Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
J Neuropathol Exp Neurol. 2023 Jan 20;82(2):110-119. doi: 10.1093/jnen/nlac115.
Alzheimer disease (AD) is currently the leading cause of cognitive decline and dementia worldwide. Recently, studies have suggested that other neurodegenerative comorbidities such as limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), Lewy body disease (LBD), and cerebrovascular disease frequently co-occur with Alzheimer disease neuropathologic change (ADNC) and may have significant cognitive effects both in isolation and synergistically with ADNC. Herein, we study the relative clinical impact of these multiple neurodegenerative pathologies in 704 subjects. Each of these pathologies is relatively common in the cognitively impaired population, while cerebrovascular pathology and ADNC are the most common in cognitively normal individuals. Moreover, while the number of concurrent neuropathologic entities rises with age and has a progressively deleterious effect on cognition, 44.3% of cognitively intact individuals are resistant to having any neurodegenerative proteinopathy (compared to 15.2% of cognitively impaired individuals) and 83.5% are resistant to having multiple concurrent proteinopathies (compared to 64.6% of cognitively impaired individuals). The presence of at least 1 APOE ε4 allele was associated with impaired cognition and the presence of multiple proteinopathies, while APOE ε2 was protective against cumulative proteinopathies. These results indicate that maintenance of normal cognition may depend on resistance to the development of multiple concurrent proteinopathies.
阿尔茨海默病（AD）是目前全球导致认知能力下降和痴呆的主要原因。最近的研究表明，其他神经退行性共病，如边缘为主的与年龄相关的 TDP-43 蛋白病相关的神经病理改变（LATE-NC）、路易体病（LBD）和脑血管病，常与阿尔茨海默病神经病理改变（ADNC）共存，并可能对认知能力产生显著的单独或协同影响。在此，我们研究了 704 例患者中这些多种神经退行性病变的相对临床影响。这些病理改变中的每一种在认知障碍人群中都相对常见，而脑血管病和 ADNC 在认知正常个体中最为常见。此外，虽然并发神经病理实体的数量随年龄增加而增加，并对认知能力产生逐渐的有害影响，但 44.3%的认知正常个体对任何神经退行性蛋白病都有抵抗力（相比之下，认知障碍个体为 15.2%），83.5%的认知正常个体对多种并发蛋白病有抵抗力（相比之下，认知障碍个体为 64.6%）。至少存在 1 个 APOE ε4 等位基因与认知障碍和多种蛋白病的存在相关，而 APOE ε2 对累积性蛋白病有保护作用。这些结果表明，维持正常认知能力可能取决于对多种并发蛋白病的发展的抵抗力。
