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

Background: While All-cause dementia (ACD) may often be characterized by the abnormal deposition of extracellular β-amyloid (Aβ) 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. Objective: This 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. Methods: CSF fatty acid profiles were analyzed from CU (n=68), MCI (n=38), and ACD (n=37) individuals aged 77.3 plus-or-minus sign 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 Aβ42, tau, and the Aβ42/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. Results: The top 10 fatty acids in CSF fractions demonstrated superior discrimination between CU individuals and those with MCI compared to traditional markers such as Aβ42, tau, and the Aβ42/tau ratio. Furthermore, incorporating a panel of these fatty acid biomarkers alongside Aβ42/tau significantly improved diagnostic accuracy. Age, sex, smoking, hypertension, APOE genotype, and diabetes did not significantly influence the model's performance. Conclusion: This study suggests that changes in fatty acid metabolism occur in the early stages of ACD pathology. Thus, strategies that regulate fatty acid metabolism may prevent cognitive decline in an older population.