Association of blood pressure with cognitive function at midlife: a Mendelian randomization study

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RESEARCH ARTICLE

Open Access

Association of blood pressure with cognitive function at midlife: a Mendelian randomization study Daokun Sun1, Emy A. Thomas1, Lenore J. Launer2, Stephen Sidney3, Kristine Yaffe4 and Myriam Fornage1,5*

Abstract Background: Whether high blood pressure has a causal effect on cognitive function as early as middle age is unclear. We investigated whether high blood pressure (BP) causally impairs cognitive function at midlife using Mendelian Randomization (MR). Methods: We applied a two-sample MR approach to investigate the causal relationship between BP and midlife cognitive performance measured by the Digit Symbol Substitution Test (DSST), Rey Auditory Verbal Learning Test (RAVLT), and Stroop Interference test. We used a total of 109 genetic polymorphisms with established associations with BP as instrumental variables and estimated gene-cognitive function association in 1369 middle-aged adults (Mean age (SD): 50.8 (3.3), 54.0% women) from the CARDIA study. Results: A 10 mmHg increment in genetically-predicted systolic, diastolic, or pulse pressure was associated with a 4.9 to 7.7-point lower DSST score (P = 0.002, SBP; P = 0.005, DBP and P = 0.008, PP), while a 10 mmHg increment in genetically-predicted SBP was associated with a 0.7 point lower RAVLT and a 2.3 point higher Stroop (P = 0.046 and 0.011, respectively). Conclusions: This MR analysis shows that high BP, especially SBP, is causally associated with poorer processing speed, verbal memory, and executive function during midlife. These findings emphasize the need for further investigation of the role and mechanisms of BP dysregulation on cognitive health in middle age and perhaps, more broadly, across the lifespan. Keywords: Mendelian randomization, Blood pressure, Cognitive disorders, Risk factors, Dementia

Background Hypertension is one of the long-established modifiable risk factors for age-related dementia [1]. Several studies have reported that high blood pressure (BP) developed by middle age is associated with cognitive decline [2, 3] and with global and domain-specific cognitive impairment * Correspondence: [email protected] 1 Brown Foundation Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, 1825 Pressler Street, Houston, TX 77030, USA 5 Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA Full list of author information is available at the end of the article

in late life [4, 5]. However, other studies have reported nonmonotonic or null relationships between high BP and latelife cognitive function [6, 7]. The inconsistency of results may be due to differences in study populations, study design, and methodological aspects. Reverse causation may also play a role. Randomized clinical trials (RCTs) that examine the long-term effects of elevated blood pressure on cognitive ability would represent a gold standard but are costly and difficult to conduct since only randomization based on