Preclinical models of Alzheimer's disease (AD) suggest APOE modulates brain function in structures vulnerable to AD pathophysiology. However, genome-wide association studies now demonstrate that AD risk is shaped by a broader polygenic architecture, estimated via polygenic risk scoring (AD-PRS). Despite this breakthrough, the effect of AD-PRS on brain function in young individuals remains unknown. In a large sample (N = 608) of young, asymptomatic individuals, we measure the impact of both (i) APOE and (ii) AD-PRS on a vulnerable cortico-limbic scene-processing network heavily implicated in AD pathophysiology. Integrity of this network, which includes the hippocampus (HC), is fundamental for maintaining cognitive function during ageing. We show that AD-PRS, not APOE, selectively influences activity within the HC in response to scenes, while other perceptual nodes remained intact. This work highlights the impact of polygenic contributions to brain function beyond APOE, which could aid potential therapeutic/interventional strategies in the detection and prevention of AD.

中文翻译：

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阿尔茨海默病的多基因风险影响海马的场景选择性。


阿尔茨海默病 (AD) 的临床前模型表明，APOE 可以调节易受 AD 病理生理学影响的大脑结构的功能。然而，全基因组关联研究现在表明，AD 风险是由更广泛的多基因结构决定的，通过多基因风险评分 (AD-PRS) 进行估计。尽管取得了这一突破，但 AD-PRS 对年轻人大脑功能的影响仍然未知。在年轻、无症状个体的大样本 (N = 608) 中，我们测量了 (i) APOE 和 (ii) AD-PRS 对与 AD 病理生理学密切相关的脆弱皮质边缘场景处理网络的影响。该网络（包括海马体 (HC)）的完整性对于在衰老过程中维持认知功能至关重要。我们表明 AD-PRS（而不是 APOE）选择性地影响 HC 内响应场景的活动，而其他感知节点保持完整。这项工作强调了 APOE 之外的多基因对大脑功能的影响，这可能有助于检测和预防 AD 的潜在治疗/干预策略。