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Basic Science and Pathogenesis
Hannah M Klinger1, Vaibhav A Janve2, Mabel Seto1,3
1Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 24, 2025
Summary
Whole blood gene expression in unimpaired older adults showed associations with cognitive decline, particularly when interacting with Alzheimer's disease biomarkers like Aβ-PET and p-tau217.
Area of Science:
- Neuroscience
- Genomics
- Biomarkers
Background:
- Bulk brain tissue studies link gene expression to Alzheimer's disease (AD) and cognitive decline.
- Previous findings focused on older adults and end-of-life changes.
- Identifying early AD biological pathways in accessible samples like blood is crucial.
Purpose of the Study:
- To identify whole blood transcriptomic signals associated with cognitive decline in clinically unimpaired older adults.
- To explore relationships between gene expression and in vivo AD phenotypes (Aβ-PET, p-tau217).
- To elucidate early biological pathways implicated in Alzheimer's disease.
Main Methods:
- Analyzed whole blood gene expression data from 1,737 participants in the A4 and LEARN studies.
- Used linear mixed-effects models to assess associations between gene expression and longitudinal cognitive performance (PACC).
- Investigated interactions between gene expression, sex, APOEε4 status, Aβ-PET burden, and p-tau217 levels, with FDR correction.
Main Results:
- No single gene transcript directly correlated with cognitive decline after FDR correction.
- 167 genes showed associations with cognition when interacting with biomarkers.
- Specific genes (e.g., ETF1P2, ZSCAN2) were linked to faster cognitive decline in individuals with high Aβ-PET burden, with some interactions involving sex and APOEε4.
Conclusions:
- Whole blood transcriptomic signals are associated with cognitive decline primarily through interactions with Alzheimer's disease biomarkers (Aβ-PET, p-tau217) and sex.
- These findings highlight the potential of blood-based gene expression for understanding early AD pathogenesis.
- Further research, including enrichment analysis and external validation, is needed to fully elucidate the involved biological pathways.
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