabolites were from classes nucleobases (hypoxanthine), lysophosphatidylcholines (LPC C18:0, C16:0, C17:0, C18:1, C18:2), and ceramides (d16:1/24:0, d18:2/24:0, d16:1/23:0, d18:1/24:0) (Figure 1). LPCs, ceramides, and amino acids were significantly enriched (p<0.05). Compared to no decline group, memory decline only group had greater changes in 21 metabolites enriched for PCs, LPCs, and amino acids. Gait decline only group had greater changes in 106 metabolites enriched for triglycerides, ceramides, and cholesteryl esters. Dual decline group had greater changes in 121 metabolites enriched for LPCs, amino acids, and triglycerides (p<0.05). After multiple comparisons adjustment, LPC C18:0 showed greater decrease in dual decline group, and PC C32:2 showed greater increase in gait decline only group (q<0.05).ConclusionMetabolite changes over time may underlie age‐related decline in memory, gait speed, or both, especially in LPCs, ceramides, and amino acids. Older adults experiencing dual decline have the most extensive alterations in metabolic profiling, especially in LPCs, triglycerides, and amino acids. Notably, these metabolites are main building blocks for cardiolipin, an essential lipid for regulation and assemblage of electron transport complexes and mitochondrial morpho‐functional architecture. Pathway analyses and further validation are warranted.