Nucleic Acid Liquid Biopsies in Alzheimer’s Disease: Current State, Challenges, and Opportunities

Abstract

Alzheimer’s disease is the most common neurodegenerative disease and affects persons of all races, ethnic groups, and sexes. The disease is characterized by neuronal loss leading to cognitive decline and memory loss. There is no cure and the effectiveness of existing treatments is limited and depends on the time of diagnosis. The long prodromal period, during which patients’ ability to live a normal life is not affected despite neuronal loss, often leads to a delayed diagnosis because it can be mistaken for normal aging of the brain. In order to make a substantial impact on AD patients, early diagnosis may provide a greater therapeutic window for future therapies to slow AD-associated neurodegeneration. Current gold standards for disease detection include magnetic resonance imaging and positron emission tomography scans, which visualize amyloid β and phosphorylated tau depositions and aggregates. Liquid biopsies, already an active field of research in precision oncology, are hypothesized to provide early disease detection through minimally or non-invasive sample collection techniques. Liquid biopsies in Alzheimer’s disease have been studied in cerebrospinal fluid, blood, ocular, oral, and olfactory fluids. However, most of the focus has been on blood and cerebrospinal fluid due to biomarker specificity and sensitivity attributed to the effects of the blood-brain barrier and inter-laboratory variation during sample collection. Many studies have identified amyloid β and phosphorylated tau levels as putative biomarkers, however, advances in next-generation sequencing-based liquid biopsy methods have led to significant interest in identifying nucleic acids species associated with Alzheimer’s disease from liquid tissues. Differences in cell-free RNAs and DNAs have been described as potential biomarkers for AD and hold the potential to affect disease diagnosis, treatment, and future research avenues.

A nanoparticle priming agent reduces cellular uptake of cell-free DNA and enhances the sensitivity of liquid biopsies

“…Moreover, although we have limited our study to ctDNA testing in plasma for cancer detection, we believe that this work lays the groundwork for the potential development of priming agents for liquid biopsies at large. Given that our priming agent modulates cfDNA clearance, its use could be investigated beyond applications in oncology, such as for detection of microbial cfDNA during early infection ( 3 ) or for low abundance cfDNA biomarkers in other disease areas ( 43–45 ). Additionally, we believe that the concept of a priming agent that perturbs endogenous biomarker clearance in vivo marks a paradigm shift in how we think about the limit of detection of molecular diagnostics.…”