Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC, USA.
J Alzheimers Dis. 2023;94(3):1121-1132. doi: 10.3233/JAD-230397.
The lack of efficient preventive interventions against Alzheimer's disease (AD) calls for identifying efficient modifiable risk factors for AD. As diabetes shares many pathological processes with AD, including accumulation of amyloid plaques and neurofibrillary tangles, insulin resistance, and impaired glucose metabolism, diabetes is thought to be a potentially modifiable risk factor for AD. Mounting evidence suggests that links between AD and diabetes may be more complex than previously believed.
To examine the pleiotropic architecture of AD and diabetes mellitus (DM).
Univariate and pleiotropic analyses were performed following the discovery-replication strategy using individual-level data from 10 large-scale studies.
We report a potentially novel pleiotropic NOTCH2 gene, with a minor allele of rs5025718 associated with increased risks of both AD and DM. We confirm previously identified antagonistic associations of the same variants with the risks of AD and DM in the HLA and APOE gene clusters. We show multiple antagonistic associations of the same variants with AD and DM in the HLA cluster, which were not explained by the lead SNP in this cluster. Although the ɛ2 and ɛ4 alleles played a major role in the antagonistic associations with AD and DM in the APOE cluster, we identified non-overlapping SNPs in this cluster, which were adversely and beneficially associated with AD and DM independently of the ɛ2 and ɛ4 alleles.
This study emphasizes differences and similarities in the heterogeneous genetic architectures of AD and DM, which may differentiate the pathogenic mechanisms of these diseases.
由于缺乏针对阿尔茨海默病 (AD) 的有效预防干预措施，因此需要确定 AD 的有效可改变风险因素。由于糖尿病与 AD 具有许多相同的病理过程，包括淀粉样斑块和神经原纤维缠结的积累、胰岛素抵抗和葡萄糖代谢受损，因此糖尿病被认为是 AD 的潜在可改变风险因素。越来越多的证据表明，AD 和糖尿病之间的联系可能比以前认为的更为复杂。
检查 AD 和糖尿病 (DM) 的多效性结构。
采用个体水平数据，采用发现-复制策略进行单变量和多效性分析，来自 10 项大型研究。
我们报告了一种潜在的新型 NOTCH2 基因多效性，其 rs5025718 次要等位基因与 AD 和 DM 的风险增加相关。我们证实了先前在 HLA 和 APOE 基因簇中发现的相同变体与 AD 和 DM 风险的拮抗关联。我们显示了相同变体在 HLA 簇中与 AD 和 DM 的多个拮抗关联，这些关联不能用该簇中的主导 SNP 来解释。尽管 ɛ2 和 ɛ4 等位基因在 APOE 簇中与 AD 和 DM 的拮抗关联中起主要作用，但我们在该簇中发现了非重叠的 SNP，这些 SNP 独立于 ɛ2 和 ɛ4 等位基因与 AD 和 DM 不利和有益相关。
这项研究强调了 AD 和 DM 异质遗传结构的差异和相似之处，这可能区分了这些疾病的发病机制。
