Impact of Lewy body and limbic-predominant TDP-43 neuropathology on cognitive and neuropsychiatric trajectory in Alzheimer’s disease: a retrospective neuropathological study

Introduction: Alzheimer's disease (AD) is the leading cause of neurodegenerative dementia, and mixed neuropathological changes including Lewy body (LB-NC) and TDP-43 (LATE-NC) are commonly observed in patients with AD. We examined the baseline cross-sectional and longitudinal effects of these co-pathologies on cognitive and neuropsychiatric trajectories. Methods: We investigated 77 participants who had available autopsy data and showed intermediate to high levels of AD neuropathological change from the ADNI database. Participants were categorized based on the presence or absence of LB-NC or LATE-NC. The impact of LB-NC and LATE-NC on baseline and longitudinal clinical features was assessed using linear regression and linear mixed-effects models, respectively. Results: Thirty-eight (49.4%) had LB-NC, and 39 (50.6%) had LATE-NC. At baseline, the presence of LB-NC was not associated with cognitive function or neuropsychiatric symptoms, whereas the presence of LATE-NC was associated with better trail-making test performance and less severe sleep disturbance. Longitudinally, the presence of LB-NC was associated with faster cognitive decline in global cognitive function, memory, language, and executive function, whereas the presence of LATE-NC was associated with a slower decline in language function. Neither LB-NC nor LATE-NC influenced the longitudinal trajectory of neuropsychiatric symptoms. Conclusion: Among patients with pathologically confirmed AD, the presence of LB-NC accelerated cognitive decline, whereas the presence of LATE-NC was not associated with overall cognitive trajectories. Investigating comorbid pathologies is essential for prognostic stratification and the development of personalized therapeutic strategies in AD.