Polygenic Susceptibility to Hypertension and Cognitive Performance in Middle-aged Persons Without Stroke or Dementia

Background and Objectives: Mounting evidence indicates that hypertension leads to a higher risk of dementia. Hypertension is a highly heritable trait, and a higher polygenic susceptibility to hypertension (PSH) is known to associate with higher risk of dementia. We tested the hypothesis that a higher PSH leads to worse cognitive performance in middle-aged persons without dementia. Confirming this hypothesis would support follow-up research focused on using hypertension-related genomic information to risk-stratify middle-aged adults before hypertension develops.

Methods: We conducted a nested, cross-sectional genetic study within the UK Biobank. Study participants with a history of dementia or stroke were excluded. We categorized participants as having low (≤20^th percentile), intermediate, or high (≥80^th percentile) PSH according to results of 2 polygenic risk scores for systolic and diastolic blood pressure (BP) generated with data on 732 genetic risk variants. A general cognitive ability score was calculated as the first component of an analysis that included the results of five cognitive tests. Primary analyses focused on Europeans, and secondary analyses included all race/ethnic groups.

Results: Of the 502,422 participants enrolled in the UKB, 48,118 (9.6%) completed the cognitive evaluation, including 42,011 (8.4%) of European ancestry. 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 (P<0.001). Secondary analyses including all race/ethnic groups and using diastolic BP-related genetic variants yielded similar results (P<0.05 for all tests). Analyses evaluating each cognitive test separately indicated that Reaction Time, Numeric Memory, and Fluid Intelligence drove the association between PSH and general cognitive ability score (all individual tests, P<0.05).

Discussion: Among non-demented, community-dwelling, middle-aged Britons, a higher PSH is associated with worse cognitive performance. These findings suggest that genetic predisposition to hypertension influences brain health in persons who have not yet developed dementia. Because information on genetic risk variants for elevated BP is available long before the development of hypertension, these results lay the foundation for further research focused on using genomic data for the early identification of high-risk middle-aged adults.