In vivo-measured Lewy body pathology is associated with neuropsychiatric symptoms across the Alzheimer's disease continuum.

Intracellular alpha-synuclein aggregates, known as Lewy bodies (LB), are commonly observed in Alzheimer's disease (AD) dementia. Post-mortem studies have shown a higher frequency of neuropsychiatric symptoms among individuals with AD and LB co-pathology. However, the effects of in vivo-measured LB pathology on neuropsychiatric symptoms in AD remain underexplored. This study aimed to evaluate cross-sectional and longitudinal effects of in vivo-measured LB pathology on neuropsychiatric symptoms across the AD continuum. We analyzed data from 1,169 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Participants had in vivo measures of LB pathology (assessed using an alpha-synuclein seed amplification assay), amyloid-beta (Aβ) and phosphorylated tau (p-tau) levels in cerebrospinal fluid (CSF), and neuropsychiatric symptoms evaluated using the Neuropsychiatric Inventory-Questionnaire (NPI-Q). Logistic and Cox proportional hazards regression models were used to assess cross-sectional and longitudinal effects, respectively, adjusting for age, sex, and cognitive status. Participants had a mean baseline age of 73.05 (SD 7.22) years, 47.13% were women, 426 (36.44%) cognitively unimpaired, and 743 (63.56%) cognitively impaired. In cross-sectional analyses, LB pathology was associated with higher rates of anxiety, apathy, motor disturbances, and appetite disturbances. In longitudinal analyses, LB pathology increased the risk of developing psychosis and anxiety. These effects were independent of Aβ and p-tau. Our results suggest that in vivo-measured LB pathology is closely associated with neuropsychiatric symptoms across the AD continuum. These findings underscore the potential of in vivo LB detection as a marker for identifying individuals at increased risk of neuropsychiatric symptoms, both in clinical trials and in clinical practice.