Effects of Multiple Neuropathologic Features and their Interactions on Cognitive Performance

Introduction: Dementia affects millions of Americans with symptoms such as impaired ability to recall, reason, or make decisions. While Alzheimer’s Disease (AD) accounts for most dementia cases, multiple neuropathologic features often coexist, complicating diagnosis and treatment. Recent studies have revealed the complexity of neuropathology with the majority of participants exhibiting multiple neuropathologic features, emphasizing the need for a thorough understanding of the association between individual and combinations of neuropathologic features on cognitive performance. This study aims to examine the individual and combined effects of Alzheimer’s disease neuropathologic change (ADNC), Lewy body disease (LBD), vascular brain injury (VBI), and limbic predominant, age related, TDP-43 encephalopathy (LATE) on cognitive performance. Methods: This study used longitudinal clinical visit data and autopsy results from 880 participants from the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS). A linear mixed effects model was used to investigate the effects of neuropathologic features on cognitive performance across four domains: episodic memory, attention/working memory, semantic memory/language, and executive function. Additionally, interactions between two neuropathologic features were analyzed to determine whether there is an additive effect on cognitive decline. Results: The rate of decline in overall cognitive performance was fastest among participants in the ADNC + LATE category (-0.46, 95% CI: -0.52, -0.41). The ADNC + LBD category had the fastest decline for attention/working memory (-0.11, CI: -0.14, -0.08), semantic memory/language (-0.19, CI: – 0.22, -0.15), and executive function domains (-0.25, CI: -0.30, -0.21). For the episodic memory domain, the fastest decline was seen in the LATE-only category (-0.08, CI: -0.11, -0.06). Less than additive effect was seen for most interactions between two neuropathologic features. The less than additive interaction between ADNC + VBI were all statistically significant across domains, along with ADNC + LATE for episodic memory. Discussion: Overall, the annual change in z-scores was generally greater for categories with multiple neuropathologic features compared to those with a single feature alone. Among the single neuropathologic features, ADNC had the greatest annual change in all domains except episodic memory, suggesting that ADNC contributes more to cognitive decline than the other neuropathologic features. The variety in trends across domains may also indicate that the effect of neuropathologic features on cognitive performance differ between cognitive domains. The analysis of interactions between ADNC and LBD, VBI, and LATE revealed that most combinations had a slower rate of decline than what would be expected if each neuropathologic feature contributed independently in an additive model. This indicates that the combined effects of these pathologies are not merely additive but involve more complex interactions. The findings highlight the complexity of analyzing the additive effects and their differential impacts on various cognitive domains. Given that the interactions vary between studies, it is crucial to consider multiple neuropathologic features when assessing cognitive decline and dementia.