Early Gut Microbiome Alterations in Mild Cognitive Impairment Reflect Changes in Alzheimer Disease

Introduction: Alterations in the gut-brain axis have been increasingly linked to neurodegenerative diseases, including Alzheimer disease (AD). It remains unclear whether these microbiome changes are already present during early cognitive decline. We examined whether gut microbiome alterations characteristic of AD are detectable in mild cognitive impairment (MCI) and whether these changes follow a similar pattern across the cognitive continuum. Methods: This case-control study included 78 participants: 37 cognitively healthy controls, 20 individuals with MCI, and 21 individuals with prodromal or mild AD. Cognitive performance was assessed using the CERAD neuropsychological battery, and disease severity was assessed using the Clinical Dementia Rating. Dietary data were collected, and fecal samples were analyzed using 16S rRNA gene amplicon sequencing. Results: We identified 16 bacterial genera associated with cognitive status. Genera such as Lacticaseibacillus , Raoultella , and Buttiauxella were reduced in AD, with similar decreases already evident in MCI. In contrast, Anaerovorax and an unclassified Comamonadaceae genus were increased in AD. Several alterations showed a consistent trend from normal cognition through MCI to AD. Discussion: Gut microbiome alterations characteristic of AD appear already present in early cognitive decline and follow a similar pattern in MCI. These findings support the potential of microbiome profiles as early, noninvasive biomarkers of AD.