Metabolomics and Risk of Dementia: A Systematic Review of Prospective Studies.

BACKGROUND: The projected increase in the prevalence of dementia has sparked interest in understanding the pathophysiology and underlying causal factors in its development and progression. Identifying novel biomarkers in the preclinical or prodromal phase of dementia may be important for predicting early disease risk. Applying metabolomic techniques to prediagnostic samples in prospective studies provides the opportunity to identify potential disease biomarkers. OBJECTIVE: The objective of this systematic review was to summarize the evidence on the associations between metabolite markers and risk of dementia and related dementia subtypes in human studies with a prospective design. DESIGN: We searched PubMed, PsycINFO, and Web of Science databases from inception through December 8, 2023. Thirteen studies (mean/median follow-up years: 2.1-21.0 y) were included in the review. RESULTS: Several metabolites detected in biological samples, including amino acids, fatty acids, acylcarnitines, lipid and lipoprotein variations, hormones, and other related metabolites, were associated with risk of developing dementia. Our systematic review summarized the adjusted associations between metabolites and dementia risk; however, our findings should be interpreted with caution because of the heterogeneity across the included studies and potential sources of bias. Further studies are warranted with well-designed prospective cohort studies that have defined study populations, longer follow-up durations, the inclusion of additional diverse biological samples, standardization of techniques in metabolomics and ascertainment methods for diagnosing dementia, and inclusion of other related dementia subtypes. CONCLUSIONS: This study contributes to the limited systematic reviews on metabolomics and dementia by summarizing the prospective associations between metabolites in prediagnostic biological samples with dementia risk. Our review discovered additional metabolite markers associated with the onset of developing dementia and may help aid in the understanding of dementia etiology. The protocol is registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (https://www.crd.york.ac.uk/prospero/; registration ID: CRD42022357521).

Diet-derived and diet-related endogenously produced palmitic acid: Effects on metabolic regulation and cardiovascular disease risk.

Palmitic acid is the predominant dietary saturated fatty acid (SFA) in the US diet. Plasma palmitic acid is derived from dietary fat and also endogenously from de novo lipogenesis (DNL) and lipolysis. DNL is affected by excess energy intake resulting in overweight and obesity, and the macronutrient profile of the diet. A low-fat diet (higher carbohydrate and/or protein) promotes palmitic acid synthesis in adipocytes and the liver. A high-fat diet is another source of palmitic acid that is taken up by adipose tissue, liver, heart and skeletal muscle via lipolytic mechanisms. Moreover, overweight/obesity and accompanying insulin resistance increase non-esterified fatty acid (NEFA) production. Palmitic acid may affect cardiovascular disease (CVD) risk via mechanisms beyond increasing low-density lipoprotein-cholesterol (LDL-C), notably synthesis of ceramides and possibly through branched fatty acid esters of hydroxy fatty acids (FAHFAs) from palmitic acid. Ceramides are positively associated with incident CVD, whereas the role of FAHFAs is uncertain. Given the new evidence about dietary regulation of palmitic acid metabolism there is interest in learning more about how diet modulates circulating palmitic acid concentrations and, hence, potentially CVD risk. This is important because of the heightened interest in low carbohydrate (carbohydrate controlled) and high carbohydrate (low-fat) diets coupled with the ongoing overweight/obesity epidemic, all of which can increase plasma palmitic acid levels by different mechanisms. Consequently, learning more about palmitic acid biochemistry, trafficking and how its metabolites affect CVD risk will inform future dietary guidance to further lower the burden of CVD.

A genome-wide association study of red-blood cell fatty acids and ratios incorporating dietary covariates: Framingham Heart Study Offspring Cohort.

Recent analyses have suggested a strong heritable component to circulating fatty acid (FA) levels; however, only a limited number of genes have been identified which associate with FA levels. In order to expand upon a previous genome wide association study done on participants in the Framingham Heart Study Offspring Cohort and FA levels, we used data from 2,400 of these individuals for whom red blood cell FA profiles, dietary information and genotypes are available, and then conducted a genome-wide evaluation of potential genetic variants associated with 22 FAs and 15 FA ratios, after adjusting for relevant dietary covariates. Our analysis found nine previously identified loci associated with FA levels (FADS, ELOVL2, PCOLCE2, LPCAT3, AGPAT4, NTAN1/PDXDC1, PKD2L1, HBS1L/MYB and RAB3GAP1/MCM6), while identifying four novel loci. The latter include an association between variants in CALN1 (Chromosome 7) and eicosapentaenoic acid (EPA), DHRS4L2 (Chromosome 14) and a FA ratio measuring delta-9-desaturase activity, as well as two loci associated with less well understood proteins. Thus, the inclusion of dietary covariates had a modest impact, helping to uncover four additional loci. While genome-wide association studies continue to uncover additional genes associated with circulating FA levels, much of the heritable risk is yet to be explained, suggesting the potential role of rare genetic variation, epistasis and gene-environment interactions on FA levels as well. Further studies are needed to continue to understand the complex genetic picture of FA metabolism and synthesis.