The growing trend of population aging is resulting in a surge in the prevalence of cognitive decline associated with aging (Brito et al., 2023). According to 2023 reports, 6.7 million individuals aged 65 and older in the United States have Alzheimer’s disease (AD), with projections indicating a rise to 13.8 million by 2060 (Alzheimers Dement, 2023). Cognitive impairment is increasingly recognized as a major public health challenge worldwide, and can significantly affect an individual’s daily life and independence. For example, studies have shown that individuals with subjective cognitive decline may experience significant quality of life decline and functional limitations within 6 months (Hendriksen et al., 2024). The higher prevalence of cognitive impairment among older adults may be related to a variety of factors, including chronic disease, psychosocial factors, and lifestyle. For example, studies have found that up to 76.0% of older adults living in foster care in the French West Indies have severe cognitive impairment (Boucaud-Maitre et al., 2024). In addition, cognitive decline may also be associated with specific biomarkers, such as amyloid PET scan disclosure in individuals with subjective cognitive decline can reveal the risk of future cognitive decline (Hendriksen et al., 2024). In contrast, in patients with cerebral small vessel disease, the mismatch between high white matter signal and cognitive function also suggests that cognitive decline may be associated with cerebrovascular lesions (Zeng et al., 2024). These findings emphasize the multifactorial nature and complexity of cognitive decline and the importance of early identification and intervention. However, to date, knowledge of cognitive impairment remains limited.

The role of the gut microbiome in neurodegenerative diseases is increasingly being acknowledged (Loh et al., 2024; Alpino et al., 2024). The fermentation of fiber-rich diets results in the production of short-chain fatty acids (SCFAs), primarily consisting of saturated fatty acids with 1 to 6 carbon atoms. The dosage of SCFAs, particularly butyrate, may be critical in determining their effects on psychophysiological and behavioral processes (Dalile et al., 2019). Recent studies indicate that butyrate can enhance memory and cognitive functions in mice by inhibiting microglia-mediated neuroinflammation and neuronal apoptosis (Wang et al., 2023; Wei et al., 2023). In a vascular dementia model, administration of butyrate-producing bacteria resulted in increased butyrate levels in the feces and the brain, significantly reduced cognitive deficits, and histopathological changes in the hippocampus (Liu et al., 2015). Butyrate may also exert neuroprotective effects by increasing neurotrophic factor levels and improving mitochondrial autophagy dysregulation (Guo et al., 2025). As the global population ages, cognitive decline has become an important public health issue. In recent years, more and more studies have shown that the gut microbiota and its metabolites (e.g., butyrate) play an important role in the aging process. Transplantation of gut microbes from older mice to younger mice resulted in inflammation of the gut and brain with cognitive decline, and further studies found that older gut microbes produced fewer butyrate-producing bacteria (Mishra et al., 2024). In addition, a study of older adults with mild cognitive impairment found that elevated levels of butyrate in participants’ feces were associated with lower levels of the AD biomarker Aβ-42 (Nagpal et al., 2019). Therefore, studying the relationship between butyrate intake and cognitive function in older adults is important for understanding the mechanisms of cognitive changes during aging.

The present study investigated the relationship between butyrate and cognitive function in older adults by analyzing data from NHANES and a representative group of older adults to address gaps in previous studies and reveal the potential benefits of dietary modifications in preventing cognitive decline.

This study analyzed data from a cross-sectional survey conducted between 2011 and 2014, focusing on older individuals. The findings revealed a substantial connection between butyrate intake and enhanced cognitive scores, even after accounting for potential confounding factors. Additionally, a notable dose-dependent relationship existed between butyrate intake and cognitive function in the Q1-Q4 intervals. The relationship between butyrate intake and AFT exhibited a significant nonlinear pattern, with an inflection point at approximately 1.73 g/day of butyrate intake. Before this point, AFT increased gradually with increasing butyrate intake; however, beyond the inflection point, the curve tended to decrease, suggesting that there might be an optimal range of butyrate intake for cognitive function beyond which additional intake may negatively impact cognitive function. For patients aged <80 years with hypertension without diabetes or stroke, butyrate had significant cognitive protective factors, although no significant differences were observed in the overall study population.

The relationship between AD and gut microbes has been extensively investigated in clinical studies, demonstrating a significant correlation between cognitive function and the prevalence of butyrate-producing bacteria (Verhaar et al., 2021; Hung et al., 2022). A clinical study involving 56 observers revealed a significant correlation between increased free water imaging in gray matter regions and a scarcity of butyrate-producing microorganisms in individuals belonging to the groups with AD and mild cognitive impairment (Yamashiro et al., 2024). Individuals with obesity typically exhibit imbalances in their gut microbiota, characterized by an increase in Aspergillus and a decrease in Clostridium butyrate levels. These imbalances have been strongly linked to cognitive decline. Furthermore, research indicates that oral Clostridium butyrate supplementation can effectively improve cognitive function in these individuals (Zheng et al., 2024). A prospective cohort study involving 135 patients, including those with cognitive normality, subjective cognitive decline, or mild cognitive impairment (MCI), found that patients with prodromal AD phenotype had lower levels of SCFA-producing bacteria, particularly butyrate-producing ones, compared to the control group with cognitive normality, with similar results observed in those with prior MCI (Liu et al., 2022; Liu et al., 2019). Research has demonstrated that vitamins B, D, and E possess neuroprotective qualities in the context of AD and Parkinson’s disease (Jia et al., 2024; Dysken et al., 2014; Wang et al., 2021; Samson et al., 2022; Zhou, 2023). Moreover, research on polyunsaturated fatty acids (PUFAs) has shown that increased levels of PUFAs and continuous supplementation with PUFAs over a period of time might potentially improve motor dysfunction and decelerate the advancement of cognitive decline in patients with AD (Chiu et al., 2008; Avallone et al., 2019; Chu et al., 2022). Clinical studies have shown that omega-3 PUFA supplements can enhance the presence of bacteria that are responsible for the production of butyrate and Mycobacterium anisopliae (Costantini et al., 2017; Zhuang et al., 2018; Zheng et al., 2021).

Clostridium butyrate (Cb), a member of the Clostridium genus and classified as a bacillus, is notable for its capability to produce butyrate, which has been associated with potential benefits for neurological ailments and the aging process (Stoeva et al., 2021). Research indicates that administering Cb to AD mice for 4 weeks effectively prevents Aβ accumulation, reduces microglia activation, and mitigates cognitive impairments (Sun et al., 2020). Oral administration of Cb improved motor functions impaired by MPTP, reduced dopaminergic neuron loss, mitigated synaptic dysfunction, and inhibited microglia activation in mice (Sun et al., 2021). Additionally, it significantly alleviated cognitive impairments and neuronal damage in a mouse model of sepsis-associated encephalopathy (Liu et al., 2020). Systematic transplantation and grafting of fecal microbiota from healthy wild-type mice to animals with AD improved the development of amyloid β-plaques and neurofibrillary tangles, decreased neuroglial reactions, and relieved cognitive impairment (Kim et al., 2020). Administering butyrate directly enhances cognitive function in mice with AD (Wang et al., 2022; Zhou et al., 2023). A comprehensive investigation incorporating both preclinical and clinical research discovered that a maternal diet low in fiber negatively affected cognitive function and synaptic plasticity in the offspring. Furthermore, it was determined that butyrate consumption, but not propionate, could reverse this impairment. Subsequent mechanistic studies revealed that histone deacetylase 4 is the primary mediator of butyrate-dependent neurocognitive improvement (Yu et al., 2020).

Although the exact mechanisms linking butyrate intake to cognitive increase remain unclear, our results are biologically plausible. Prior research has demonstrated a negative relationship between serum quinolinic acid levels and cognitive function and cortical gray matter reduction in human obesity. Quinolinic acid is known to harm neurons, alter intracellular signaling in dendritic spines, and decrease brain-derived neurotrophic factor (BDNF). However, butyrate, a gut microbiota metabolite, prevents quinolinic acid-induced damage by epigenetically enhancing H3K18ac on BDNF promoters, offsetting low BDNF levels and improving cognition (Ge et al., 2023). The oral administration of butyrate in mice exposed to lead improves cognitive memory by inhibiting STAT3 signaling in microglia and stimulating ACSS2 expression in hippocampal neurons. This increases acetyl-CoA levels, restoring H3K9ac deposition and BDNF expression (Li et al., 2024). Reduced butyrate production by the aged gut microbiota leads to decreased signaling of FFAR2/3, inhibiting mucin formation and increasing permeability, inflammation, and brain abnormalities (Mishra et al., 2024).

In our supplemental analyses, butyrate intake was found to be positively associated with Z-scores in participants younger than 70 years of age, whereas this relationship was no longer significant in participants older than 70 years of age. The possible reasons behind this are as follows: the composition and function of the intestinal microbiota undergoes significant changes with age, which may lead to less efficient production and absorption of butyrate (Ling et al., 2022). In addition, in older adults 70 years of age and older, chronic inflammation, oxidative stress, or other neurodegenerative pathologic changes that may be present may mask the potential benefits of butyrate (Khansari et al., 2009; Mou et al., 2022).

Employing a multifaceted approach, this study comprehensively assessed cognitive function through various tests, including CERAD-DRT, CERAD-IRT, DSST, AFT, and Z scores. To ensure a rigorous analysis, we accounted for confounders identified in prior research. To further investigate the possible relationship between butyrate consumption and cognitive performance, a dose–response study was also conducted.

Nonetheless, it is crucial to recognize the study’s limitations. First, given its cross-sectional design, determining the precise temporal relationship between butyrate intake and cognitive function remains elusive. Randomized controlled trials are essential for further validating our findings. Second, although efforts were made to account for potential confounding factors, it was not possible to completely remove the chance of reverse causation or residual confounding. Third, our reliance on self-reported 24-h dietary recalls for butyrate intake data introduced the risk of measurement and recall inaccuracies. Fourth, due to the limitations of the retrospective study, we did not collect information on whether participants additionally ingested butyrate supplements; we should take this factor into account in future studies and should be mindful of the scope of application in terms of interpretation of results. Lastly, further research is needed to determine if our findings extend beyond the specific US adult population studied.

In summary, our study found an association between butyrate consumption and cognitive performance among a nationally representative cohort of older adults in the United States of America. The findings hint at the possibility of a causal relationship, which warrants further investigation through large-scale prospective studies. Our results indicated that elevating butyrate levels, whether through dietary means or otherwise, could potentially contribute to maintaining brain function during aging.