Polygenic Susceptibility to Hypertension is Associated with Worse Cognitive Performance in Middle-Aged Persons without Dementia

Background Mounting evidence indicates that hypertension leads to higher risk of cognitive decline and dementia. Hypertension is a highly heritable trait and a higher polygenic susceptibility to hypertension (PSH) is known to be associated with higher risk of dementia. We tested the hypothesis that a higher PSH leads to worse cognitive performance in middle-aged persons without dementia. Methods We conducted a nested, cross-sectional, genetic study within the UK Biobank, a large population study that enrolled middle-aged Britons. Study participants with a history of dementia or stroke were excluded. We categorized participants as having low (≤20th percentile), intermediate (>20th and <80th percentile), or high (≥80th percentile) PSH according to results of 2 polygenic risk scores for systolic and diastolic blood pressure (BP), generated with genomic data on 732 genetic risk variants for these traits. Cognitive performance was evaluated via 5 simple tests: Pairs Memory, Reaction Time, Numeric Memory, Prospective Memory and Fluid Intelligence. A general cognitive ability score was calculated as the first principal component of a principal component analysis that included the results of these 5 tests. Primary analyses focused on Europeans and secondary analyses included all race/ethnic groups. Results Out of 409,551 study participants of European ancestry with available genomic data, 42,080 (10.3%) completed all 5 tests. Multivariable regression models using systolic BP-related genetic variants indicated that, compared to study participants with low PSH, those with intermediate and high PSH had reductions of 3.9% (beta -0.039, SE 0.012) and 6.6% (beta - 0.066, SE 0.014), respectively, in their general cognitive ability score (test for trend p <0.001). Secondary analyses including all race/ethnic groups (n=48,118) and using diastolic BP-related genetic variants yielded similar results (both instances, p<0.05). Analyses evaluating each cognitive test separately indicated that Reaction Time, Numeric Memory and Fluid Intelligence drove the association of PSH with the general cognitive ability score (all individual tests, p<0.05). Conclusions Among non-demented, community-dwelling, middle-aged Britons, a higher PSH is associated with worse cognitive performance. These findings suggest the genetic predisposition to hypertension influence brain health in persons who have not yet developed dementia. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This is study was funded by the US National Institutes of Health (grants P30AG021342, K76AG059992, R03NS112859). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The UK Biobank has approval from the North West Centre for Research Ethics Committee This study was conducted using the UK Biobank resource under an approved data request (project number 58743). The Institutional Review Board of Yale University gave ethical approval for this particular analysis of UK Biobank data. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.