Molecular and brain regional/network-wise pathophysiological changes at preclinical stages of Alzheimer's disease (AD) have primarily been found through knowledge-based studies conducted in late-stage mild cognitive impairment/dementia populations. However, such an approach may compromise the objective of identifying the earliest spatial-temporal pathophysiological processes. We investigated 261 individuals with subjective memory complaints, a condition at increased risk of AD, to test a whole-brain, non-a-priori method based on partial least squares in unraveling the association between plasma Aβ42/Aβ40 ratio and an extensive set of brain regions characterized through molecular imaging of Aβ accumulation and cortical metabolism. Significant associations were mapped onto large-scale networks, identified through an atlas and by knowledge, to elaborate on the reliability of the results. Plasma Aβ42/40 ratio was associated with Aβ-PET uptake (but not FDG-PET) in regions generally investigated in preclinical AD such as those belonging to the default mode network, but also in regions/networks normally not accounted - including the central executive and salience networks - which likely have a selective vulnerability to incipient Aβ accumulation.

The present whole-brain approach is promising to investigate early pathophysiological changes of AD to fully capture the complexity of the disease, which is essential to develop timely screening, detection, diagnostic, and therapeutic interventions.

阿尔茨海默病 (AD) 临床前阶段的分子和大脑区域/网络病理生理变化主要是通过在晚期轻度认知障碍/痴呆症人群中进行的基于知识的研究发现的。然而，这种方法可能会损害识别最早的时空病理生理过程的目标。我们调查了 261 名有主观记忆问题的个体，这是一种 AD 风险增加的情况，以测试基于偏最小二乘的全脑非先验方法，以解开血浆 Aβ42/Aβ40 比率与广泛的一组通过 Aβ 积累和皮质代谢的分子成像表征的大脑区域。重要的关联被映射到大规模网络上，通过地图集和知识识别，详细说明结果的可靠性。血浆 Aβ42/40 比率与 Aβ-PET 摄取相关（但与 FDG-PET 无关）在临床前 AD 中普遍研究的区域（例如属于默认模式网络的区域）以及通常不考虑的区域/网络中 - 包括中央执行和显着网络——它们可能对初期的 Aβ 积累具有选择性的脆弱性。

目前的全脑方法有望研究 AD 的早期病理生理变化，以充分捕捉疾病的复杂性，这对于开发及时的筛查、检测、诊断和治疗干预措施至关重要。