question: INTRODUCTION No large-scale characterizations of neurofilament light chain (NfL) have been conducted in diverse populations. METHODS Baseline data were analyzed among n = 890 Mexican Americans and n = 813 non-Hispanic Whites from the multi-ethnic Health & Aging Brain among Latino Elders (HABLE) study. Plasma NfL was measured on the Simoa platform. RESULTS In unadjusted models, NfL was significantly associated with age (P < .001), hypertension (P < .001), dyslipidemia (P = .02), and diabetes (P < .001). Covarying for age and sex, NfL was associated with neurodegeneration (P < .001) and global amyloid burden levels (P = .02) in a subset with available data. NfL levels were significantly associated with diagnostic groups (Normal Cognition [NC], mild cognitive impairment [MCI], Dementia; P < .001); however, there was no cut-score that yielded acceptable diagnostic accuracy. NfL levels produced a sensitivity of 0.60 and specificity of 0.78 with negative predictive value of 89% for detecting amyloid positivity. DISCUSSION Plasma NfL levels are significantly impacted by age and medical co-morbidities that are common among older adults, which complicate its utility as a diagnostic biomarker.