Spotlight on early-career researchers: a Neuronet interview with Alexander Neumann

In this Neuronet spotlight on early-career researcher interview, we speak with Alexander Neumann, who currently studies the genetics of Alzheimer’s disease biomarkers, by examining rare genetic variants obtained from whole exome sequencing at the University of Antwerp – VIB Center for Molecular Neurology (VIB CMN). We asked Alexander about his career, research, as well as about challenges & opportunities in his field.


What made you decide to follow a career in science?

I always liked science, but I got especially interested in the brain after watching the movie “The Matrix”, when I was 13 years old. Spoiler alert for a 23-year-old film: the premise of the movie is that humans live in a computer simulation nearly indistinguishable from reality, thanks to a brain-computer interface. This got me thinking about how the brain perceives and constructs reality. I googled “how does the brain work”, but soon realized, that there is much we do not know, so this is when I decided that I want to become a neuroscientist.


What excites you most about your work?

During my bachelor and master studies, I increasingly became interested in clinical topics, as well as genetics. The prospect of using research to understand different disorders and lessen suffering is very motivating. In addition, just figuring out something unknown is also exciting. e.g. finding, that a previously unrecognized genetic variant has an impact on Alzheimer’s disease. Even if in practice discoveries are typically small, iterative and require further confirmation by other researchers, it is nice to report, we did not know X and maybe we do now.


What is an exome-wide rare variant analysis?

We know that genetics are very important in the development of Alzheimer’s disease and we know of many genetic variants, which affect the disease. However, we have not identified most of the relevant variants, yet. Furthermore, the mechanisms by which these genes affect Alzheimer’s are very unclear as well. Genetic studies of Alzheimer’s disease biomarkers could be helpful in this regard, but are sparse.

In our study, we aimed to identify rare variants affecting Alzheimer’s disease biomarkers in cerebrospinal fluid. For each gene, we investigated, whether participants with rare alleles have higher or lower biomarker levels than participants with common alleles. By definition, few people in a study will carry a rare allele, which makes it very tricky to detect rare variants, which influence biomarker levels. We therefore focused on analysing rare variants within exomes of genes only, the part of the genome, which directly codes the protein sequence, as opposed to the more regulatory regions of the genome. This focus has several advantages, among others:

  1. Measuring only variants within exomes is cheaper, than measuring across the whole genome, which allows for a greater sample size and
  2. Variants within exomes tend to have larger, easier to detect, effects. In total we studied 9576 genes and 480 participants.


You recently published a scientific article as part of research, funded through the Innovative Medicines Initiative’s EMIF project.

What were your main findings?

Our main findings concern the biomarkers Neurofilament light chain and YKL-40. The presence of these proteins in cerebrospinal fluid indicates neuronal injury and inflammation, and levels are often elevated in Alzheimer’s disease patients.

We observed, that study participants with higher markers of neuronal injury and inflammation tended to also carry more often rare alleles in the following genes: IFFO1, DTNB, NLRC3 and SLC22A10. This suggests that having rare variants in these genes may make the brain more susceptible to injury and inflammation, which then may contribute to the development of Alzheimer’s disease.

Though note, while we observed a clear overall association between rare variants and biomarker levels, many participants also had rare alleles in these genes, but normal biomarker levels and no diagnosis, so the relationship is not 1:1.


What impact do you hope your work will have in the long run?

Research like this could contribute to the development of early prediction systems, which do not only indicate, whether an individual is at risk of developing Alzheimer’s but also by which mechanisms they are likely to develop it. This could be crucial information for prevention strategies. For example, two people may have the same high risk of developing the disease, but one may have genetic variants predisposing the formation of amyloid plaques, while another person may be more susceptible to inflammation. In the latter case amyloid-targeting drugs may not be effective and anti-inflammatory strategies should be pursued. This is all highly speculative at the moment, but I can imagine a future, where an individual could take a test, which assess common and rare genetic variants, environmental risk factors, lifestyle behaviours, other biological markers and receive personalized prevention recommendations like this.


What do you see as the key challenges & opportunities for your field?

Genetic studies of Alzheimer’s disease are steadily increasing in sample size, the first recently having included more than one million participants. However, we still have not identified most risk variants and the reliable estimation of all genetic risk effects will require even higher sample sizes. Beyond just increasing participant number, diversity in genetic ancestry needs to be increased as well. Genetic studies performed in European populations can only to a degree be generalized to other populations with e.g. African or Asian ancestry. In summary, we need bigger studies with more diverse populations.


What has been your experience of working as part of public-private partnership?

Collaborations like the EMIF-AD study, which includes many different research centres all over Europe, are crucial for Alzheimer’s disease research. They enable sufficient sample sizes to perform analyses, which go beyond diagnoses, and allow the investigation of different disease mechanisms. The partnership also provides easy access to expertise from different institutes and ensures the quality of research.


Selected papers:

This study focused on rare variants, but my colleagues were involved in a large GWAS identifying common variants contributing to Alzheimer’s disease. The paper will be published in Nature Genetics, but a preprint can be found on medRxiv: Bellenguez, Céline, et al. “New insights on the genetic etiology of Alzheimer’s and related dementia.” MedRxiv (2020).

Neumann A, Küçükali F, Bos I, et al. (2022) Rare variants in IFFO1, DTNB, NLRC3 and SLC22A10 associate with Alzheimer’s disease CSF profile of neuronal injury and inflammation. Molecular Psychiatry. DOI: 10.1038/s41380-022-01437-6.