BACKGROUNDApproximately 40% of people aged ≥ 65 experience memory loss, particularly in episodic memory. Identifying the genetic basis of episodic memory decline is crucial for uncovering its underlying causes.METHODSWe investigated common and rare genetic variants associated with episodic memory decline in 742 (632 for rare variants) Ashkenazi Jewish individuals (mean age 75) from the LonGenity study. All‐atom molecular dynamics simulations were performed to uncover mechanistic insights underlying rare variants associated with episodic memory decline.RESULTSIn addition to the common polygenic risk of Alzheimer's disease, we identified and replicated rare variant associations in ITSN1 and CRHR2. Structural analyses revealed distinct memory pathologies mediated by interfacial rare coding variants such as impaired receptor activation of corticotropin releasing hormone and dysregulated L‐serine synthesis.DISCUSSIONOur study uncovers novel risk loci for episodic memory decline. The identified underlying mechanisms point toward heterogenous memory pathologies mediated by rare coding variants.Highlights We demonstrated the contribution of the common polygenic risk of Alzheimer's disease to episodic memory decline. We discovered and replicated two risk genes associated with episodic memory decline implicated by rare variants, were discovered and replicated. We demonstrated molecular mechanisms and potential novel memory pathologies underlying interfacial rare coding variants. Molecular dynamics simulations were performed to understand the downstream effects of risk rare coding variants.

中文翻译：

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与年龄相关的情景记忆下降相关的遗传变异涉及不同的记忆病症


背景大约 40% 的 65 ≥的人会经历记忆丧失，尤其是在情景记忆方面。确定情景记忆衰退的遗传基础对于揭示其根本原因至关重要。方法我们调查了 LonGenity 研究中 742 名（罕见变异为 632 名）德系犹太人（平均年龄 75 岁）与情景记忆下降相关的常见和罕见遗传变异。进行了全原子分子动力学模拟，以揭示与情景记忆下降相关的罕见变异背后的机制见解。结果除了阿尔茨海默病的常见多基因风险外，我们还在 ITSN1 和 CRHR2 中鉴定并复制了罕见的变异关联。结构分析揭示了由界面罕见编码变体介导的不同记忆病理，例如促肾上皮质激素释放激素的受体激活受损和 L-丝氨酸合成失调。讨论我们的研究发现了情景记忆下降的新风险位点。已确定的潜在机制指向由罕见编码变体介导的异质性记忆病理。亮点 我们证明了阿尔茨海默病的常见多基因风险对情景记忆下降的贡献。我们发现并复制了两个与罕见变异相关的情景记忆下降相关的风险基因，被发现并复制。我们证明了界面罕见编码变体的分子机制和潜在的新记忆病理学。进行分子动力学模拟以了解风险罕见编码变体的下游影响。