Multiomics Investigation of Hypertension and White Matter Hyperintensity as a Source of Vascular Dementia or a Comorbidity to Alzheimer's Disease

Abstract

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.

Keywords: Alzheimer's disease; CSF biomarkers; comorbidity; hypertension; vascular dementia; white matter hyperintensity.