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

Abstract

ABSTRACTBackgroundMounting 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.MethodsWe 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.ResultsOut 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).ConclusionsAmong 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.