Background: Age-related comorbidity is common and significantly increases the burden for the healthcare of the elderly. Alzheimer’s disease (AD) and hypertension are the two most prevalent age-related conditions and are highly comorbid. While hypertension is a risk factor for vascular dementia (VD), hypertension with AD (ADHyp+) is often characterized as probable vascular dementia. In the absence of imaging and other diagnostic tests, differentiating the two pathological states is difficult.

Objective: Our goals are to (1) identify differences in CSF-based vascular dementia profiles, if any, between individuals who have AD only (ADHyp-), and individuals with ADHyp+ using CSF levels of amyloid β, tau and p-tau, and (2) compare genome-wide DNA profiles of ADHyp- and ADHyp+ with an unaffected control population.

Method: Genotype and clinical data were used to compare healthy controls to AD Hyp- vs. AD Hyp+. We compared the CSF biomarkers followed by evaluating genome wide profiles in three groups, and mapped SNPs to genes based on position and lowest p-value. The significant genes were examined for co-expression and known disease networks.

Results: We found no differences between Aβ, tau and p-tau levels between ADHyp- and ADHyp+. We found TOMM40 to be associated with ADHyp- as expected but not with ADHyp+. Interestingly, SLC9A3R2 polymorphism was associated with ADHyp+, and significant gene expression changes were observed for neighboring genes.

Conclusion: Through this exploratory study using a novel cohort stratification design, we highlight the genetic differences in clinically similar phenotypes, indicating the utility of genetic profiling in aiding differential diagnosis of ADHyp+ and VD.

背景：年龄相关的合并症很常见，显着增加了老年人的医疗负担。阿尔茨海默病 (AD) 和高血压是两种最普遍的与年龄相关的疾病，并且是高度合并症。虽然高血压是血管性痴呆 (VD) 的危险因素，但伴有 AD 的高血压 (ADHyp+) 通常被定性为可能的血管性痴呆。在没有影像学和其他诊断测试的情况下，很难区分两种病理状态。

目标：我们的目标是 (1) 使用 CSF 中淀粉样蛋白 β、tau 和 p-tau 的水平，确定仅患有 AD (ADHyp-) 的个体和患有 ADHyp+ 的个体之间基于 CSF 的血管性痴呆特征的差异（如果有）， (2) 将 ADHyp- 和 ADHyp+ 的全基因组 DNA 谱与未受影响的对照人群进行比较。

方法：使用基因型和临床数据将健康对照与 AD Hyp- 与 AD Hyp+ 进行比较。我们比较了 CSF 生物标志物，然后评估了三组的全基因组概况，并根据位置和最低 p 值将 SNP 映射到基因。检查重要基因的共表达和已知疾病网络。

结果：我们发现 ADHyp- 和 ADHyp+ 之间的 Aβ、tau 和 p-tau 水平没有差异。我们发现 TOMM40 与预期的 ADHyp- 相关，但与 ADHyp+ 无关。有趣的是，SLC9A3R2 多态性与 ADHyp+ 相关，并且观察到邻近基因的显着基因表达变化。

结论：通过这项使用新型队列分层设计的探索性研究，我们强调了临床相似表型的遗传差异，表明遗传图谱在辅助 ADHyp+ 和 VD 的鉴别诊断中的效用。