Abstract Background Amyloid cardiomyopathy (ATTR-CM) is often underdiagnosed, with very few diagnosed before the onset of symptoms, leading to delayed use of disease-modifying therapies that could have substantial prognostic implications early in the disease course. In the US, the disease has a substantially higher prevalence among Black adults, who are further challenged by lower access to healthcare services and lower preventative care, further reducing the ability for clinician-led diagnosis. We sought to develop an approach for identifying ATTR-CM on noisy single-lead ECGs obtainable on portable and wearable ECG devices, allowing broad use in community screening. Purpose To develop a portable/wearable device-adapted AI-ECG algorithm capable of detecting ATTR-CM on noisy single-lead ECGs. Methods We identified patients with ATTR-CM from 2015 through June 2023 across 5 hospitals of a large U.S.-based hospital system using positive bone scintigraphy scans or pharmacotherapy with an approved transthyretin stabilizer. In the development cohort, we used lead I of 12 lead ECGs, commonly captured by portable and wearable ECG devices, to train a novel noise-adapted model explicitly designed to infer information against simulated real-world noises. For this, ECG signals were augmented using random Gaussian real-world noise within four frequency ranges at multiple signal-to-noise ratios. We tested the model in an independent set of cases and matched controls drawn from July through December 2023. Results The development cohort consisted of 1,011 ECGs from 234 patients (median age 79 years [IQR:70-85], 17% women), with 10:1 age- and sex-matched 10,110 controls with 10,110 ECGs (age 79 [IQR:70-85] years 17.7% female). In the independent test set of 139 ECGs from 47 patients (age 80 [75-86] years, 32% women) and matched controls (1390 ECGs and patients) from July through December 2023, the AUROC (area under the receiver operating characteristic curve) of the AI-ECG model for ATTR-CM was 0.90 [95%CI: 0.88-0.92] (A). The AUPRC was 0.44 [0.36-0.53]. The sensitivity and specificity of the model were 0.85 and 0.80. The positive predictive value ranged from 0.12 at a 3% prevalence level to 0.59 at a 25% prevalence (B). Conclusions A novel portable and wearable-devices adapted model demonstrates promising performance for detecting ATTR-CM on single-lead ECGs, representing a more accessible method for screening in community-dwelling adults.