Bile acids inform about a sex‐specific resilience phenotype against Alzheimer’s disease implicating a role for the gut microbiome and the exposome

Abstract

AbstractBackgroundBile acids (BAs) are byproducts of cholesterol metabolism involved in lipid absorption, signaling and energy homeostasis. BA synthesis and metabolism, regulated by human and gut bacteria co‐metabolism, are influenced by the exposome. Our prior studies at a population level illustrated a correlation between altered BA profiles and cognitive and brain imaging changes in MCI and AD. More information is needed to determine if these are causal in sub‐populations, and if their modulation can impact disease course.MethodAbsolute serum levels of 33 primary, secondary, and conjugated BAs were measured on a targeted mass spectrometry‐based platform in 1117 fasted subjects (502 women) drawn from the AD Neuroimaging Initiative (ADNI‐1/GO‐2; AD (N = 180), MCI (N = 607) and CN (N = 330). Analysis centered on adjusted and/or stratified linear models with an interpretative focus emphasizing individual‐level granularity.ResultIn stratified analysis, men but not women showed strong association between levels and ratios of BAs and diagnosis. Inclusion of two (informative) bile acids and their ratios increases AUCs for AD vs control from ∼0.72 to ∼0.82‐0.85 (p<0.001) in APOEε4 genotype‐stratified analyses. Some specific associations were APOEε4 genotype‐dependent; some specific microbiome‐mediated ratios in BAs were associated with AD diagnosis in APOEε4− only and secondary bile acid synthesis was associated with AD diagnosis in APOEε4+ only. Other associations were APOEε4 genotype‐independent ‐ higher ratios of primary BAs to total BAs were associated with reduced AD prevalence. Levels of cholic acid below sharp thresholds 25 or 50 nM (in APOEε4+ and APOEε4−, respectively) at 24 months were associated with 5‐ to 7‐fold increased relative risk of MCI to AD progression, establishing a potential biomarker for a resilience phenotype.ConclusionLeveraging the combined power of ADNI and metabolomics with a focus on granularity and complementarity revealed previously unobserved relationships between BAs, sex, APOEε4 genotype, and AD etiology. These data identify a resilience class and provide a roadmap for stratifying subjects and targeting therapies in a precision medicine approach while gaining deeper insights linking peripheral‐central metabolism influenced by the exposome. BAs are a potential modifiable factor that mediates causal linkages between endogenous and exogenous factors in the susceptibility or resilience against AD.