<p><b>IMPORTANCE: </b>Subjective cognitive decline (SCD) may be an early indicator of Alzheimer disease and related dementias (ADRD), yet its association with plasma biomarkers remains unclear among middle-aged and older adults (aged 50-86 years).</p><p><b>OBJECTIVE: </b>To examine associations between plasma biomarkers of amyloid, tau, neuroaxonal damage, and glial activation with SCD in a heterogeneous cohort of Hispanic and/or Latino adults.</p><p><b>DESIGN, SETTING, AND PARTICIPANTS: </b>This cross-sectional study used survey-weighted data from the Study of Latinos-Investigation of Neurocognitive Aging, an ancillary study of the Hispanic Community Health Study/Study of Latinos. Participants were aged 50 to 86 years and resided in 4 major US cities. Data were collected from 2016 to 2018 and analyzed between December 2024 and June 2025.</p><p><b>EXPOSURE: </b>Plasma biomarkers included amyloid-beta (Aβ42/40), phosphorylated tau-181 (ptau-181), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP), quantified using Simoa (Quanterix HD-X) and log-transformed (ln) to reduce skewness.</p><p><b>MAIN OUTCOMES AND MEASURES: </b>SCD was assessed using the short-form Everyday Cognition Scale (ECog-12), evaluating global-, executive-, and memory-related SCD, and a single-item cognitive concerns question. Survey-weighted linear and logistic regression models tested associations between biomarkers and SCD, adjusting for demographic, cardiovascular, kidney, and APOE genotype covariates.</p><p><b>RESULTS: </b>Among 5712 adults (mean [SD] age, 63.47 (8.15) years; unweighted 3663 [53.92%] female), higher ln(ptau-181) was associated with ECog-12 memory (unstandardized β = 0.088; 95% CI, 0.005-0.170). Higher ln(NfL) levels were associated with greater ECog-12 global (unstandardized β = 0.169; 95% CI, 0.074-0.265), executive (unstandardized β = 0.182; 95% CI, 0.087-0.277), and memory (unstandardized β = 0.156; 95% CI, 0.065-0.248) domains. Higher ln(GFAP) levels were associated with greater ECog-12 global (unstandardized β = 0.109; 95% CI, 0.019-0.198) and executive (unstandardized β = 0.121; 95% CI, 0.031-0.211) domains. Ln(Aβ42/40) was not associated with SCD domains. Cognitive concerns significantly modified the associations between ln(NfL) and ECog-12 domains, with more pronounced associations among those reporting cognitive concerns. No biomarkers were associated with the single-item cognitive concerns score.</p><p><b>CONCLUSIONS AND RELEVANCE: </b>In this study of middle-aged and older Hispanic and/or Latino adults, plasma biomarkers of p-tau181, NfL, and GFAP, but not Aβ42/40, were associated with greater SCD. These findings underscore their potential utility in early ADRD detection strategies.</p>