Razavi, Ali, Hou, Jiahui, Lin, Shu-Ju, Zhang, Chunling, Kremen, William S., Fennema-Notestine, Christine, Elman, Jeremy, Holmans, Peter  ORCID: https://orcid.org/0000-0003-0870-9412, Faraone, Stephen V., Gaiteri, Chris, Hess, Jonathan L. and Glatt, Stephen J.
2026.
Predicted brain-regional gene expression patterns in individuals living with Alzheimer’s Disease.
Neurobiology of Aging
166
, pp. 29-40.
10.1016/j.neurobiolaging.2026.04.006
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Abstract
Studying brain gene expression in Alzheimer’s Disease (AD) remains difficult as postmortem brain is difficult to access, cannot be used to guide donor treatment, may be confounded by environmental factors before and after death, and is difficult to link to early AD states or disease progression. To circumvent these limitations, several studies have tested blood transcriptome biomarkers for AD. However, gene-expression levels in the blood have limited correlation with those in the brain. To evaluate the potential of monitoring Alzheimer’s progression with peripheral data, we used transcriptome-imputation to identify brain-region-specific AD-associated gene-expression differences in cohorts with blood-based transcriptome data. This approach provides a high-resolution image of AD-associated molecular differences in the brains of individuals actively living with disease. We analyzed eight AD studies (777 AD cases, 779 cognitively unimpaired controls), imputing transcriptomes in 10 brain regions via the Brain Gene Expression and Network Imputation Engine (BrainGENIE). Hundreds of differentially expressed genes (DEGs) associated with AD were identified in nine brain regions, with anterior cingulate cortex and amygdala showing the most differential expression. AD-associated genes were enriched in pathways such as proteostasis, mitochondrial dysfunction, and immune activation. We observed significant yet moderate concordance between imputed AD-associated changes and those directly measured in the dorsolateral prefrontal cortex and cerebellum. These transcriptomic changes can guide future in vitro studies focused on pathogenesis or be targets of novel therapeutic development. In conclusion, we demonstrated the scope and utility of brain expression imputation from the peripheral transcriptome, laying the groundwork for biomarker discovery and prospective AD studies.
| Item Type: | Article |
|---|---|
| Date Type: | Publication |
| Status: | Published |
| Schools: | Schools > Medicine |
| Publisher: | Elsevier |
| ISSN: | 0197-4580 |
| Date of Acceptance: | 27 April 2026 |
| Last Modified: | 02 Jun 2026 13:58 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/186931 |
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