Fonteh, A. N. | bioRxiv Science

bioRxiv2025

Early Metabolic Alterations in Cerebrospinal Fluid Fatty Acid Profiles Linked to Cognitive Decline and All-Cause Dementia

BackgroundWhile All-cause dementia (ACD) may often be characterized by the abnormal deposition of extracellular {beta}-amyloid (A{beta}) in the brain cortex and hyperphosphorylated tau (p-tau) as neurofibrillary tangles intracellularly, there is a need to identify early metabolic changes that may accompany these pathological changes. ObjectiveThis study evaluated the predictive value of fatty acids in cerebrospinal fluid (CSF) fractions in differentiating cognitively unimpaired (CU), mild cognitive impairment (MCI), and ACD participants. MethodsCSF fatty acid profiles were analyzed from CU (n=68), MCI (n=38), and ACD (n=37) individuals aged 77.3 {+/-} 7.7 years, sourced from the Huntington Medical Research Institutes (HMRI). Multivariable binary logistic regression identified the most effective CSF fatty acid biomarkers for distinguishing CU, MCI, and ACD groups. The top-performing CSF fatty acid biomarkers were combined with A{beta}42, tau, and the A{beta}42/tau ratio to evaluate their collective diagnostic performance. The model was adjusted for covariates, including age, sex, smoking status, hypertension, diabetes, and APOE genotype. Receiver operating characteristic (ROC) curves were generated for the top 10 CSF fatty acids ranked by area under the curve (AUC), sensitivity, and specificity, and their significance was assessed using the DeLong test. ResultsThe top 10 fatty acids in CSF fractions demonstrated superior discrimination between CU individuals and those with MCI compared to traditional markers such as A{beta}42, tau, and the A{beta}42/tau ratio. Furthermore, incorporating a panel of these fatty acid biomarkers alongside A{beta}42/tau significantly improved diagnostic accuracy. Age, sex, smoking, hypertension, APOE genotype, and diabetes did not significantly influence the models performance. ConclusionThis study suggests that changes in fatty acid metabolism occur in early ACD pathology. Thus, strategies that regulate fatty acid metabolism may prevent cognitive decline in an older population. HighlightsO_LIThis study revealed that CSF fractions fatty acids have a better discriminatory power for CU from MCI than CSF A{beta}42, tau, and A{beta}42/tau ratio. C_LIO_LIA panel of CSF fraction fatty acids combined with A{beta}42/tau remarkably improved its diagnostic performance for differential diagnosis of CU, MCI, and ACD. C_LIO_LIClinical evaluation of these fatty acids will strengthen the detection of early cognitive impairment. A prospective large cohort multicenter study of the diagnostic utility of CSF fractions fatty acids will provide robust evidence before extensive clinical usage of these fatty acids. C_LI

neuroscience↗

bioRxiv2024

Differential Patterns of Gut and Oral Microbiomes in Hispanic Individuals with Cognitive Impairment

Alzheimers disease and related dementias (ADRD) have been associated with alterations in both oral and gut microbiomes. While extensive research has focused on the role of gut dysbiosis in ADRD, the contribution of the oral microbiome remains relatively understudied. Furthermore, the potential synergistic interactions between oral and gut microbiomes in ADRD pathology are largely unexplored. This study aims to evaluate distinct patterns and potential synergistic effects of oral and gut microbiomes in a cohort of predominantly Hispanic individuals with cognitive impairment (CI) and without cognitive impairment (NC). We conducted 16S rRNA gene sequencing on stool and saliva samples from 32 participants (17 CI, 15 NC; 62.5% female, mean age = 70.4 {+/-} 6.2 years) recruited in San Antonio, Texas, USA. Correlation analysis through MaAslin2 assessed the relationship between participants clinical measurements (e.g., fasting glucose and blood cholesterol) and their gut and saliva microbial contents. Differential abundance analysis evaluated taxa with significant differences between CI and NC groups, and alpha and beta diversity metrics assessed within-sample and group compositional differences. Our analyses revealed no significant differences between NC and CI groups in fasting glucose or blood cholesterol levels. However, a clear association was observed between gut microbiome composition and levels of fasting glucose and blood cholesterol. While alpha and beta diversity metrics showed no significant differences between CI and NC groups, differential abundance analysis revealed an increased presence of oral genera such as Dialister, Fretibacterium, and Mycoplasma in CI participants. Conversely, CI individuals exhibited a decreased abundance of gut genera, including Shuttleworthia, Holdemania, and Subdoligranulum, which are known for their anti-inflammatory properties. No evidence was found for synergistic contributions between oral and gut microbiomes in the context of ADRD. Our findings suggest that similar to the gut microbiome, the oral microbiome undergoes significant modifications as individuals transition from NC to CI. Notably, the identified oral microbes have been previously associated with periodontal diseases and gingivitis. These results underscore the necessity for further investigations with larger sample sizes to validate our findings and elucidate the complex interplay between oral and gut microbiomes in ADRD pathogenesis.

neuroscience↗