Cerebrospinal fluid mitochondrial DNA in the Alzheimer's disease continuum

Area of Science:

• Neuroscience
• Biochemistry
• Genetics

Background:

• Previous studies suggested low cell-free mitochondrial DNA (mtDNA) levels in cerebrospinal fluid (CSF) as a potential Alzheimer's disease (AD) biomarker.
• A lack of validation studies necessitated replication of these findings in a larger cohort.

Purpose of the Study:

• To validate the utility of CSF cell-free mtDNA as a biomarker for Alzheimer's disease (AD).
• To assess the impact of preanalytical and analytical factors on mtDNA quantification in CSF.

Main Methods:

• Droplet digital PCR was used to quantify mtDNA in CSF from 124 AD spectrum patients and 140 healthy controls.
• Evaluated preanalytical variables including freeze-thaw cycles and serial dilution linearity.
• Analyzed mtDNA levels across diagnostic groups and assessed diagnostic accuracy using ROC analysis.

Main Results:

• CSF mtDNA levels exhibited high interindividual variability and significant overlap between AD patients and controls.
• While the AD group showed higher mtDNA counts, ROC analysis yielded an AUC of 0.715, indicating limited diagnostic power.
• mtDNA quantification demonstrated high stability and low analytical variability.

Conclusions:

• CSF cell-free mtDNA levels display substantial interindividual variation and overlap across phenotypes, limiting their sensitivity as an AD biomarker.
• The proposed utility of CSF mtDNA as a novel biomarker for Alzheimer's disease requires further investigation due to low diagnostic sensitivity.