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To overcome this constraint, CNS-directed strategies often employ receptor-mediated transcytosis through engineered formats such as bispecific antibodies or brain-shuttle constructs targeting BBB receptors (e.g., TfR or insulin receptor) together with pathological targets such as A or tau, thereby improving brain delivery compared with conventional antibodies (Terstappen et al., 2021)

Instead of asking 'why not stack them,' the question becomes 'what specific outcome justifies adding a second compound with incomplete human safety data?' For research exploring maximal metabolic intervention where single-agent tirzepatide has plateaued, the stack may be defensible

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