Indirect Genetic Convergence Between Atrial Fibrillation and Alzheimer’s Disease via a Staged AF–VaNCD–ALZ Pathway: Multi-Tissue TWAS Evidence and Translational Implications

Atrial fibrillation (AF) is consistently associated with a higher risk of dementia, yet direct genetic overlap between AF and Alzheimer’s disease (AD) appears limited. In this study, we performed a multi-tissue transcriptome-wide association study (TWAS) using AF and AD summary statistics and tested them against 42 hypothesis-driven gene sets. These gene sets were selected to capture biological domains relevant to a proposed heart–brain pathway, including NAD+ metabolism, mitochondrial function, cellular senescence, apoptosis, complement activation, synaptic plasticity, glutamatergic signaling, and related cardiometabolic and neuroimmune processes. Across 84 meta-level tests, only eight reached permutation significance, suggesting that broad pathway-level convergence between AF and AD is selective rather than global. AF showed strong positive enrichment in NAD+/SIRT1 and mitochondrial programs, especially in cardiac tissues, whereas AD was dominated by complement activation and negative enrichment in senescence regulation. Cross-disease concordance was low, with approximately 75% of genes showing mixed or opposing directional effects between AF and AD. Integration with an independent Alzheimer’s disease–vascular neurocognitive disorder (ALZ–VaNCD) TWAS indicated that AF signals align most closely with a VaNCD-like vascular intermediate layer before converging on a shared long-term potentiation and synaptic plasticity node and secondarily engaging AD-enriched complement and senescence pathways. These results support an indirect four-stage model in which AF-related metabolic vulnerability contributes to vascular-metabolic stress, which then converges on synaptic failure and amplifies AD-like neuroimmune responses. This framework may support mechanism-based patient subtyping, staged biomarker panels, and enriched prevention trials, offering a precision-oriented approach to reducing AF-associated cognitive decline.