Cross-tissue omics-guided drug repurposing triangulates novel targetable mechanisms for Alzheimer's disease and candidate genetic biomarkers for treatment stratification.

White matter hyperintensities (WMH) are covert magnetic resonance imaging (MRI) - markers of microvascular dysfunction and are primary vascular contributors to dementia, emphasizing its importance in prevention strategies. Here, we integrate gene expression and protein levels measured across plasma, cerebrospinal fluid (CSF), brain and multiple other tissues from population-based and biobank-scale data to triangulate druggable genes influencing WMH-burden and Alzheimer's disease (AD) and to map their spatial localization specifically in brain-cell types. Lowering the expression levels of CALCRL, MAP3K11, PKN2 and EPHB4 shows putative causal associations with reduced WMH-burden, and AD risk. These targets of clinically approved drugs, enriched in key cell types of the neurovascular unit and exhibiting cell-type specific effects in peripheral CD4 + T cell subsets, are implicated in regulating neuroimmune interactions and amyloid-β homeostasis. Gene-drug interaction analysis identifies higher levels of GLTPD2 modifying the antidepressants associated increase in dementia risk contributing to a 73.3% risk reduction relative to the use of drugs. Furthermore, pharmagenic pathway studies identify the coagulation cascade as a targetable pathway associated with AD risk (HR: 2.23, 95% CI:1.85-2.69), providing orthogonal support to emerging therapies targeting coagulation components in treating neurodegenerative disorders.