INTRODUCTION: The presence and interaction of multiple comorbid neuropathologies are a major contributor to the worldwide dementia burden. METHODS: We analyzed 1183 subjects from the National Alzheimer's Coordinating Center dataset with various combinations of isolated and mixed neurodegenerative pathologies and conducted mixed-effects multiple linear regression modeling to comprehensively compare the neurocognitive and neuropsychological trajectories between groups over time. RESULTS: In combination with Alzheimer's disease neuropathologic change, various combinations of limbic-predominant age-related transactive response DNA-binding protein 43 encephalopathy, Lewy body dementia, and cerebrovascular disease further impair global cognition and specific neurocognitive domains; however, they do not appear to extensively affect the rate of decline with time across these domains, suggesting an additive but not synergistic effect. DISCUSSION: These findings corroborate the known cumulative effects of mixed pathologies on cognition and add nuance to our understanding of their specific interactions, which is crucial for the development of biomarkers and effective therapeutics. HIGHLIGHTS: Mixed neurodegenerative pathologies are common in the elderly population. The most common neurodegenerative pathologies were Alzheimer's disease neuropathologic change (ADNC), cerebrovascular disease (CVD), Lewy body dementia (LBD), and limbic-predominant age-related transactive response DNA-binding protein 43 encephalopathy (LATE). The addition of various combinations of comorbid CVD, LBD, and LATE to ADNC worsened overall performance on cognitive and neuropsychological testing across time. In general, the addition of multiple comorbid neurodegenerative pathologies did not influence the rate of decline across the evaluated time period.