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

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 AD-Hyp+ with an unaffected control population. METHODS 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.