Lancet Neurol：TDP-43蛋白病——老年认知衰退的新途径

CYW

AbstractBACKGROUND: Transactive response DNA-binding protein of 43 kDa (TDP-43) proteinopathy in older adults frequently coexists with Alzheimer's disease pathology and hippocampal sclerosis. It is unclear whether there is a link between APOE ε4 and TDP-43 proteinopathy, and the role of APOE ε4 in the association of TDP-43 proteinopathy with hippocampal sclerosis remains to be examined. We investigated the relationships of TDP-43 proteinopathy and hippocampal sclerosis with APOE ε4.
METHODS: We used data from two community-based cohort studies of ageing and dementia: the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP). A battery of cognitive tests examining multiple cognitive domains is given to ROS-MAP participants each year, and a measure of annual global cognitive function for each participant is derived by averaging Z scores of these tests. The final clinical diagnosis is assigned after death by a neurologist using all available clinical data without access to post-mortem pathology. Amyloid-β, paired helical filament tau, Lewy bodies, TDP-43, and hippocampal sclerosis were microscopically evaluated in the midbrain, medial temporal, and neocortical regions that capture the progression of each neuropathology. TDP-43 proteinopathy topographic stage was recorded as an ordinal variable, and TDP-43 burden was defined by averaging a semi-quantitative six-point scale across six brain regions. The relationships among APOE ε4, TDP-43 proteinopathy, and hippocampal sclerosis were tested with regression models controlled for sex and age at death, and they were further explored with a mediation analysis using the quasi-Bayesian Monte Carlo method.
FINDINGS: ROS began data collection in 1994, and MAP began data collection in 1997. The data included in this study were analysed from Jan 16, 2017, to July 12, 2017. When analysis began in January, 2017, a total of 1059 ROS-MAP participants who were deceased had APOE genotype and complete pathological measures for amyloid-β, paired helical filament tau, and TDP-43 proteinopathy stage. After excluding 15 participants with other pathological diagnoses, 1044 participants, 1042 of whom also had measures of Lewy body pathology, were included in this study (470 from ROS and 574 from MAP). APOE ε4 count was associated with higher TDP-43 proteinopathy stage (odds ratio [OR] 2·0, 95% CI 1·6-2·6; p=1·9 × 10-9) and TDP-43 burden (0·40, 0·28-0·52; p=1·2 × 10-10). Amyloid-β, paired helical filament tau, or Lewy body pathology did not fully explain this association. APOE ε4 increased the odds of hippocampal sclerosis (OR 2·1, 95% CI 1·4-3·0; p=1·7 × 10-4); this effect was largely mediated by TDP-43 burden (mediated effect p<1·0 × 10-4) but not directly by APOE ε4 (direct effect p=0·40). APOE ε4 was associated with worse global cognition proximate to death even after adjusting for amyloid-β and paired helical filament tau (estimated effect -0·18, 95% CI -0·31 to -0·04; p=0·010), but this association was attenuated by additionally adjusting for TDP-43 burden (-0·09, -0·22 to 0·04; p=0·18).
INTERPRETATION: APOE ε4 seems to increase TDP-43 burden, and this effect in turn was associated with higher odds of hippocampal sclerosis, a pathology potentially downstream of TDP-43 proteinopathy. TDP-43 proteinopathy contributes to the detrimental effect of APOE ε4 on late-life cognition through mechanisms independent of Alzheimer's disease pathology, and future research should consider that TDP-43 proteinopathy might be an integral component of APOE-related neurodegeneration.
FUNDING: US National Institute on Aging and Alzheimer's Association.

43 kDa反式响应DNA结合蛋白（TDP－43）是一种老年蛋白质病变，常与阿尔茨海默病理病变和海马硬化并存，但目前尚不清楚APOE ε4、TDP-43 蛋白病变与海马硬化之间的相关性。近日研究人员通过对2个衰老与痴呆研究队列 (ROS以及MAP队列) 资料的考察探究三者之间的相关性。

研究首先通过认知测试考察参与者年度全脑认知变化，患者死亡后通过神经科资料对患者病情进行最终诊断，对淀粉样蛋白-β、成对tau螺旋纤维、路易体、TDP-43和海马硬化在中脑、内侧颞叶和新皮层区域进行了显微评估，记录6个脑区平均TDP-43负荷。通过性别和年龄调整后回归模型考察APOEε4、TDP-43蛋白病与海马硬化症的关系，并采用准贝叶斯蒙特卡罗方法进一步探讨APOE 4、TDP-43蛋白病与海马硬化的关系。

总计考察了1044名患者病理数据，包含APOE基因型和完整的淀粉样蛋白-β、tau螺旋丝和TDP-43蛋白病变分期数据。研究发现APOE ε4计数与TDP-43病变分期（OR=2.0）以及TDP-43负担（OR=0.4）进展相关，而 Aβ，tau螺旋丝以及路易体与TDP-43病变不相关。APOE ε4导致海马硬化风险增加（OR=2.1），这种影响很大程度上是由TDP-43负担而非APOE ε4 直接影响造成的。调整Aβ，tau螺旋丝病变后，APOE ε4与患者死亡前认知能力下降显著相关，但调整TDP-43负担后，该相关性消失。

研究认为APOE ε4增加TDP-43蛋白病负担，并最终导致海马硬化风险增加，TDP-43蛋白病通过与阿尔茨海默病理无关的机制参与了老年认知衰退过程。

原始出处：

Hyun-Sik Yang et al. Evaluation of TDP-43 proteinopathy and hippocampal sclerosis in relation to APOE ε4 haplotype status： a community-based cohort study. Lancet Neurol. August 06， 2018.