Multiomics investigation of hypertension and white matter hyperintensi-ty as a source of vascular dementia or a comorbidity to alzheimer’s disease

Background: Age-related comorbidity is common and significantly increases the bur-den 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 pathologi-cal 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 AD-Hyp+ 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 AD-Hyp+. We found TOMM40 to be associated with ADHyp-as expected but not with ADHyp+. Inter-estingly, 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.