Rai_2026_Nat.Commun__

Alzheimer's disease (AD) remains a major unmet medical challenge, with limited tools that integrate early diagnosis and therapeutic intervention. Considering the pivotal roles of amyloid-beta (Abeta) and cholinesterases (ChEs) in AD etiology, we report dual-functional theranostic NIR-I probes. The lead candidate, I-43, exhibits favorable NIR optical properties (Stokes shift <= 220 nm) and binds strongly to Abeta fibrils, with K(d) values of 58.2 +/- 9.7 nM for Abeta(1-40) and 104 +/- 25 nM for Abeta(1-42). Histological staining of brain tissues from transgenic APP-PS1 mice and human autopsy samples confirms selective detection of Abeta plaques with a high signal-to-noise ratio and minimal cross-reactivity toward pathogenic tau tangles and alpha-synuclein. In addition, I-43 exhibits fluorescence response toward AChE, shows inhibitory activity (IC(50) = 0.38 microM), and enhances memory in a scopolamine-induced amnesia in Swiss albino mice. Despite this, limited aqueous solubility and metabolic stability necessitate structural modifications and formulation strategies to broaden the scope in preclinical studies. Herein, we demonstrate that probes can be engineered to label key AD biomarkers with ChEs inhibitory activity, paving the way to an alternate theranostic approach in AD management.