Transcriptome-Wide Association Analysis Reveals Shared Synaptic Plasticity and Divergent Aging Mechanisms in Alzheimer’s Disease and Vascular Dementia

Alzheimer’s disease and vascular dementia often overlap clinically and neuropathologically, but their genetic architectures have rarely been compared directly at the pathway level. In this study, transcriptome-wide association analysis was applied to summary statistics from the largest available Alzheimer’s disease genome-wide association study and a 2026 vascular neurocognitive disorder meta-analysis. The resulting gene-level signals were tested for enrichment across 42 curated gene sets covering cellular senescence, mitochondrial function, synaptic plasticity, telomere maintenance, GLP-1/insulin signaling, NAD metabolism, apoptosis, immune function, glial biology, and related pathways. Across 84 gene-set by disease tests, six reached permutation significance. Long-term potentiation was enriched in both Alzheimer’s disease and vascular neurocognitive disorder, with Stouffer Z values of +5.27 and +4.73, respectively, suggesting a shared vulnerability of synaptic plasticity. Alzheimer’s disease also showed negative enrichment for regulation of cellular senescence, with Stouffer Z = −5.83, and oxidative phosphorylation, with Stouffer Z = −4.80, driven by genes including YPEL3 and NDUFS2. Vascular neurocognitive disorder showed positive enrichment for telomere maintenance, with Stouffer Z = +4.25, and PI3K–AKT–mTOR signaling, with Stouffer Z = +3.88, led by genes such as POT1, RPA1, and PIKFYVE. Concordance at the gene level within shared pathways was modest, while several large-effect loci, including CR1, CLU, and TREM2, were disproportionately associated with Alzheimer’s disease. These findings point to convergence on synaptic failure, alongside disease-specific aging and stress-response liabilities. The results should be interpreted as hypothesis-generating and may help define molecular subtypes for future biomarker and therapeutic stratification studies.