Research Interests

Which brain cell types and genes are targeted by genetic risk variants for ageing-related brain conditions, from Alzheimer's disease to small vessel disease?

Most genetic risk variants for Alzheimer's disease lie outside genes, within cell type-specific regulatory elements called enhancers. We generated the first enhancer-promoter interactome maps for human brain cell types and showed that Alzheimer's risk variants are strongly enriched in microglia enhancers (Nott*, Holtman*, Coufal*, et al., Science 2019), building on nuclei isolation methods we developed to make rare brain cell types accessible to genomic and proteomic profiling, shared openly with the research community (Nott et al., Nat Protoc 2021).

We found that genetic risk across a range of ageing-related neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, multiple sclerosis and ALS, converges broadly on microglia, while the specific downstream genes and pathways affected are largely disease-specific (Askarova, Yaa, Marzi & Nott, PLOS Genetics 2025).

Not every ageing-related brain condition is driven by the same cell types, however. We generated cell type-resolved epigenomic maps of the human brain neurovascular unit and found that, in contrast to Alzheimer's disease, genetic susceptibility for cerebral small vessel disease is broadly enriched across vascular cell types, including endothelial cells, pericytes and astrocytes (Ziegler, Askarova, et al. & Nott, Neuron 2026). Together, this work is revealing how the cellular origins of genetic risk differ across ageing-related brain conditions, with direct implications for identifying the right cell types to target therapeutically.

Looking ahead, we are using single nuclei epigenomic approaches to look beyond the major brain cell types, examining additional rare cell types and subtypes to build a more complete picture of where genetic risk for ageing-related brain conditions acts.

How do vascular and immune cells contribute to the epigenetic basis of ageing-related brain conditions such as Alzheimer's disease and small vessel disease?

Vascular dysfunction is an early and tractable feature of Alzheimer's disease and the principal driver of cerebral small vessel disease. We generated the first cell type-resolved epigenomic maps of the human brain neurovascular unit, showing that Alzheimer's risk is predominantly immune-driven with a more modest vascular contribution, whereas small vessel disease risk is broadly enriched across vascular cell types including endothelial cells, pericytes and astrocytes (Ziegler, Askarova, et al. & Nott, Neuron 2026). Integrating this epigenomic evidence with chromatin architecture and gene expression data nominated genetically supported, repurposable drug candidates for dementia, including a vitamin D receptor agonist acting through microglia.

Despite this progress, we still have a limited understanding of how brain cell type epigenomes change in the context of disease. This is important for knowing the directionality of effect — that is, whether a change is a cause or a consequence of disease — so that these changes can ultimately be corrected therapeutically. Building on this, we are examining changes in vascular and immune cells in Alzheimer's disease and small vessel disease, in particular cerebral amyloid angiopathy (CAA) — a common but understudied small vessel pathology closely linked to Alzheimer's disease.

This approach will identify the transcriptional drivers, such as transcription factors, that underlie these disease-associated changes, which can then be targeted to correct or alter gene expression programmes. For example, we have identified a lysosomal-associated transcription factor as a key regulator of disease-associated changes in microglia. We aim to translate these gene regulatory discoveries into new and repurposed therapeutic targets for vascular and immune contributions to ageing-related brain conditions.

When during life do genetic risk factors for ageing-related brain conditions first become active, and can this reveal windows for early intervention?

Ageing is the single largest risk factor for dementia, yet how brain cell types change at the epigenomic level across a normal lifespan is largely unknown. Our prior work indicates that genetic susceptibility for ageing-related brain conditions can already be detected early in life: using brain tissue spanning paediatric and adult life stages, we found that genetic heritability for Alzheimer's disease is associated with microglia, whereas heritability for small vessel disease is associated with vascular cell types such as endothelial cells, pericytes and astrocytes (Ziegler, Askarova, et al. & Nott, Neuron 2026). This indicates that genetic susceptibility for these conditions can have an impact across the life course, well before disease onset.

This is the subject of ongoing work in the lab, where we are examining the epigenome of brain cell types across a human life course. Our goal is to identify genetic risk loci that are altered across life and intersect these findings with disease-associated epigenomic changes, to pinpoint inflection points where disease-associated changes emerge and whether they occur ahead of clinical symptoms — offering a potential window for early, targeted intervention.

We are extending this work to ask how oligodendrocytes and microglia communicate with one another across ageing and disease, to understand the gene regulatory programmes that underlie resilience versus dysfunction in Alzheimer's disease. As part of this, we are also looking at the oldest old, to understand the epigenetic basis of resilience to disease into extreme old age.