Beyond the streetlight: a TREAT-AD perspective on where to find new Alzheimer's targets.

Despite extensive investments in Alzheimer's disease (AD) therapeutic development, progress toward effective interventions remains modest. The landscape of potential novel therapeutic strategies is rapidly growing, but prioritization, validation, and tools to advance targets to trial are lagging. The Target Enablement to Accelerate Therapy Development for Alzheimer's Disease (TREAT-AD) consortium has integrated systems-level data from large-scale studies profiling thousands of human brains, yielding target-specific risk scores that partition disease risk into discrete biological domains and enable data-driven target interrogation. Here, we compared clinical trial targets with top-ranked TREAT-AD targets and found a limited overlap as well as differences in the biology emphasized by each set. The current AD therapeutic development landscape remains largely under the "streetlight" of familiar biology, while unbiased measures of disease risk point toward other disease-associated processes that remain comparatively underexplored. These findings underscore opportunities to more deliberately diversify therapeutic portfolios and complement existing development efforts with evidence derived from unbiased human data. HIGHLIGHTS: Clinical AD trials remain focused on well-characterized biology. TREAT-AD integrates genetic and multi-omic data to prioritize novel targets. Limited overlap exists between clinical and high-risk data-driven targets. Risk-associated targets uniquely implicate mitochondrial, lipid, and other pathways. Advancing "dark" targets is critical to diversify AD therapeutic strategies.