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Diagnostic pregnancy tests are the most widely used immunoassays for home-based use. These tests employ the well-established lateral flow assay (LFA) technique, reminiscent of affinity chromatography relying on the dual action of two orthogonal anti-hCG antibodies. Immunoassays suffer from several drawbacks, including challenges in antibody manufacturing, suboptimal accuracy, and sensitivity to adverse storing conditions. Additionally, LFAs are typically designed for single use, as the LFA technique is non-reusable. An alternative to overcome these drawbacks is to leverage molecularly imprinted polymer (MIP) technology to generate polymer-based hCG-receptors and, subsequently, non-bioreceptor-based tests. Here, we report the development of MIP nanogels for hCG detection, exploiting epitopes and magnetic templates for high-yielding dispersed phase imprinting. The resulting nanogels were designed for orthogonal targeting of two immunogenic epitopes (SV and PQ) and were thoroughly characterized with respect to physical properties, binding affinity, specificity, and sensitivity. Molecular dynamics simulations indicated a pronounced conformational overlap between the templates and the epitopes in the native protein, supporting their suitability for templating cavities for hCG recognition. Quartz crystal microbalance (QCM)-based binding tests and kinetic interaction analysis by surface plasmon resonance (SPR) revealed nanomolar dissociation constants for the MIP nanogels and their corresponding template peptides and low uptake of lutenizing hormone (LH), structurally resembling to hCG. Receptor reusability was demonstrated in the multicycle SPR sensing mode using a low pH regeneration buffer. The results suggest the feasibility of using imprinted nanogels as a class of cost-effective, stable alternatives to natural antibodies for hCG detection. We foresee applications of these binders with respect to reusable pregnancy tests and other hCG-related disease diagnostics.

INTRODUCTION We examined the relations of misfolded alpha synuclein (α‐synuclein) with Alzheimer's disease (AD) biomarkers in two large independent cohorts. METHODS We included Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably Two (BioFINDER‐2) and Alzheimer's Disease Neuroimaging Initiative (ADNI) participants (n = 2315, cognitively unimpaired, mild cognitive impairment, AD dementia) who had cross‐sectional cerebrospinal fluid (CSF) α‐synuclein measurement from seed‐amplification assay as well as cross‐sectional and longitudinal amyloid beta (Aβ) and tau levels (measured in CSF and/or by positron emission tomography). All analyses were adjusted for age, sex, and cognitive status. RESULTS Across cohorts, the main biomarker associated with α‐synuclein positivity at baseline was higher levels of Aβ pathology (all p values ≤ 0.02), but not tau. Looking at longitudinal measures of AD biomarkers, α‐synuclein –positive participants had a statistically significant faster increase of Aβ load, although of modest magnitude (1.11 Centiloid/year, p = 0.02), compared to α‐synuclein –negative participants in BioFINDER‐2 but not in ADNI. DISCUSSION We showed associations between concurrent misfolded α‐synuclein and Aβ levels, providing in vivo evidence of links between these two molecular disease pathways in humans. Highlights: Amyloid beta (Aβ), but not tau, was associated with alpha‐synuclein (α‐synuclein) positivity. Such association was consistent across two cohorts, beyond the effect of age, sex, and cognitive status. α‐synuclein–positive participants had a small, statistically significant faster increase in Aβ positron emission tomography levels in one of the two cohorts.