The gut microbiome as an early biomarker of preclinical Alzheimer disease

Abstract Background The current paradigm of Alzheimer disease (AD) pathology teaches that people progress from cognitive normality, to cognitive normality with biomarker evidence of disease (preclinical AD), and ultimately to symptomatic AD with cognitive impairment. Recent work suggests that the gut microbiomes of symptomatic AD patients have distinct taxonomic compositions compared to healthy cognitively normal controls. However, knowledge about changes in the gut microbiome before the onset of symptomatic AD is limited. Method In this cross‐sectional study we compared the taxonomic composition, microbial functional potential, and metagenome‐assembled genomes (MAGs) abundances in a cohort of 93 cognitively normal individuals, 43 of whom had biomarker evidence of preclinical AD. Result Preclinical AD individuals have distinct gut microbial taxonomic profiles compared to their healthy controls. Observed microbiome features correlated with amyloid, but not tau or neurodegeneration biomarkers, suggesting that the gut microbial community changes early in the disease process. We identified specific taxa and microbial pathways that were associated with preclinical AD; inclusion of these microbiome features improved the accuracy, sensitivity, and specificity of machine learning classifiers for preclinical AD status. Conclusion Gut microbiome correlates of preclinical AD neuropathology have the potential to improve our understanding of AD etiology, enable the identification of gut‐derived biomarkers of AD or AD risk, and guide development of novel therapeutic interventions.