Stool and Plasma Metabolites and APOE status in the Boston Puerto Rican Health Study

TL;DR

This study explores how the APOE e4 gene variant, linked to Alzheimer's disease, affects metabolites in blood and stool, focusing on bile acid metabolism and gut-related compounds in Puerto Rican individuals.

Contribution

The study is the first to concurrently examine untargeted metabolites in stool and plasma in relation to APOE e4 genotype in a Latino population.

Findings

Plasma metabolites related to primary bile acid metabolism were overrepresented in APOE e4 carriers.

Stool metabolites showed overrepresentation of dipeptides in APOE e4 carriers, though no individual metabolites reached significance.

Findings align with prior evidence of bile acid dysregulation in APOE e4 carriers.

Abstract

The Apolipoprotein E (APOE) e4 variant is the strongest known genetic risk factor for dementia and Alzheimer's disease. It has been associated with alterations in glucose and lipid metabolism, increased risk of diabetes, metabolic syndrome, and dysbiosis of the gut microbiota. To our knowledge, no studies have concurrently examined untargeted metabolites in both stool and plasma with APOE‐e4 genotype. Evidence is especially lacking in Latinos/Hispanics who have unique metabolic and microbiome profiles and are at an increased risk of dementia.

Our analysis focused on 209 Boston Puerto Rican Health Study participants (median age 68 y) who provided concurrent stool and blood samples for untargeted metabolomic profiling (Metabolon, Inc) and had APOE e4 genotyping. Multivariate analyses in MaAsLin2 were used to identify stool and plasma metabolites associated with APOE status (carrier of at least one APOE e4 allele, vs non‐carrier). Overrepresentation analysis (ORA) was used to identify metabolite sets enriched in those with APOE e4 genotype.

In plasma, ORA identified overrepresentation of Primary Bile Acid Metabolism metabolites among associations with APOE e4 (pFDR = 0.0205). Consistently, MaAsLi2 identified several bile acid plasma metabolites associated with APOE e4, such as glycocholate (pFDR = 0.047), glycochenodeoxycholate‐3‐sulfate (pFDR = 0.11), glycohyocholate (pFDR = 0.18), and glycochenodeoxyhcholate (FDR q = 0.21). In stool, ORA identified dipeptide (pFDR = 0.0067) as overrepresented among those with APOE e4; no metabolites met the pFDR < 0.25 threshold in MaAsLin2 analyses.

Our findings are consistent with prior reports highlighted dysregulation in bile acid metabolism in APOE e4carriers. More work is needed to understand the role of APOEe4, stool and serum metabolome, bile acid metabolism in cognitive function and and dementia risk.