Detecting Alzheimer’s Disease Biomarkers with Next-Generation Sequencing

Dr. Lesley Cheng

Lesley’s groundbreaking research is a milestone for not only degenerative diseases but health conditions of all types. It’s a step towards personalized medicine. Get a glimpse of the future.

A hallmark sign of Alzheimer’s disease is the presence of amyloid plaques, which collect in the brain and destroy neurons. Even after this neurodegeneration sets in, however, Alzheimer’s disease-induced dementia does not manifest for another decade. By the time cognitive deficits are first detected, it is often too late to treat the disease with any significant impact.

Alzheimer’s disease is the most common cause of dementia, and as the world’s population ages, the disease will only become more prevalent. Despite its pervasiveness, there are currently no objective diagnostic tests for Alzheimer’s disease; rather, doctors primarily rely on cognitive testing and family history to diagnose it. But, to prevent Alzheimer’s disease from overburdening patients and families in the future, scientists must develop objective methods to detect and treat Alzheimer’s disease before the cognitive deficits set in.

Dr. Lesley Cheng, a postdoctoral scholar in Prof. Andrew Hill’s laboratory at La Trobe University in Melbourne, Australia, is developing a novel blood test for detecting Alzheimer’s disease as soon as amyloid plaques first appear in the brain. Her work began with discovering 16 biomarkers that are strongly associated with Alzheimer’s disease and can be differentiated from healthy genetic variations. Then, with the help of next-generation sequencing (NGS) technology from Thermo Fisher Scientific, Dr. Cheng developed a blood test that collects circulating exosomes, so she could sequence the microRNAs (miRNAs) contained within and detect those that express Alzheimer’s disease markers.

Dr. Cheng gave an inspirational talk at TEDx Melbourne about her breakthrough work, where she described how this NGS technology is enabling her lab to develop an early detection test.

As pioneers and world leaders in biomarker detection via exosome analysis, the Hill Lab quickly realized the utility of the Ion Personal Genome Machine (PGM) System for NGS to advance their research. As such, in mid-2011, they were one of the first labs in Australia to purchase the Ion PGM System, and since then, Dr. Cheng has been using this system to refine her early detection method for Alzheimer’s disease. She uses the PGM system for deep sequencing, and she has devised methods to sequence nucleic acids from small-volume samples.

Using the PGM System, Dr. Cheng and her lab have become leaders in using exosomes to detect Alzheimer’s disease, as well as other neurodegenerative disorders such as Parkinson’s disease. A year ago, the lab expanded their throughput capabilities by purchasing the Ion Chef and Ion S5 Systems. “Having our own Ion Chef and Ion S5 instruments in the lab means we can sequence when we want, no different than with any other essential instrument of the lab,” says. Dr. Cheng. 

In future studies, Dr. Cheng will use Applied Biosystems TaqMan miRNA Assays, Invitrogen mirVana miRNA Mimics,
and CRISPR-Cas9 technology to validate her miRNA candidates in cell cultural models. The Ion S5 System will continue to play a critical role in those studies, enabling Dr. Cheng to examine the consequences of disease-associated miRNA knockdowns and identify potential therapeutic targets.

Today, Dr. Hill’s group continues to push the boundaries of discovery and implementation using these sequencing systems. With NGS technology, Dr. Cheng has been able to produce libraries from small miRNA yields extracted from exosomes or small serum samples, and this capability, she says, has attracted collaborators from all over Australia. 

As she has collated more miRNA panels for specific diseases, she has discovered discrete biomarkers for each one. Not only does this provide novel routes to diagnosis, but provides her lab with the ability to dissect specific pathological pathways for each disease. In the future, systems from Thermo Fisher Scientific can be used to quickly sequence exosomal miRNA sequences to diagnose not only neurodegenerative disease, but also any other disorder with defined miRNA biomarkers.

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Published on August 30, 2016