Early signature in the blood lipidome associated with subsequent cognitive decline in the elderly: A case-control analysis nested within the Three-City cohort study

Abstract

Background Brain lipid metabolism appears critical for cognitive aging, but whether alterations in the lipidome relate to cognitive decline remains unclear at the system level. Methods We studied participants from the Three-City study, a multicentric cohort of older persons, free of dementia at time of blood sampling, and who provided repeated measures of cognition over 12 subsequent years. We measured 189 serum lipids from 13 lipid classes using shotgun lipidomics in a case-control sample on cognitive decline (matched on age, sex and level of education) nested within the Bordeaux study center (discovery, n = 418). Associations with cognitive decline were investigated using bootstrapped penalized regression, and tested for validation in the Dijon study center (validation, n = 314). Findings Among 17 lipids identified in the discovery stage, lower levels of the triglyceride TAG50:5, and of four membrane lipids (sphingomyelin SM40:2,2, phosphatidylethanolamine PE38:5(18:1/20:4), ether-phosphatidylethanolamine PEO34:3(16:1/18:2), and ether-phosphatidylcholine PCO34:1(16:1/18:0)), and higher levels of PCO32:0(16:0/16:0), were associated with greater odds of cognitive decline, and replicated in our validation sample. Interpretation These findings indicate that in the blood lipidome of non-demented older persons, a specific profile of lipids involved in membrane fluidity, myelination, and lipid rafts, is associated with subsequent cognitive decline. Funding The complete list of funders is available at the end of the manuscript, in the Acknowledgement section.

Oligodendrocytes in the aging brain

“…Analysis of myelin composition in the aging primate brain shows that the lipid content of myelin, especially that of cholesterol, one of the major myelin lipids, shows greater changes than the protein composition, which remains more stable (46). Furthermore, a recent lipidomic analysis spanning a 12 year period showed that reduced Downloaded from http://portlandpress.com/neuronalsignal/article-pdf/doi/10.1042/NS20210008/915170/ns-2021-0008.pdf by guest on 28 June 2021 blood levels of membrane lipids, including sphingomyelin was associated with cognitive decline in participants (47). This suggests that changes in lipid content, rather than protein content, of myelin are largely accountable for myelin changes in cognitive decline.…”

“…It is possible that this supply is compromised in aging. Evidence shows altered blood lipidome, including lower levels of myelin lipids such as sphingomyelin, is associated with reduced cognitive status in aging [ 47 ].…”

The serum metabolome mediates the concert of diet, exercise, and neurogenesis, determining the risk for cognitive decline and dementia

“…More specifically, we: (1) determined whether markers of HN were associated with CD and/or dementia 12 years after the samples were taken, and (2) whether exercise and key nutritional factors, including our previously identified metabolites 11 and lipids, 19 could modulate the neurogenic process.…”

“…Therefore, using serum samples collected at inclusion from a longitudinal dementia cohort, we investigated the effect of the systemic environment (i.e., serum) of participants with, and without, subsequent CD and dementia on the neurogenic process using the in vitro assay. More specifically, we: (1) determined whether markers of HN were associated with CD and/or dementia 12 years after the samples were taken, and (2) whether exercise and key nutritional factors, including our previously identified metabolites 11 and lipids, 19 could modulate the neurogenic process.…”

Metabolomic and Inflammatory Signatures of Symptom Dimensions in Major Depression

“…A major class of ether-linked phospholipids are plasmalogens that are ubiquitous in mammalian cell membranes and plasma lipoproteins. They are enriched in the myelin sheath and are key components of “lipid rafts” (Di Paolo and Kim 2011, Dean and Lodhi 2018, Lefevre-Arbogast, Hejblum et al 2021). They are relevant for these specific membrane microdomains, which act as dynamic platforms for several cellular processes, including signaling pathways, molecular trafficking and protein interactions (Di Paolo and Kim 2011) and play critical role in neurotransmission and synaptic plasticity (Sebastiao, Colino-Oliveira et al 2013).…”