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DNA Methylation Concordance Between Fresh-Frozen and Formalin-Fixed Paraffin-Embedded Human Brain Tissue in Neurodegenerative Diseases
Abbas M, Villareal JAB, Zhang Y, Ebrahimi E, Deaton L, Holliday LS, Chen L, Prokop S et al.. Preprints.org, 2026-09-24
Topic: Genetics and APOE
Formalin-fixed, paraffin-embedded (FFPE) brain tissue is a major archival resource, yet its suitability for high-density DNA methylation profiling is limited by fixation-induced DNA fragmentation and crosslinking. Fresh-frozen (FF) tissue is the gold standard, but its availability is limited, especially for neurodegenerative diseases. DNA methylation was profiled using the Illumina Infinium MethylationEPIC v2 array on paired FFPE and FF brain tissue from 26 donors with neurodegenerative disease (Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, or mixed pathology). After quality control, 50 samples remained, including 24 FFPE–FF pairs (6 matched cortical regions, 18 unmatched regions). Concordance was assessed using Pearson correlations of M-values. Variation across samples was evaluated by Principal Component Analysis (PCA) of the 10,000 most variable CpG sites. Cell-type compositions were estimated using the HiBED R package to deconvolute bulk methylation profiles. FFPE and FF samples showed high concordance (median Pearson r = 0.86). Matched-region pairs had higher correlations (median Pearson r = 0.93) than unmatched-region pairs (p < 0.001. PCA suggested that the preservation method was a major driver of variation, with PC1 explaining 24.2–48.5% of the variance, while PC2 captured additional variation (6.7–14.3%). FFPE samples had higher QC failure rates (26.5% vs. 0%) and elevated probe dropout. Preservation significantly affected cell-type composition, including astrocytes, GABAergic neurons, endothelial cells, and oligodendrocytes (FDR < 0.05), whereas diagnosis had no effect (FDR 0.81–0.98). Overall, FFPE brain tissue showed concordance with FF tissue on the EPIC v2 array. These findings support the use of FFPE brain samples for epigenome-wide association studies, particularly when fresh-frozen cohorts are unavailable. Investigators should account for preservation-related variance, and anatomical matching is recommended.
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APA 7th
Abbas, M., Villareal, J. A. B., Zhang, Y., Ebrahimi, E., Deaton, L., Holliday, L. S., et al. (2026). DNA Methylation Concordance Between Fresh-Frozen and Formalin-Fixed Paraffin-Embedded Human Brain Tissue in Neurodegenerative Diseases. Preprints.org. https://doi.org/10.20944/preprints202609.2166.v1
Vancouver
Abbas M, Villareal JAB, Zhang Y, Ebrahimi E, Deaton L, Holliday LS, et al. DNA Methylation Concordance Between Fresh-Frozen and Formalin-Fixed Paraffin-Embedded Human Brain Tissue in Neurodegenerative Diseases. Preprints.org. 2026. doi:10.20944/preprints202609.2166.v1.
BibTeX
@article{abbas2026-0316398d,
author = {Abbas, M. and Villareal, J. A. B. and Zhang, Y. and Ebrahimi, E. and Deaton, L. and Holliday, L. S. and Chen, L. and Prokop, S. and others},
title = {{DNA Methylation Concordance Between Fresh-Frozen and Formalin-Fixed Paraffin-Embedded Human Brain Tissue in Neurodegenerative Diseases}},
journal = {Preprints.org},
year = {2026},
doi = {10.20944/preprints202609.2166.v1},
url = {https://doi.org/10.20944/preprints202609.2166.v1}
}
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Key findings
- PCA suggested that the preservation method was a major driver of variation, with PC1 explaining 24.2–48.5% of the variance, while PC2 captured additional variation (6.7–14.3%).
- Preservation significantly affected cell-type composition, including astrocytes, GABAergic neurons, endothelial cells, and oligodendrocytes (FDR < 0.05), whereas diagnosis had no effect (FDR 0.81–0.98).
- Overall, FFPE brain tissue showed concordance with FF tissue on the EPIC v2 array.
- These findings support the use of FFPE brain samples for epigenome-wide association studies, particularly when fresh-frozen cohorts are unavailable.
Study details
- Effect size48.5%; 14.3%; 26.5%
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 24 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, sample size, studied in people and randomised / blinded because the record does not state it. We have no data on times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 15 of the 62 points we could judge it on, which is 24 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (Preprints.org) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 2 / 3 | Effect reported as a number, without an interval or test |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 15 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 15 of the 62 points we could judge it on is 24 out of 100. |
| Total | 24 / 100 | Capped to 16 because this is not a peer-reviewed article. |
What each of these 20 components measures, and what this score is not →
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