Preclinical models of Alzheimer's disease (AD) suggest that volumetric reductions in medial temporal lobe (MTL) structures manifest before clinical onset. AD polygenic risk scores (PRSs) are further linked to reduced MTL volumes (the hippocampus/amygdala); however, the relationship between the PRS and specific subregions remains unclear. We determine the relationship between the AD-PRSs and MTL subregions in a large sample of young participants (N = 730, aged 22-35 years) using a multimodal (T1w/T2w) approach. We first demonstrate that the PRSs for the hippocampus/amygdala predict their respective volumes and specific hippocampal subregions (pFDR < 0.05). We further observe negative relationships between the AD-PRSs and whole hippocampal/amygdala volumes. Critically, we demonstrate novel associations between the AD-PRSs and specific hippocampal subfields such as CA1 (β = -0.096, pFDR = 0.045) and the fissure (β = -0.101, pFDR = 0.041). We provide evidence that the AD-PRS is linked to specific MTL subfields decades before AD onset. This may help inform preclinical models of AD risk, providing additional specificity for intervention and further insight into mechanisms by which common AD variants confer susceptibility.

中文翻译：

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阿尔茨海默病多基因风险中的多模态海马和杏仁核子域体积测量。

阿尔茨海默病 (AD) 的临床前模型表明，内侧颞叶 (MTL) 结构的体积减少在临床发病前就已显现。AD 多基因风险评分 (PRS) 进一步与 MTL 体积（海马/杏仁核）减少有关；然而，PRS 与特定次区域之间的关系仍不清楚。我们使用多模式 (T1w/T2w) 方法确定了大量年轻参与者样本（N = 730，年龄 22-35 岁）中 AD-PRS 和 MTL 子区域之间的关系。我们首先证明海马/杏仁核的 PRS 预测它们各自的体积和特定的海马亚区 (pFDR < 0.05)。我们进一步观察到 AD-PRS 与整个海马/杏仁核体积之间的负相关。关键的是，我们证明了 AD-PRS 与特定海马亚区之间的新关联，例如 CA1（β = -0.096，pFDR = 0.045）和裂隙（β = -0.101，pFDR = 0.041）。我们提供证据表明 AD-PRS 与 AD 发病前几十年的特定 MTL 子领域有关。这可能有助于为 AD 风险的临床前模型提供信息，为干预提供额外的特异性，并进一步深入了解常见 AD 变体赋予易感性的机制。