IMPORTANCEThe American Heart Association (AHA) Life's Simple 7 (LS7) score captures 7 biological and lifestyle factors associated with promoting cardiovascular health.OBJECTIVES To test whether healthier LS7 profiles are associated with significant brain health benefits in persons without stroke or dementia, and to evaluate whether genomic information can recapitulate the observed LS7. DESIGN, SETTING, AND PARTICIPANTSThis genetic association study was a nested neuroimaging study within the UK Biobank, a large population-based cohort study in the United Kingdom. Between March 2006 and October 2010, the UK Biobank enrolled 502 480 community-dwelling persons aged 40 to 69 years at recruitment. This study focused on a subset of 35 914 participants without stroke or dementia who completed research brain magnetic resonance imaging (MRI) and had available genome-wide data. All analyses were conducted between March 2021 and March 2022.EXPOSURES The LS7 (blood pressure, low-density lipoprotein cholesterol, hemoglobin A 1c , smoking, exercise, diet, and body mass index) profiles were ascertained clinically and genomically. Independent genetic variants known to influence each of the traits included in the LS7 were assessed. The total LS7 score ranges from 0 (worst) to 14 (best) and was categorized as poor (Յ4), average (>4 to 9) and optimal (>9). MAIN OUTCOMES AND MEASURESThe outcomes of interest were 2 neuroimaging markers of brain health: white matter hyperintensity (WMH) volume and brain volume (BV). RESULTSThe final analytical sample included 35 914 participants (mean [SD] age 64.1 [7.6] years; 18 830 [52.4%] women). For WMH, compared with persons with poor observed LS7 profiles, those Open Access. This is an open access article distributed under the terms of the CC-BY License.

Background: Blood pressure is the strongest contributor to clinically evident cerebrovascular disease. We investigated the role of blood pressure on white matter (WM) microstructure among asymptomatic individuals without clinically evident cerebrovascular disease. Methods: We conducted a nested study within the UK Biobank, restricting our analysis to participants without cerebrovascular disease or dementia and with available brain diffusion tensor imaging (DTI). We tested for association between systolic blood pressure (SBP) and six different DTI metrics: fractional anisotropy (FA), mean diffusivity (MD), tensor mode (MO), intra-cellular volume fraction (ICVF), isotropic or free water volume fraction (ISOVF), and orientation dispersion index (OD) across 48 WM tracts using multivariable linear regression adjusted for potential confounders. We used Bonferroni-corrected p-values (0.05/48) for statistical significance. Results: We analyzed 33,440 participants. Mean age was 63.0 (SD 7.7), and 17,688 (53%) were female. Higher SBP is independently associated with pervasive decrease in FA and ICVF and increase in MD (Figure), after adjustment for vascular risk-factors. SBP was also associated with lower neurite OD (a more specific metric of axonal damage) in bilateral posterior corona radiata, external capsule, medial lemniscus, and corticospinal tracs. FA and OD of external capsule and posterior corona radiata had the largest drop per 10 mmHg increase of SBP (steepest slope). Conclusions: Higher SBP is associated with pervasive WM microstructure dysintegrity in asymptomatic individuals without evident cerebrovascular disease. DTI metrics of the posterior corona radiata and external capsule are most reflective of variations in SBP and may provide a potential biomarker to assess subtle WM microstructural damage in hypertensive patients or monitor treatment response in clinical trials.

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 (≤20thpercentile), intermediate, or high (≥80thpercentile) 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.

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.

Background and objectivesWe aimed to investigate the white matter (WM) microstructural/cytostructural disintegrity patterns related to higher systolic blood pressure (SBP), and whether they mediate SBP effects on cognitive performance in middle-aged adults.MethodsUsing the UK Biobank study of community-dwelling volunteers aged 40–69 years, we included participants without a history of stroke, dementia, demyelinating disease or traumatic brain injury. We investigated the association of SBP with MRI diffusion metrics: fractional anisotropy (FA), mean diffusivity (MD), intracellular volume fraction (a measure of neurite density), isotropic (free) water volume fraction (ISOVF) and orientation dispersion across WM tracts. Then, we determined whether WM diffusion metrics mediated the effects of SBP on cognitive function.ResultsWe analysed 31 363 participants—mean age of 63.8 years (SD: 7.7), and 16 523 (53%) females. Higher SBP was associated with lower FA and neurite density, but higher MD and ISOVF. Among different WM tracts, diffusion metrics of the internal capsule anterior limb, external capsule, superior and posterior corona radiata were most affected by higher SBP. Among seven cognitive metrics, SBP levels were only associated with ‘fluid intelligence’ (adjusted p<0.001). In mediation analysis, the averaged FA of external capsule, internal capsule anterior limb and superior cerebellar peduncle mediated 13%, 9% and 13% of SBP effects on fluid intelligence, while the averaged MD of external capsule, internal capsule anterior and posterior limbs, and superior corona radiata mediated 5%, 7%, 7% and 6% of SBP effects on fluid intelligence, respectively.DiscussionAmong asymptomatic adults, higher SBP is associated with pervasive WM microstructure disintegrity, partially due to reduced neuronal count, which appears to mediate SBP adverse effects on fluid intelligence. Diffusion metrics of select WM tracts, which are most reflective of SBP-related parenchymal damage and cognitive impairment, may serve as imaging biomarkers to assess treatment response in antihypertensive trials.