Cerebral beta-amyloid (Aβ) accumulation is the earliest detectable pathophysiological event along the Alzheimer's disease (AD) continuum, therefore an accurate quantification of incipient Aβ abnormality is of great importance to identify preclinical AD. Both cerebrospinal fluid (CSF) Aβ concentrations and Position Emission Tomography (PET) with specific tracers provide established biomarkers of Aβ pathology. Yet, they identify two different biological processes reflecting the clearance rate of soluble Aβ as opposed to the cerebral aggregation of insoluble Aβ fibrils. Studies have demonstrated high agreement between CSF and PET-based Aβ measurements on diagnostic and prognostic levels. However, an open question is whether risk factors known to increase AD prevalence may promote an imbalance between these biomarkers, leading to a higher cumulative Aβ cerebral aggregation for a given level of cleared Aβ in the CSF. Unveiling such interactions in cognitively unimpaired (CU) individuals shall provide novel insights into the biological pathways underlying Aβ aggregation in the brain and ultimately improve our knowledge on disease modelling. With this in mind, we assessed the impact of three major unmodifiable AD risk factors (age, APOE-ϵ4 and sex) on the association between soluble and deposited Aβ in a sample of 293 middle-aged CU individuals who underwent both lumbar puncture and PET imaging using the [18F]flutemetamol tracer. We looked for interactions between CSF Aβ42/40 concentrations and each of the assessed risk factors, in promoting Aβ PET uptake both in candidate regions of interest and in the whole brain. We found that, for any given level of CSF Aβ42/40, older age and female sex induced higher fibrillary plaque deposition in neocortical areas including the anterior, middle and posterior cingulate cortex. By contrast, the modulatory role of APOE-ϵ4 was uniquely prominent in areas known for being vulnerable to early tau deposition, such as the entorhinal cortex and the hippocampus bilaterally. Post hoc three-way interactions additionally proved evidence for a synergistic effect among the risk factors on the spatial topology of Aβ deposition as a function of CSF Aβ levels. Importantly, findings were replicated in an independent sample of CU individuals derived from the ADNI cohort. Our data clarify the mechanisms underlying the higher AD prevalence associated to those risk factors and suggest that APOE-ϵ4 in particular paves the way for subsequent tau spreading in the medial temporal lobe, thus favoring a spatial co-localization between Aβand tau and increasing their synergistic interaction along the disease continuum.

中文翻译：

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年龄，性别和APOE-ϵ4改变了认知完好个体中可溶性和纤维状β淀粉样蛋白之间的平衡：地形学模式和在两个独立队列中的复制

脑β-淀粉样蛋白（Aβ）积累是沿阿尔茨海默氏病（AD）连续体的最早可检测到的病理生理事件，因此准确定量早期Aβ异常对于鉴定临床前AD非常重要。脑脊液（CSF）Aβ浓度和带有特定示踪剂的位置发射断层扫描（PET）都提供了Aβ病理学的已建立生物标志物。然而，他们发现了两种不同的生物学过程，它们反映了可溶性Aβ的清除率，而不是可溶性Aβ原纤维的脑聚集。研究表明，脑脊液和基于PET的Aβ测量在诊断和预后水平上具有高度一致性。但是，一个尚待解决的问题是，已知增加AD患病率的风险因素是否会加剧这些生物标记之间的失衡，对于脑脊液中给定水平的Aβ，导致较高的累积Aβ脑聚集。在认知无障碍（CU）个体中揭示这种相互作用将为大脑中Aβ聚集的生物学途径提供新颖的见解，并最终改善我们对疾病建模的认识。考虑到这一点，我们评估了293名接受腰穿和PET穿刺的中年CU个体样本中三个主要的不可改变的AD危险因素（年龄，APOE-ϵ4和性别）对可溶性和沉积性Aβ关联的影响。使用[18F]氟替莫尔示踪剂进行成像。我们研究了脑脊液Aβ42/ 40浓度与每种评估的危险因素之间的相互作用，以促进感兴趣的候选区域和整个大脑中AβPET的摄取。我们发现 对于任何给定的CSFAβ42/ 40水平，老年和女性在新皮层区域（包括前扣带，中扣带和后扣带皮层）中引起较高的纤维斑沉积。相比之下，APOE- the4的调节作用在易受早期tau沉积影响的区域（如内嗅皮层和双侧海马）中尤为突出。事后三方相互作用还证明了风险因素之间的协同作用对Aβ沉积的空间拓扑结构与脑脊液Aβ水平的作用具有协同作用。重要的是，研究结果在来自ADNI队列的CU个体的独立样本中重复进行。