Metabolites Associated with Memory and Gait: A Systematic Review

Abstract

We recently found that dual decline in memory and gait speed was consistently associated with an increased risk of dementia compared to decline in memory or gait only or no decline across six aging cohorts. The mechanisms underlying this relationship are unknown. We hypothesize that individuals who experience dual decline may have specific pathophysiological pathways to dementia which can be indicated by specific metabolomic signatures. Here, we summarize blood-based metabolites that are associated with memory and gait from existing literature and discuss their relevant pathways. A total of 39 eligible studies were included in this systematic review. Metabolites that were associated with memory and gait belonged to five shared classes: sphingolipids, fatty acids, phosphatidylcholines, amino acids, and biogenic amines. The sphingolipid metabolism pathway was found to be enriched in both memory and gait impairments. Existing data may suggest that metabolites from sphingolipids and the sphingolipid metabolism pathway are important for both memory and gait impairments. Future studies using empirical data across multiple cohorts are warranted to identify metabolomic signatures of dual decline in memory and gait and to further understand its relationship with future dementia risk.

APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge

“…In line with our ST findings, they highlight APOE - and amyloid-associated decreases in a number of PCs, a class of phospholipid linked to memory decline. 70 Although a handful of PCs were highest in the E4 5XFAD brain, the majority of PCs were present in lower concentrations relative to the other groups, consistent with findings from the postmortem human brain. 67 Regional segregation of lipid concentrations revealed that for most PCs, APOE -dependent changes in lipid concentrations were more striking in the isocortex, hippocampus, and fiber tracts relative to other brain regions.…”

Dual cognitive and mobility impairments and future dementia ‐ Setting a research agenda

“…18 A recent systematic review showed metabolites from sphingolipids and the sphingolipid metabolism pathway are important for both memory and gait impairments. 19 In agreement with the metabolic origin of dual decline, MCR is found to be associated with obesity-related polygenetic risk scores for body mass index and waist circumference. 20 It is worth noting that the lysoPCs are the main building blocks for cardiolipin, an essential lipid for the regulation and assemblage of electron transport complexes and mitochondrial morpho-functional architecture.…”

“…Those with dual decline also showed the most extensive alterations in metabolomic profiling of lipids and lipid metabolism, especially lysophosphatidylcholines (lysoPCs) 18 . A recent systematic review showed metabolites from sphingolipids and the sphingolipid metabolism pathway are important for both memory and gait impairments 19 . In agreement with the metabolic origin of dual decline, MCR is found to be associated with obesity‐related polygenetic risk scores for body mass index and waist circumference 20 .…”

Exploring the aging process of cognitively healthy adults by analyzing cerebrospinal fluid metabolomics using liquid chromatography-tandem mass spectrometry

“…A large-scale cohort study comparing 150 healthy individuals using non-targeted plasma LC–MS metabolomics revealed the levels of phospholipids (phosphocholine), phosphoserine, and prostaglandin changed with aging [ 11 ]. A recent systematic review of 39 studies on memory and gait decline with aging found that the five most age-correlated plasma or serum metabolites were sphingolipids, fatty acids, phosphatidylcholines, amino acids, and biogenic amines [ 41 ]. These results suggest that lipid metabolism is closely associated with aging by affecting membrane permeability, energy metabolism, signaling pathways, and gene expression; the decreased glycerophosphocholine in the CSF of the old age group in our study suggests defective cell membrane turnover and BBB breakdown in the aged brain.…”