Obesity-associated gut microbiome influences diet-induced metabolic and cognitive outcomes in older adults.

Obesity in older adults is a known risk factor for Alzheimer's disease and related dementias, potentially driven by metabolic dysfunction, inflammation and gut dysbiosis. The gut-brain axis, influenced by diet and the gut microbiome, is increasingly recognized as a contributor to neurodegeneration. In this sub-analysis of a 10-week randomized dietary education intervention (NCT06121986), we examined how obesity modulates gut microbiome, metabolome, and cognitive responses in 31 adults aged 55-85, with or without mild cognitive impairment. Participants received education on either a Mediterranean Diet or a Modified Mediterranean-Ketogenic Diet. Analyses were stratified by baseline obesity (BMI ≥30 kg/m²). Individuals with obesity exhibited lower microbial alpha-diversity, higher Bacteroides, and lower Akkermansia and Christensenellaceae_R-7_group, along with poorer memory and executive function. Only in the obese group did fat loss correlate with improvements in episodic memory and cognitive flexibility. In contrast, increased fat mass was associated with improved memory in non-obese participants. Gains in skeletal muscle mass predicted cognitive improvement in adults aged ≥73. Changes in gut (acetate, propionate, lactate) and plasma (acetate, pyruvate, citric acid) metabolites were linked to cognitive and body composition outcomes. These exploratory findings highlight the gut-muscle-brain axis as a modifiable target to enhance cognitive health in aging populations.