tau 介导血管风险和 Aβ 对认知能力下降的协同影响。
Tau Mediates Synergistic Influence of Vascular Risk and Aβ on Cognitive Decline.
机构信息
Department of Neurology, Massachusetts General Hospital, Boston, MA.
Harvard Medical School, Boston, MA.
出版信息
Ann Neurol. 2022 Nov;92(5):745-755. doi: 10.1002/ana.26460. Epub 2022 Aug 13.
OBJECTIVE
Elevated vascular risk and beta-amyloid (Aβ) burden have been synergistically associated with cognitive decline in preclinical Alzheimer's disease (AD), although the underlying mechanisms remain unclear. We examined whether accelerated longitudinal tau accumulation mediates the vascular risk-Aβ interaction on cognitive decline.
METHODS
We included 175 cognitively unimpaired older adults (age 70.5 ± 8.0 years). Baseline vascular risk was quantified using the office-based Framingham Heart Study general cardiovascular disease risk score (FHS-CVD). Baseline Aβ burden was measured with Pittsburgh Compound-B positron emission tomography (PET). Tau burden was measured longitudinally (3.6 ± 1.5 years) with Flortaucipir PET, focusing on inferior temporal cortex (ITC). Cognition was assessed longitudinally (7.0 ± 2.0 years) using the Preclinical Alzheimer's Cognitive Composite. Linear mixed effects models examined the interactive effects of baseline vascular risk and Aβ on longitudinal ITC tau. Additionally, moderated mediation was used to determine whether tau accumulation mediated the FHS-CVD*Aβ effect on cognitive decline.
RESULTS
We observed a significant interaction between elevated baseline FHS-CVD and Aβ on greater ITC tau accumulation (p = 0.004), even in individuals with Aβ burden below the conventional threshold for amyloid positivity. Examining individual vascular risk factors, we found elevated systolic blood pressure and body mass index showed independent interactions with Aβ on longitudinal tau (both p < 0.0001). ITC tau accumulation mediated 33% of the interactive association of FHS-CVD and Aβ on cognitive decline.
INTERPRETATION
Vascular risks interact with subthreshold levels of Aβ to promote cognitive decline, partially by accelerating early neocortical tau accumulation. Our findings support vascular risk reduction, especially treating hypertension and obesity, to attenuate Aβ-related tau pathology and reduce late-life cognitive decline. ANN NEUROL 2022;92:745-755.
目的
在临床前阿尔茨海默病（AD）中，升高的血管风险和β-淀粉样蛋白（Aβ）负担与认知能力下降呈协同作用，尽管其潜在机制尚不清楚。我们研究了加速纵向 tau 积累是否介导血管风险与 Aβ 对认知能力下降的相互作用。
方法
我们纳入了 175 名认知正常的老年人（年龄 70.5±8.0 岁）。使用基于办公室的弗雷明汉心脏研究一般心血管疾病风险评分（FHS-CVD）量化基线血管风险。使用匹兹堡化合物-B 正电子发射断层扫描（PET）测量基线 Aβ 负担。使用 Flortaucipir PET 纵向测量 tau 负担（3.6±1.5 年），重点关注下颞叶皮层（ITC）。使用临床前阿尔茨海默病认知综合量表（Preclinical Alzheimer's Cognitive Composite）纵向评估认知。线性混合效应模型研究了基线血管风险和 Aβ 对纵向 ITC tau 的交互作用。此外，使用调节中介来确定 tau 积累是否介导了 FHS-CVD*Aβ 对认知能力下降的影响。
结果
我们观察到基线 FHS-CVD 升高与 Aβ 之间存在显著的相互作用，导致 ITC tau 积累增加（p=0.004），即使在 Aβ 负担低于传统的淀粉样蛋白阳性阈值的个体中也是如此。检查个体血管危险因素时，我们发现升高的收缩压和体重指数与 Aβ 对纵向 tau 有独立的相互作用（均 p<0.0001）。ITC tau 积累解释了 FHS-CVD 和 Aβ 对认知能力下降的交互关联的 33%。
结论
血管风险与亚阈值水平的 Aβ 相互作用，促进认知能力下降，部分原因是加速早期新皮层 tau 积累。我们的研究结果支持降低血管风险，特别是治疗高血压和肥胖症，以减轻 Aβ 相关的 tau 病理学并减少晚年认知能力下降。
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