Integrated Multi-Tissue Transcriptomics Reveals Antagonistic Pleiotropy in Aging and Alzheimer's Disease

Aging is the strongest risk factor for Alzheimer's disease (AD); however, some individuals age without major cognitive decline, suggesting that resilience and vulnerability may be associated with distinct molecular trajectories. To investigate these trajectories, we performed an integrated transcriptomic analysis of human dermal fibroblasts (GSE113957) and multi-region brain profiles (GSE48350), extending previous dataset-specific studies that focused primarily on age prediction, regional variation, or synaptic/immune signatures. Healthy aging and AD were compared within a novel antagonistic pleiotropy (AP) framework. This approach prioritized genes and candidate transcriptional regulators with opposing age and disease-associated expression patterns. Across tissues, healthy aging was associated with relative preservation of metabolic, mitochondrial, and lipid-homeostatic programs, whereas AD was associated with suppression of these programs alongside greater inflammatory and immune pathway activity. AP-Vulnerability genes (Age↓/AD↑), including TAC1, FREM3, and SLC25A46, declined with age but were induced in AD. Conversely, AP-Resilience genes (Age↑/AD↓), including PTH2, PPDPF, and NEFH, increased during healthy aging but were reduced in AD. Pathway analyses suggested an association between metabolic programs and resilience, and between immune activation and vulnerability. Transcription-factor inference prioritized PPARG, NFE2L2, and TEAD4 as candidate resilience-associated regulators, showing directionally opposite patterns relative to immune- and developmental-related regulators in AD.