Abstract
<title>Abstract</title> <p>Background Despite the potential of electroretinography (ERG), defined as the summed mass electrical activity of the retina, as a non-invasive biomarker of cognitive dysfunction, the lack of comprehensive synthesis and standardized evaluation of ERG modalities has limited its clinical translation as a reliable biomarker in Alzheimer’s Disease and related dementia (ADRD). This scoping review aimed to characterize the landscape of ERG and its clinical utility as a discriminant biomarker for ADRD in older adults and to identify gaps for future studies. Methods and findings Eight databases (Web of Science, Scopus, PubMed, Embase, Google Scholar, PsycINFO, CENTRAL, and ClinicalTrials.gov) were searched using controlled vocabulary and MESH terms without date or language restrictions. Retrieved articles were organized by databases and imported into covidence for screening by three independent team members with discrepancies resolved through discussion. Inclusion was limited to original research involving human participants aged ≥ 50 years and used ERG as a biomarker in ADRD and/or normal aging. Evidence was consolidated through adoption of the synthesis without meta-analysis (SWiM) framework. Of the 2,777 articles identified and screened, 25 were included. Most were comparative cross-sectional studies (n = 18) that utilized PERG (n = 14) non-portable ERG (n = 23). ffERG showed reduced a- and b-wave amplitudes, decreased PhNR/b-wave ratios, and prolonged implicit times, while PERG (P1, N1, P50, N95) and mfERG (N1, P1, N2) responses were consistently attenuated and delayed. Cognitive associations were modest and selective, with some studies reporting inverse relationships between ERG latencies, MMSE scores, and amyloid burden. Conclusion In conclusion, irrespective of ERG modality, ADRD was consistently associated with retinal dysfunction marked by impaired synaptic transmission and delayed neural processing across retinal circuits. These findings indicate both global and localized involvement of photoreceptor, bipolar, and retinal ganglion cell pathways, supporting the potential of ERG as a non-invasive, in vivo biomarker of retinal neurodegeneration. However, the modest and selective associations with cognitive outcomes suggest that ERG alterations, while reflective of underlying neurodegenerative processes, have limited direct correlation with cognitive severity. The current evidence base remains constrained by predominantly cross-sectional designs, small sample sizes, and the use of non-portable systems, limiting standardization and clinical translation. Nevertheless, emerging links with cognitive decline and amyloid pathology underscore the need for well-powered longitudinal and multimodal studies to clarify the clinical utility of ERG in ADRD.</p>