My research in 60 seconds — Addressing the unmet needs in Alzheimer’s research through scalable nanopore sequencing

Large-scale Alzheimer’s genetics research with nanopore technology – the Long-Read Sequencing project

According to the World Health Organisation, 55 million people have dementia worldwide and each year there are nearly 10 million new cases¹. This suggests there is an urgent need to better understand the mechanisms of these diseases to support their treatment and prevention.

Kimberley Billingsley is a Postdoctoral Research Fellow at the Center for Alzheimer’s and Related Dementias (CARD), National Institutes of Health (NIH). Here she leads the Long-Read Sequencing team which, within the Long-Read Sequencing project, are applying nanopore technology to sequence thousands of human brain samples to generate a new long-read resource for the wider research community.

The Long-Read Sequencing project aims to look at complex variants, small variants, and repeat sequences, as well as methylation, to compare the differences between samples derived from healthy individuals and those with Alzheimer's disease to accelerate understanding of the genetic architecture of this neurodegenerative disease.

Previous large-scale genetic sequencing efforts for research into Alzheimer's disease and related dementias have been performed using short-read sequencing technologies — which is not optimised to identify structural variation, repeat expansions or methylation.

My background is looking at structural variants. I went through the pain of trying to do that with short-read sequencing. — Kimberley Billingsley

While long-read capable sequencing technologies substantially overcome this limitation, they have previously not been considered as a feasible replacement at scale due to being too expensive, not scalable enough, or too error-prone.

As Kimberley explains, this is where nanopore technology comes in.

Nanopore technology provides full genome characterisation of all variant types including small variants, structural variants, complex copy number variants and methylation including 5mC and 5hmC.

And with Oxford Nanopore’s high-throughput sequencing device — namely the PromethION 48, capable of sequencing over 4900 genomes per year — the technology delivers the scalability needed.

Kimberley highlighted that nanopore sequencing “was the only option” to provide long sequencing reads required to complete a project of this scale and how “it just wouldn’t have been possible” with other sequencing technologies.

The importance of genetically diverse datasets

Another key focus of the project is to include genomes derived from individuals in populations previously underrepresented in genomic studies.

Every individual and population has some baseline genetic diversity. Studying these subtle changes can provide new insights into human biology, identify variants associated with certain populations and/or diseases, and potentially improve clinical and personalised medicine programs in the future.

Including diverse populations in genomic research is not only scientifically important, but also opens opportunities to improve health outcomes globally.

Those with a similar genetic background will benefit most from genetic research that is based on individuals who are genetically similar to them. Therefore, using diverse data sets helps to ensure that genomics research does not perpetuate current global health disparities but instead helps to bridge this gap.

“Generating long-read data from diverse populations is really important especially with Alzheimer's and Parkinson’s disease. There are a lot of papers coming out that there is a lot of population specific mutations so if we are not including those samples in the genetic analysis, we are never going to find that information". — Kimberley Billingsley

The Long-Read Sequencing team have already sequenced their first non-European cohorts and are now starting to look for these disease- and population-specific variants.

To find out more about this research you can also watch Kimberly’s full talk from London Calling 2023 below, where she goes into further detail about the project.

Watch all of the talks from London Calling 2023 here