Considering Biomarkers of Neurodegeneration in Alzheimer's Disease: The Potential of Circulating Cell-Free DNA in Precision Neurology.

Neurodegenerative diseases, such as Alzheimer's disease (AD), are a growing public health crisis, exacerbated by an aging global population and the lack of effective early disease-modifying therapies. Early detection of neurodegenerative disorders is critical to delaying symptom onset and mitigating disease progression, but current diagnostic tools often rely on detecting pathology once clinical symptoms have emerged and significant neuronal damage has already occurred. While disease-specific biomarkers, such as amyloid-beta and tau in AD, offer precise insights, they are too limited in scope for broader neurodegeneration screening for these conditions. Conversely, general biomarkers like neurofilament light chain (NfL) provide valuable staging information but lack targeted insights. Circulating cell-free DNA (cfDNA), released during cell death, is emerging as a promising biomarker for early detection. Derived from dying cells, cfDNA can capture both general neurodegenerative signals and disease-specific insights, offering multi-layered genomic and epigenomic information. Though its clinical potential remains under investigation, advances in cfDNA detection sensitivity, standardized protocols, and reference ranges could establish cfDNA as a valuable tool for early screening. cfDNA methylation signatures, in particular, show great promise for identifying tissue-of-origin and disease-specific changes, offering a minimally invasive biomarker that could transform precision neurology. However, further research is required to address technological challenges and validate cfDNA's utility in clinical settings. Here, we review recent work assessing cfDNA as a potential early biomarker in AD. With continued advances, cfDNA could play a pivotal role in shifting care from reactive to proactive, improving diagnostic timelines and patient outcomes.