Alzheimer’s Disease PhD: Editing Brain-Cell DNA Marks to Study Disease Risk

Alzheimer’s Disease PhD: Editing Brain-Cell DNA Marks to Study Disease Risk

Quick Decision

The project aims to connect cell-type-specific DNA-methylation, ATAC-seq and H3K27ac maps from human brain with Alzheimer’s-risk loci, then test selected regulatory regions through CRISPR epigenome editing and cellular readouts. The early focus is microglia, making this a genetics-to-function project in neural-cell models. Its main feasibility risk is that the editing methods are still being optimized; clarify what works in the intended model, the milestones and fallback experiments. official project description Exeter award ref. 6025 initiative fee policy

Research Problem and Doctoral Work

What remains unsolved

Alzheimer’s disease (AD) is associated with epigenetic changes across several brain-cell types. The project asks whether some of these changes fall within regulatory elements and actually affect gene regulation or cell behaviour. A DNA-methylation association in post-mortem tissue does not by itself show that the change caused disease: it may reflect pathology, aging or altered cell composition. Cell specificity matters because a regulatory element active in microglia may not be active in neurons.

Recent work underlines the problem. An Exeter-associated meta-analysis integrated AD epigenome-wide association studies across cortex. A 2025 Exeter-team analysis identified a replicated neuronal/synaptic DNA co-methylation module in AD with psychosis. A 2026 study with a final analysis set of 826 post-mortem samples reported two reproducible epigenomic subtypes with distinct cell-specific and microglial signatures. These studies motivate moving beyond bulk association and nearest-gene annotation; they do not establish that any single methylation change is causal. (2021 AD EWAS meta-analysis, 2025 co-methylation study, 2026 epigenomic subtypes, 2025 field review)

Advertised doctoral work

The official project description sets out three linked objectives:

1. Prioritize candidate regulatory loci. Integrate existing cell-type-specific post-mortem brain DNA methylation, chromatin accessibility (ATAC-seq) and H3K27ac data from the Exeter AD EWAS. Combine these with available gene-expression, genetic-association and regulatory-annotation data to identify loci in active promoters or enhancers and infer likely target genes, rather than defaulting to the nearest gene.
2. Perturb selected loci. Use catalytically inactive Cas9 (dCas9) fused to DNA-methylation, demethylation or chromatin-remodelling enzymes to induce or reverse disease-associated epigenetic states. Proposed models include relevant cell lines and hiPSC-derived cortical neurons or microglia. Initial studies will focus on microglia, with neuronal or other glial work guided by computational results.
3. Measure consequences. Confirm editing, for example with bisulfite pyrosequencing, then examine gene expression and cellular phenotypes. For the strongest candidates, the team may add transcriptomic, methylomic or chromatin-accessibility profiling to study changes in regulatory networks and cell state.

This is targeted epigenome editing, not simply gene knockout. The description says initial analyses will let the student help shape which loci, cell types and pathways proceed to experiments. It does not name a fixed target list, number of loci or guaranteed output. (official project description)

The project-linked 2026 FANS paper describes optimized workflows for isolating brain-cell nuclei for downstream multi-omic assays. A separate 2026 study by the Cambridge-linked team used CRISPR-engineered isogenic hiPSC lines to test an AD-associated PTK2B variant in macrophages and microglia. It linked the risk allele to altered chromatin accessibility and CEBPB binding, with chemokine and migration phenotypes; effects on PTK2B/CLU expression were modest and not fully resolved. That study supports the plausibility of functional testing in these models, but edits a DNA sequence variant rather than the epigenetic state proposed here. (2026 FANS study, 2026 PTK2B study)

Feasibility and research angles

The project starts from existing cell-type-resolved data and an established Exeter FANS/epigenomics pipeline, reducing dependence on building the discovery dataset from scratch. A defensible research angle is to require converging evidence before editing a locus: disease association in the relevant cell type, active chromatin marks, plausible links to a target gene, and consistency with expression or genetic evidence. The exact data available and ranking rules should be discussed with the team.

The main technical risk is platform readiness. The project says the supervisory team is still optimizing its CRISPR epigenome-editing methods through an innovation-and-collaboration award. Success may depend on delivery, editing efficiency, locus choice and cell-model state. A 2025 pooled CRISPR microglia protocol and related QTL-screening work show active development of iPSC-microglia tools in the wider network, but knockout screens do not prove a targeted epigenetic editor works at the chosen locus. The QTL/CRISPR manuscript cited in the project is a preprint and should be treated as preliminary. (Washer et al., 2025 microglia CRISPR protocol, project-cited pooled QTL/CRISPR preprint)

Post-mortem associations can reflect consequences of disease, aging or cell-composition differences. hiPSC-derived neurons and microglia also do not fully reproduce mature adult brain tissue. Ask about donor cohorts, sample counts, model provenance, non-targeting and editing controls, off-target checks, and plans for a weak or unsuccessful perturbation. The scientific value lies in testing the regulatory function of disease-associated marks, not in a guarantee that every candidate will yield a clear mechanism.

School, Programme and Field Context

The project PDF names Clinical and Biomedical Sciences as the department and the University of Exeter as primary institution. Exeter’s research-degree page lists an MPhil/PhD in Clinical and Biomedical Sciences, with full-time and part-time modes, and identifies neurodegeneration, complex disease epigenetics, genomics and data science among relevant areas. The department describes research in neurodegeneration, genomic/epigenomic variation, functional genomics and reproducible data science; its facilities include genetics, single-cell omics, bio-imaging and flow cytometry. These areas align with the planned work, but do not prove reserved access to any specific instrument, cohort or partner facility. (project PDF, Clinical and Biomedical Sciences PGR route, department research themes, Exeter dementia research)

Exeter lists 136th overall in QS World University Rankings 2027 and =157 overall in THE 2027. Its Clinical and Biomedical Sciences PGR page separately reports top-125 placement in Life Sciences and top-175 in Medical and Health in THE World University Rankings 2026. In REF 2021, Exeter’s Clinical Medicine unit (UoA 1) was assessed as 45% 4-star and 48% 3-star. These are institution- or unit-level indicators, not ratings of this lab or doctoral project. (Exeter rankings, REF 2021 results, Clinical and Biomedical Sciences PGR page)

The FGx-DLA is a national four-year programme with cross-institutional training and a cohort network. Exeter is the listed primary institution; Oxford and Cambridge are described as sources of hiPSC neurodegeneration models and editing expertise. Their participation does not establish joint registration, a dual degree or a fixed placement. The offer should identify the registration route, expected base and any partner-site work. (Exeter FGx-DLA programme, UK Human Functional Genomics Initiative)

Supervisor and Lab Assessment

Research directions and team roles

Emma Dempster is the named lead supervisor. Her Exeter profile describes work on regulatory genomic variation in brain disorders, CRISPR-based epigenomic methods and regulatory profiling in discrete cell populations from post-mortem brain. Jonathan Mill is Professor of Epigenomics at Exeter and leads the Complex Disease Epigenomics Group. These areas directly match the advertised data and experimental direction. (Emma Dempster profile, Jonathan Mill profile)

The project names Sam Washer at Oxford in connection with hiPSC-derived neurodegeneration models and microglial expertise. His Oxford profile focuses on functional genomics and CRISPR screening in iPSC-derived microglia. Erica Bello at Cambridge is Head of Target Discovery at the Milner Therapeutics Institute and works on complex disease models, functional genomics and gene editing. This is a relevant collaboration network, but only Dempster is explicitly identified as lead; the co-supervision split and partner-campus arrangements are not public. (Sam Washer profile, Erica Bello profile)

Recent relevant work

• Chioza et al. (2026), PLOS ONE: optimized FANS workflows for human and mouse brain-cell nuclei and showed compatibility with DNA/histone modifications, chromatin accessibility and gene-expression assays. Dempster and Mill are co-authors. This supports the cell-specific assay foundation, but does not establish which AD datasets are used or whether they have matching sample numbers and permissions. (paper)
• Bello et al. (2026), iScience: engineered an AD-associated PTK2B allele in hiPSCs and assessed macrophage/microglial chromatin, transcription and phenotypes. It offers a relevant example of linking human risk signals to cell function, while showing limits: target-gene expression changes were modest, and PTK2B versus CLU attribution remained uncertain. (paper)
• Washer et al. (2025), STAR Protocols: published a pooled FACS-based CRISPR knockout-screening protocol in human iPSC-derived microglia. This is relevant platform and model experience, but it is a knockout protocol, not the targeted epigenome-editing workflow proposed here. (protocol)
• Laroche et al. (2026), Acta Neuropathologica: analysed three post-mortem cohorts with a final N=826 (835 samples initially; eight UKBBN samples were excluded for quality control and one sample for a sex mismatch) and identified two AD epigenomic subtypes with distinct microglial and other cell-type patterns; Exeter researcher Katie Lunnon is a co-author. It highlights disease and cell-type heterogeneity that can affect locus choice. (paper)
• Kouhsar et al. (2025), Alzheimer’s & Dementia: used discovery and validation cohorts to identify a replicated neuronal/synaptic co-methylation module associated with psychosis in AD; Jonathan Mill and Katie Lunnon are co-authors. This shows recent Exeter activity in brain DNA methylation but addresses a distinct subgroup. (paper)
• Weymouth, Smith and Lunnon (2025): review human-brain and purified-cell methylation evidence and discuss multi-omic integration and methodological gaps. This is a field synthesis rather than primary experimental evidence. (review)

Funding, Application, and Living Cost

The Exeter 2027 FGx-DLA round is open for September 2027 entry and closes Tuesday 5 January 2027. Scheme terms describe four-year studentships with fees and a stipend at UK Research Council rates, plus up to £5,000 per year for research training and support. The current UKRI minimum is £21,805 for 2026/27, about £1,817 per month across a year; the fee level is £5,238. Treat these as current reference figures, not a promise of the 2027/28 rate.

The project seed describes Home tuition fees and a stipend, while the current Exeter scheme page describes fees and stipend under the award. The national initiative specifically states that Exeter students need not supplement UKRI funding for international fee differences. Confirm that the eventual offer reflects this policy and the right annual rates. The £5,000 support budget covers research/training costs, not extra personal maintenance. (Exeter award ref. 6025, Exeter FGx-DLA funding page, international fee policy, UKRI stipend and fee rates)

Exeter estimates a single student’s basic living costs at £1,300–£2,000 per month, based on local averages in April 2026. At the current stipend, the nominal monthly amount is about £1,817: above the low end and below the high end of that range. Housing choice and setup costs will drive much of the difference. The Student visa financial-evidence requirement outside London is currently £1,171 per month for up to nine months; this is a legal proof threshold, not a cost estimate. (Exeter budgeting estimate, Student visa financial requirement)

Application conditions

• Submit one Exeter application and the FGx-DLA questionnaire. The questionnaire allows up to three project preferences, and only one application per person is accepted.
• Minimum academic criterion: relevant 2:1 Honours degree or international equivalent. Listed areas include genetics, molecular biology, biomedical science, human biology, biochemistry, medicine/healthcare, bioinformatics, computer science and statistics.
• English-language criterion is typically IELTS 7.0 overall with no component below 6.5, or equivalent. Evidence must be supplied by the deadline.
• Two references are required; referees should not be from the prospective supervisory team. If shortlisted, the applicant must arrange for academic references to be emailed from institutional accounts seven days before interview.
• Documents must be in English; certified translations of academic qualifications are required. The questionnaire asks about motivation and aspirations, a meaningful achievement, learning from research experience, and any use of generative AI in preparing the application.
• The project is advertised full-time. The scheme page mentions part-time study at programme level; confirm whether it applies to this specific place.

The advert does not state a cutoff hour or time zone, project-specific proposal requirement, interview dates or supervisor meeting schedule. Listed techniques are training areas, not all formal entry prerequisites. (application and eligibility details, award details)

Applicant Fit and Preparation

Required background and skills

Formal entry requires a relevant 2:1 or equivalent plus the programme’s English-language threshold. Accepted disciplines span experimental biomedical subjects and quantitative fields. The project combines computational prioritization and laboratory validation, so the strongest match is likely someone willing to work across both sides.

Preferred experience and suggested preparation

The project does not publish a separate preferred-skill list. Useful preparation may include genomic/epigenomic analysis, reproducible coding or statistics, cell culture, CRISPR methods, human genetics, neurobiology or immunology. These are suggested areas, not extra formal requirements. Applicants can draw on coursework, research projects, placements or professional experience; explain their own role, reasoning, controls and learning.

A useful questionnaire response could connect prior experience to a concrete transition from cell-specific association to a testable locus and then to interpreting a weak or context-dependent perturbation. This is preparation advice, not an admission condition.

Career directions could include academic neurogenomics/epigenomics, functional-genomics platforms, biotechnology, translational research or data-focused life-science roles. Skills England’s 2026 assessment projects 66,000 additional jobs in life-science priority occupations between 2025 and 2035, but also gives a much lower alternative scenario and explicitly warns that the projections are uncertain. NHS genomics bioinformatics is a related pathway combining biology, computing and clinical work; it has separate training/registration requirements, so this PhD alone would not confer clinical-scientist registration. (Skills England life-sciences assessment, Life Sciences Jobs Plan, NHS clinical bioinformatics career path)

Next Actions and Questions to Verify

Before applying

1. Ask the lead which cohorts and cell-type datasets are available, including sample counts, access approvals and quality checks.
2. Ask which editing platform is in optimization, whether the initial microglia model is operational, and what fallback work is planned if editing efficiency or phenotype readouts are weak.
3. Confirm that Exeter’s current international-fee policy will be reflected in the offer; ask for the 2027/28 stipend and any exclusions.
4. Confirm the exact portal checklist and deadline time zone. Prepare two suitable referees outside the supervisory team and certified translations early.

At interview

• How will loci be ranked before experiments, and what evidence is sufficient to select one?
• What are the non-targeting and positive controls, editing-efficiency threshold, off-target checks and rescue strategy?
• What balance is expected between computational analysis, cell culture and editing?
• Who will supervise each workstream, where will models/editors be used, and how often will the full team meet?

Before accepting an offer

Confirm the degree title and registration institution, base campus, any Oxford/Cambridge travel, data-access permissions, fee/stipend terms, how the annual £5,000 support is administered, and the project timetable if platform optimization is delayed.

Evidence and Sources

Project and programme

• Official project description and named lead
• Award reference 6025 and 2027 funding round
• Exeter MRC FGx-DLA programme, eligibility and application
• National programme and international fee policy
• UKRI 2026/27 stipend and fee levels

School, department and supervisors

• Clinical and Biomedical Sciences research degrees
• Department research themes and facilities
• Exeter dementia research environment
• Exeter rankings
• REF 2021 results
• Emma Dempster
• Jonathan Mill
• Sam Washer
• Erica Bello

Papers and field

• FANS for cell-type-specific cortical epigenomics (2026)
• PTK2B regulatory variant and microglial function (2026)
• Pooled CRISPR screening protocol in human iPSC microglia (2025)
• AD epigenomic subtypes and microglial signatures (2026)
• DNA co-methylation in AD with psychosis (2025)
• AD EWAS meta-analysis across cortex (2021)
• DNA methylation in Alzheimer’s disease review (2025)
• Pooled iPSC-microglia QTL/CRISPR work cited by the project (preprint)

Costs and career context

• Exeter living-cost estimate
• Student visa financial-evidence threshold
• Skills England life-sciences assessment (2026)
• Life Sciences Jobs Plan
• NHS clinical bioinformatics (genomics) career path