Neurodegenerative pathologies such as Alzheimer disease neuropathologic change (ADNC), Lewy body disease (LBD), limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and cerebrovascular disease (CVD) frequently coexist, but little is known about the exact contribution of each pathology to cognitive decline and dementia in subjects with mixed pathologies. We explored the relative cognitive impact of concurrent common and rare neurodegenerative pathologies employing multivariate logistic regression analysis adjusted for age, gender, and level of education. We analyzed a cohort of 6,262 subjects from the National Alzheimer’s Coordinating Center database, ranging from 0 to 6 comorbid neuropathologic findings per individual, where 95.7% of individuals had at least 1 neurodegenerative finding at autopsy and 75.5% had at least 2 neurodegenerative findings. We identified which neuropathologic entities correlate most frequently with one another and demonstrated that the total number of pathologies per individual was directly correlated with cognitive performance as assessed by Clinical Dementia Rating (CDR®) and Mini-Mental State Examination (MMSE). We show that ADNC, LBD, LATE-NC, CVD, hippocampal sclerosis, Pick disease, and FTLD-TDP significantly impact overall cognition as independent variables. More specifically, ADNC significantly affected all assessed cognitive domains, LBD affected attention, processing speed, and language, LATE-NC primarily affected tests related to logical memory and language, while CVD and other less common pathologies (including Pick disease, progressive supranuclear palsy, and corticobasal degeneration) had more variable neurocognitive effects. Additionally, ADNC, LBD, and higher numbers of comorbid neuropathologies were associated with the presence of at least one APOE ε4 allele, and ADNC and higher numbers of neuropathologies were inversely correlated with APOE ε2 alleles. Understanding the mechanisms by which individual and concomitant neuropathologies affect cognition and the degree to which each contributes is an imperative step in the development of biomarkers and disease-modifying therapeutics, particularly as these medical interventions become more targeted and personalized.

神经退行性病变，如阿尔茨海默病神经病理改变 (ADNC)、路易体病 (LBD)、边缘主导的年龄相关 TDP-43 脑病神经病理改变 (LATE-NC) 和脑血管疾病 (CVD) 经常共存，但人们知之甚少关于每种病理对混合病理受试者认知能力下降和痴呆的确切贡献。我们采用根据年龄、性别和教育水平进行调整的多元逻辑回归分析，探讨了并发常见和罕见神经退行性疾病的相对认知影响。我们分析了来自国家阿尔茨海默病协调中心数据库的 6,262 名受试者队列，每个人有 0 到 6 种共病神经病理学发现，其中 95.7% 的个体在尸检时有至少 1 种神经退行性发现，75.5% 的人有至少 2 种神经退行性发现。我们确定了哪些神经病理实体之间最常相关，并证明每个人的病理总数与通过临床痴呆评级 (CDR®) 和简易精神状态检查 (MMSE) 评估的认知表现直接相关。我们发现 ADNC、LBD、LATE-NC、CVD、海马硬化、Pick 病和 FTLD-TDP 作为自变量显着影响整体认知。更具体地说，ADNC 显着影响所有评估的认知领域，LBD 影响注意力、处理速度和语言，LATE-NC 主要影响与逻辑记忆和语言相关的测试，而 CVD 和其他不太常见的病理（包括皮克病、进行性核上性麻痹、和皮质基底节变性）具有更多可变的神经认知影响。此外，ADNC、LBD 和较高数量的共病神经病理学与至少一种APOE ε4 等位基因的存在相关，而 ADNC 和较高数量的神经病理学与APOE ε2 等位基因呈负相关。了解个体和伴随的神经病理学影响认知的机制以及各自贡献的程度是开发生物标志物和疾病缓解疗法的必要步骤，特别是当这些医疗干预变得更有针对性和个性化时。