AbstractBackgroundLewy body disease (LBD) is one of the most prevalent causes of dementia following Alzheimer’s disease (AD). Plasma neurofilament light chain (NfL) is a marker of neuroaxonal degeneration associated with cognitive decline in LBD, AD, and other neurodegenerative disorders. Neuropsychiatric symptoms are often present in both LBD and AD and can affect quality of life and cognitive performance. Therefore, we investigated whether the association between plasma NfL and cognition was moderated by the severity of neuropsychiatric symptoms in LBD and AD.MethodParticipants from the UCSD Shiley‐Marcos Alzheimer’s Disease Research Center with data for the informant‐reported Neuropsychiatric Inventory (NPI), plasma NfL, and AD and/or LBD neuropathology at autopsy were included (n = 204). General linear models examined whether the influence of neuropsychiatric symptoms on the association between plasma NfL and cognition at the last assessment prior to death varied by neuropathology. Participants with LBD only (n = 22), LBD+AD (n = 59) and AD only (n = 123) were included. Covariates included: age, education, sex, APOE ε4 carrier status, cognitive classification (unimpaired, MCI, or dementia), and time from last assessment to death. Given similar patterns of results for the LBD and LBD+AD pathology groups, they were combined for the final analyses. The Dementia Rating Scale (DRS) was used as the cognitive outcome measure.ResultThe three‐way NfL x NPI x pathology interaction was significant (p = .019, η p 2 = .029). In the LBD+AD group, neuropsychiatric symptoms moderated the relationship between plasma NfL and DRS total score (p = .013, η p 2 = .084) such that higher NPI scores had a more negative association between NfL and DRS (total score as well as attention, initiative/perseveration, and memory subscales). Although there was an association between NfL and DRS total score in the AD‐only group, this was not moderated by NPI score (p = .460, η p 2 = .005).ConclusionThese results highlight the importance of considering neuropsychiatric symptoms when examining the relationship between NfL and cognition, particularly in patients with suspected LBD pathology. Neuropsychiatric symptoms differ in LBD and AD, so future work will examine whether specific symptoms that are more prevalent in LBD, such as apathy, are driving the observed relationships.