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

  1. Jacob Apibilla Ayembilla
  2. Yannick N. Wadop
  3. Rebecca Bernal
  4. Biniyam A. Ayele
  5. Murali Sargurupremraj
  6. Xueqiu Jian
  7. Alfred K. Njamnshi
  8. Sudha Seshadri
  9. Alice B. S. Nono Djotsa
  10. Jayandra Jung Himali
  11. Bernard Fongang
  12. Alfred Fonteh

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Abstract

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 ± 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 Aβ 42 , tau, and the Aβ 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.

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 Aβ 42 , tau, and the Aβ 42 /tau ratio. Furthermore, incorporating a panel of these fatty acid biomarkers alongside Aβ 42 /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 early ACD pathology. Thus, strategies that regulate fatty acid metabolism may prevent cognitive decline in an older population.

Highlights

  • This study revealed that CSF fractions’ fatty acids have a better discriminatory power for CU from MCI than CSF Aβ 42 , tau, and Aβ 42 /tau ratio.

  • A panel of CSF fraction fatty acids combined with Aβ 42 /tau remarkably improved its diagnostic performance for differential diagnosis of CU, MCI, and ACD.

  • Clinical 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.

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    1. PREreview

      This Zenodo record is a permanently preserved version of a Structured PREreview. You can view the complete PREreview at https://prereview.org/reviews/17107906.

      Does the introduction explain the objective of the research presented in the preprint? Yes
      Are the methods well-suited for this research? Somewhat appropriate The method was somewhat appropriate because the presentation of the method wasn't detailed enough. The authors need to give detailed information on the reason for the study site and the study design used. Also, the steps to arriving at their sampling weren't properly presented. The ethical approval is also missing with a significant absence of inclusion and exclusion criteria. The data type is not presented (Primary or secondary). No detailed information on the data collection tools, the data collectors, or how the details were abstracted. The data storage and management were also missing in the method section
      Are the conclusions supported by the data? Somewhat supported It was somewhat appropriate owing to the sample size and the study design used which might not be the true evidence of their findings.
      Are the data presentations, including visualizations, well-suited to represent the data? Highly appropriate and clear
      How clearly do the authors discuss, explain, and interpret their findings and potential next steps for the research? Very clearly
      Is the preprint likely to advance academic knowledge? Highly likely
      Would it benefit from language editing? No A minor grammatical error and authors need to address the paragraphs of their Preprint
      Would you recommend this preprint to others? Yes, but it needs to be improved
      Is it ready for attention from an editor, publisher or broader audience? Yes, after minor changes

      Competing interests

      The authors declare that they have no competing interests.

    2. Version published to 10.1101/2025.08.25.672205 on bioRxiv