Midlife Blood Pressure Research Articles

History of Pregnancy Loss and Risk for Higher Midlife Blood Pressure in Parous Females.

Introduction: Pregnancy loss has been associated with later cardiometabolic conditions, potentially due to shared underlying etiology, but associations with midlife blood pressure (BP) remain unclear. Methods: We examined participants enrolled 1999-2002 in prospective Project Viva. At midlife ∼18 years after enrollment, we collected lifetime pregnancy history and measured BP. Exposures included any pregnancy loss or number of pregnancy losses. Outcomes were systolic and diastolic BP (SBP, DBP), and American Heart Association (AHA) BP categories. We performed multivariable regression adjusted for race and ethnicity, education, income, perceived body size at age 10 years, and age at outcome. Results: Of 623 participants, 33.7% reported pregnancy loss, 9.6% had elevated BP, and 34.8% had hypertension. Mean(±standard deviation) age was 50.7 ± 5.0 years, SBP 118.1 ± 15.6 mmHg, and DBP 74.8 ± 11.5 mmHg. In adjusted models, any pregnancy loss was associated with higher SBP (β = 2.25 mmHg, 95% confidence interval [CI]: -0.23, 4.78). Strongest associations with SBP were among those with first pregnancy loss ≥35 years (β = 5.58 mmHg, 95% CI: 1.76, 9.40 versus 0 pregnancy losses and first pregnancy <35 years). All associations with DBP were nonsignificant but similar in direction. For AHA outcomes, pregnancy loss was associated with higher risk for elevated BP (relative-risk ratio [RRR] = 2.93, 95% CI: 1.58, 5.43) but not with hypertension (RRR = 1.45, 95% CI: 0.95, 2.22) versus normotension. In models examining race and ethnicity, SBP was higher among non-Hispanic White and Hispanic individuals with pregnancy loss; non-Hispanic Black individuals had higher BP regardless of pregnancy loss status. Conclusions: History of pregnancy loss was associated with higher SBP and elevated BP category at midlife. These findings highlight reproductive history as an important consideration for cardiopreventive strategies and interventions.

The Effect of Acute Sleep Extension on Blood Pressure Is Dependent on the Change in Sleep Efficiency.

The present study investigated the effect of acute sleep extension on blood pressure and microvascular vasodilation. Sleep and daily physical activity were objectively measured at home for two weeks using wrist actigraphy in 22 adults (60 ± 15 y). Vascular measurements were made in the morning on the 8th and 15th day. Participants spent at least 10 h in bed on the night prior to one of these testing days to extend sleep. Mean arterial blood pressure (MAP) and peak reactive hyperemia in the forearm were measured on each testing day. Reactive hyperemia and MAP were unaltered (p > 0.05) by sleep extension in the total sample. However, adults who experienced improved sleep efficiency with sleep extension (n = 10, 4.2 ± 1.4%) exhibited reduced MAP (-5.5 ± 4.6 mm Hg, p = 0.005) while adults who had little change or decreased sleep efficiency (n = 12, -1.7 ± 2.9%) showed no change in MAP. The reduction in MAP was significantly different between sleep efficiency groups (p = 0.005, Hedges' g = 1.21) after adjustment for sex and moderate-to-vigorous physical activity. The results of this study suggest that sleep extension has the potential to reduce blood pressure in midlife to older adults when the additional sleep time improves the quality of sleep.

Target trial emulation using cohort studies: estimating the effect of antihypertensive medication initiation on incident dementia.

Observational studies link high midlife systolic blood pressure to increased dementia risk. However, synthesis of evidence from randomized controlled trials has not definitively demonstrated that antihypertensive medication use reduces dementia risk. Here, we emulate target trials of antihypertensive medication initiation on incident dementia using three cohort studies, with attention to potential violations of necessary assumptions. We emulated trials of antihypertensive medication initiation on incident dementia using data from the Atherosclerosis Risk in Communities (ARIC) study, Cardiovascular Health Study (CHS), and Health and Retirement Study (HRS). We used data-driven methods to restrict participants to initiators and non-initiators with overlap in propensity scores and positive control outcomes to look for violations of positivity and exchangeability assumptions. Analyses were limited by the small number of cohort participants who met eligibility criteria. Associations between antihypertensive medication initiation and incident dementia were inconsistent and imprecise (ARIC: HR = 0.30 [0.05, 1.93]; CHS: HR = 0.66 [0.27, 1.64]; HRS: HR = 1.09 [0.75, 1.59]). More stringent propensity score restriction had little effect on findings. Sensitivity analyses using a positive control outcome unexpectedly suggested antihypertensive medication initiation increased risk of coronary heart disease in all three samples. Positive control outcome analyses suggested substantial residual confounding in effect estimates from our target trials, precluding conclusions about the impact of antihypertensive medication initiation on dementia risk through target trial emulation. Formalized processes for identifying violations of necessary assumptions will strengthen confidence in target trial emulation and avoid inappropriate confidence in emulated trial results.

Association of Cardiovascular Health in Young Adulthood With Long-Term Blood Pressure Trajectories.

Cardiovascular health (CVH) in young adulthood (YA) has been associated with cardiovascular outcomes in older age. However, little is known about the relationship between YA CVH and mid-life blood pressure (BP) trajectories. Baseline CVH (defined by 7 of the American Heart Association's [AHA] Life's Essential 8 [LE8] metrics, excluding BP) was measured in YA with individual metrics scored and averaged as a composite LE8 score. Categorical CVH status was defined as high, moderate, and low. Latent class analysis was used to identify trajectories of mid-BP (mean of systolic blood pressure [SBP] and diastolic blood pressure [DBP]) from average ages 35 to 55 years. Multinomial logistic regression was used to estimate the association of YA CVH status (continuously and categorically) with mid-life BP trajectory group membership. There were 3,688 participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study in YA with follow-up data for mid-life BP trajectories. We observed 3 BP trajectory groups, labeled as Persistently-Low, Middle, and High-Increasing. On average, each 10-points higher baseline LE8 score (mean [SD] of 73.5 [13.1]) in YA was associated with adjusted odds ratios of 0.78 (95% CI, 0.72-0.84) for membership in the Middle and 0.65 (0.57-0.73) for membership in the High-Increasing trajectory groups. Compared with categorical low CVH status at baseline, those with high CVH were significantly less likely to be in the Middle and High-Increasing BP trajectory groups. Moderate or low CVH status in YA is associated with elevated mid-life BP trajectory. These data suggest that young adult CVH promotion may be important for the primordial prevention of hypertension.

Hypertensive disorders of pregnancy and midlife maternal cognition in a prospective cohort study.

Hypertensive disorders of pregnancy (HDP) are associated with an increased risk of cardiovascular disorders, with recent evidence linking pre-eclampsia with vascular dementia. We examined associations of HDP with cognitive performance measured in midlife, in a prospective cohort study, the Avon Longitudinal Study of Parents and Children. Six cognitive function domains were measured 20 years after pregnancy at a mean age of 51 years. The cognition tests were repeated at clinics in the following two years. Cognitive function domains measured were immediate and delayed verbal episodic memory, working memory, processing speed, verbal intelligence, and verbal fluency. Exposures were pre-eclampsia, gestational hypertension (GH), and a combined category of any HDP, all compared to normotensive pregnancy. Of 3393 pregnancies included in the analysis, GH was experienced by 417 (12.3%) and pre-eclampsia by 57 (1.7%). GH was associated with lower verbal episodic memory, in the delayed logic memory test (-0.16 SDs; 95% CI -0.30, -0.03; p=.015) and there was weak evidence of an association with the immediate logic memory test (-0.13 SDs; -0.27, 0.001; p=.058). However, we did not see steeper declines by age for women with GH and there was no evidence of associations with other cognitive domains or for pre-eclampsia with any domains. Results were not substantially changed after controlling for midlife blood pressure. Our findings suggest that a history of GH is associated with slightly reduced episodic memory 20 years after pregnancy, but we found no evidence of a quicker age-related decline compared to women with normotensive pregnancies.

Investigating associations of age at natural menopause with neuroimaging indicators of brain health in later‐life, using a British population‐based birth cohort

AbstractBackgroundEarlier menopause age associates with poorer cognitive performance post‐menopause, but links with dementia risk are mixed and the potential mechanisms underlying such associations are unclear. Few studies have examined the relationship between menopause age and later‐life brain health.MethodOur study included 126 women from Insight 46, the neuroscience sub‐study of the 1946 British birth cohort, which included combined amyloid PET and MRI scanning at mean age 70.7 years (standard deviation = 0.66). Age at natural menopause was self‐reported, during midlife, as years since birth at the time of period cessation; women who reported surgical menopause were excluded (n = 63). We tested for interactions of menopause age with APOE‐ε4 status and used multivariable regression analyses to test associations of menopause age with later‐life total brain volume (TBV) and hippocampal volume. A generalised linear model with log‐linked gamma distribution tested associations with white matter hyperintensity volume (WMHV). Models were cumulatively adjusted for total intracranial volume and age at scan (model 0/M0), hormone therapy (HT) use (M1:M0+HT) and for prospective early‐life and sociodemographic (M2:M1+childhood cognition, education, adult socioeconomic position), reproductive (M3:M2+menarche age, parity), and health‐related (M4:M3+smoking, BMI and blood pressure at age 36 years, APOE‐ε4 status) covariables.ResultThe association of menopause age with WMHV was modified by APOE‐ε4 status (p = 0.024); each 1‐year increase in menopause age associated with a 7.4% decrease in WMHV for ε4 carriers (n = 35) and a 2.4% WMHV increase for non‐carriers (n = 90). Menopause age did not associate with hippocampal volume, but there was a positive association with TBV (Table 1) which remained significant until we accounted for health‐related factors in model 4 (Figure 1). In post‐hoc analysis, adjustment for blood pressure at age 36 attenuated the association by 11.24%, explaining more of the attenuation than other model 4 covariables.ConclusionWe find evidence for links between age at natural menopause and later‐life neuroimaging measures. Later menopause associated with greater brain volume, partly explained by midlife blood pressure. Interactive effects of APOE‐ε4 status on associations with WMHV, an indicator of brain pathology, warrant further investigation.

Middle Age Prevention of Future Alzheimer’s Disease and Related Dementias with Intensive Treatment of Hypertension: Middle PATH Clinical Trial Proposal

AbstractStrong epidemiological evidence from multiple studies suggests that elevated systolic blood pressure (SBP) in midlife is a risk factor for Alzheimer’s disease and Related Dementias (ADRD) later in life. The most common neuropathology of biomarker‐confirmed AD is combined AD neuropathological changes and cerebrovascular disease. Hypertension is a leading cause of cerebrovascular disease. The SPRINT MIND trial demonstrated that a goal SBP&lt;120 mm Hg reduced risk for combined mild cognitive impairment (MCI) and dementia by 15% in older individuals compared to a goal SBP&lt;140 mm Hg. SBP can be safely treated with inexpensive medications. Despite being potentially safe and cost‐effective, with strong supporting evidence for benefit, intensive SBP lowering in midlife to reduce future ADRD risk has never been studied, likely because clinical outcomes of MCI and dementia are not practical in this age range in a trial that is usually limited to about 5 years. Elevated SBP is a major risk factor for white matter hyperintensity volume (WMHV) accumulation, an MRI marker with extensive evidence demonstrating this to be associated with and predictive of incident ADRD, making WMHV a suitable surrogate outcome for the initial trial period. While we acknowledge the challenges of using a surrogate outcome, there is no suitable alternative when testing interventions to lower future ADRD risk starting in middle age, a strategy that we believe is essential. The Alzheimer’s Prevention Initiative and Wake Forest have formed a collaboration to investigate the effect of goal SBP&lt;120 mm Hg compared to the SBP achieved by enhanced usual care (SBP = 135 mm Hg) on annualized rate of WMHV accumulation in persons ages 45‐65 who have some existing vascular risk at baseline. Secondary outcomes of changes in AD blood biomarkers and relevant cognitive test scores will help elucidate whether and how SBP and AD are interactive or independent deleterious pathophysiological processes. The intention, should the initial phase prove successful, is to continue and expand the trial until a clinical benefit can definitively be assessed.

Middle Age Prevention of Future Alzheimer’s Disease and Related Dementias with Intensive Treatment of Hypertension: Middle PATH Clinical Trial Proposal

AbstractStrong epidemiological evidence from multiple studies suggests that elevated systolic blood pressure (SBP) in midlife is a risk factor for Alzheimer’s disease and Related Dementias (ADRD) later in life. The most common neuropathology of biomarker‐confirmed AD is combined AD neuropathological changes and cerebrovascular disease. Hypertension is a leading cause of cerebrovascular disease. The SPRINT MIND trial demonstrated that a goal SBP&lt;120 mm Hg reduced risk for combined mild cognitive impairment (MCI) and dementia by 15% in older individuals compared to a goal SBP&lt;140 mm Hg. SBP can be safely treated with inexpensive medications. Despite being potentially safe and cost‐effective, with strong supporting evidence for benefit, intensive SBP lowering in midlife to reduce future ADRD risk has never been studied, likely because clinical outcomes of MCI and dementia are not practical in this age range in a trial that is usually limited to about 5 years. Elevated SBP is a major risk factor for white matter hyperintensity volume (WMHV) accumulation, an MRI marker with extensive evidence demonstrating this to be associated with and predictive of incident ADRD, making WMHV a suitable surrogate outcome for the initial trial period. While we acknowledge the challenges of using a surrogate outcome, there is no suitable alternative when testing interventions to lower future ADRD risk starting in middle age, a strategy that we believe is essential. The Alzheimer’s Prevention Initiative and Wake Forest have formed a collaboration to investigate the effect of goal SBP&lt;120 mm Hg compared to the SBP achieved by enhanced usual care (SBP≥135 mm Hg) on annualized rate of WMHV accumulation in persons ages 45‐65 who have some existing vascular risk at baseline. Secondary outcomes of changes in AD blood biomarkers and relevant cognitive test scores will help elucidate whether and how SBP and AD are interactive or independent deleterious pathophysiological processes. The intention, should the initial phase prove successful, is to continue and expand the trial until a clinical benefit can definitively be assessed.

Effect of Age Range on Power for a Clinical Trial Investigating the Effect of Intensive Systolic Blood Pressure Control on White Matter Hyperintensity Volume Accumulation

AbstractBackgroundEpidemiological evidence has repeatedly demonstrated elevated systolic blood pressure (SBP) in midlife as a modifiable risk factor for Alzheimer’s Disease and Related Dementia (ADRD) later in life. Despite SBP being readily treatable with safe and inexpensive medications, no clinical intervention implementing a lower SBP goal (&lt;120 mm Hg) in midlife to lower future ADRD risk has ever been attempted. Clinical outcomes are not practical in the age range of interest (45‐65 or 45‐70) during an initial trial period of 5 years however robust evidence demonstrates white matter hyperintensity volume (WMHV) as an MRI finding associated with and predictive of incident ADRD.MethodWe used four data sets (SPRINT, Wisconsin Registry for Alzheimer’s Prevention, Framingham, and UK Biobank) with longitudinal MRI data to examine the effect of age range on power for a clinical trial proposal investigating the effect of intensive SBP control on annualized rates of WMHV accumulation in persons starting in middle age. Analyses were conducted separately in each data set. We calculated mean, standard deviations, and annualized rates of WMHV accumulation (derived from T2 FLAIR MRI), using the linear rate of change for accumulation rate, first stratifying by SBP ( = 132 mm Hg vs &lt;132mm Hg except in SPRINT where groups were stratified by goal SBP group) and then by various age ranges. Next, we examined the effect of age range on necessary sample size with 80% power and two‐tailed alpha of 0.05 for a prospective clinical trial.ResultAs expected, annualized WMHV accumulation rate is lower with younger age in all data sets. However, variability decreased (all four data sets) and the percent reduction achieved at lower SBPs is higher at younger ages (3/4 data sets), thus increasing power when excluding older individuals (e.g., &gt;65 years old, Table 1).ConclusionRestricting age to individuals to = 65 years‐old may unexpectedly increase power in a clinical trial designed to investigate the effect of goal SBP&lt;120 mm Hg on annualized WMHV accumulation rate. 45‐65 years‐old is a practical age range for the first ever clinical trial intended to investigate the effects of a lower SBP goal in middle age to reduce future ADRD risk.

Effect of Age Range on Power for a Clinical Trial Investigating the Effect of Intensive Systolic Blood Pressure Control on White Matter Hyperintensity Volume Accumulation

AbstractBackgroundEpidemiological evidence has repeatedly demonstrated elevated systolic blood pressure (SBP) in midlife as a modifiable risk factor for Alzheimer’s Disease and Related Dementia (ADRD) later in life. Despite SBP being readily treatable with safe and inexpensive medications, no clinical intervention implementing a lower SBP goal (&lt;120 mm Hg) in midlife to lower future ADRD risk has ever been attempted. Clinical outcomes are not practical in the age range of interest (45‐65 or 45‐70) during an initial trial period of 5 years however robust evidence demonstrates white matter hyperintensity volume (WMHV) as an MRI finding associated with and predictive of incident ADRD.MethodWe used four data sets (SPRINT, Wisconsin Registry for Alzheimer’s Prevention, Framingham, and UK Biobank) with longitudinal MRI data to examine the effect of age range on power for a clinical trial proposal investigating the effect of intensive SBP control on annualized rates of WMHV accumulation in persons starting in middle age. Analyses were conducted separately in each data set. We calculated mean, standard deviations, and annualized rates of WMHV accumulation (derived from T2 FLAIR MRI), using the linear rate of change for accumulation rate, first stratifying by SBP (≥132 mm Hg vs &lt;132mm Hg except in SPRINT where groups were stratified by goal SBP group) and then by various age ranges. Next, we examined the effect of age range on necessary sample size with 80% power and two‐tailed alpha of 0.05 for a prospective clinical trial.ResultAs expected, annualized WMHV accumulation rate is lower with younger age in all data sets. However, variability decreased (all four data sets) and the percent reduction achieved at lower SBPs is higher at younger ages (3/4 data sets), thus increasing power when excluding older individuals (e.g., &gt;65 years old, Table 1).ConclusionRestricting age to individuals to ≤65 years‐old may unexpectedly increase power in a clinical trial designed to investigate the effect of goal SBP&lt;120 mm Hg on annualized WMHV accumulation rate. 45‐65 years‐old is a practical age range for the first ever clinical trial intended to investigate the effects of a lower SBP goal in middle age to reduce future ADRD risk.

Differences in the association between midlife hypertension status and late‐life cognition and cognitive change: results from the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) Study

AbstractBackgroundThis study evaluates the association of midlife hypertension status and domain‐specific late‐life cognitive change allowing for possible differences by sex.MethodThe Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) cohort is a multi‐ethnic study of 1,712 Kaiser Permanente Northern California members age 65+ at enrollment in 2017. For 1,696 participants, we categorized the last examined clinical blood pressure measures from 1964‐1985 (mean age = 37.5) as hypotensive, normotensive, prehypertensive, or hypertensive. Verbal episodic memory and executive function were assessed using Spanish and English Neuropsychological Assessment Scales across three interview waves over 4 years and scores were z‐standardized to the baseline. Sex‐stratified linear mixed models with random intercepts estimated the associations of midlife hypertension status with domain‐specific baseline cognition and cognitive change using years since baseline as timescale. Models adjusted for age at blood pressure measurement, KHANDLE baseline age, race, ethnicity, education, practice effects, and interview mode (phone vs in‐person).ResultA greater proportion of men than women had midlife pre‐hypertension (44% vs 31%) or hypertension (21% vs 11%) (Table 1). Among men and women, midlife hypertension status was not associated with baseline executive function or verbal episodic memory (Table 2). Compared to men with normal midlife blood pressure, those with midlife hypotension (b = ‐0.10, 95% CI: ‐0.17, ‐0.04) or midlife hypertension experienced steeper declines in executive functioning (b = ‐0.05, 95% CI: ‐0.10, ‐0.004). Among women, only midlife hypertension was associated with decline in executive function (b = ‐0.04 95% CI: ‐0.09, 0.003), though not significantly different from normotensive women. Compared to normotensive men, those with midlife hypotension (b = ‐0.17, 95%CI: ‐0.27, ‐0.07) and those with pre‐hypertension (b = ‐0.06, 95% CI: ‐0.12, ‐0.004) experienced steeper decline in verbal episodic memory. Among women, only midlife hypertension was associated with steeper declines executive function (b = ‐0.04, 95% CI: ‐0.09, 0.003), though not significantly different from normotensive women. Though effect estimates of midlife hypertension status on cognitive outcomes differed by sex, these differences were not statistically significant.ConclusionBoth hypotension and hypertension 30‐50 years prior to cognitive assessments predicted accelerated cognitive decline in older men. Patterns were less consistent for women but not statistically distinguishable from associations among men.

Midlife hypertension is a risk factor for some, but not all, domains of cognitive decline in later life: a systematic review and meta-analysis.

Management of midlife blood pressure and hypertension status may provide a window of intervention to mitigate cognitive decline with advancing age. The aim of this review was to investigate the relationship between midlife hypertension and cognition in midlife and later life. Online electronic databases were searched from their inception to May 2022. Studies assessing midlife (40-65 years) hypertension and cognition at mid and/or later-life were included. A random effects meta-analysis was deemed appropriate. One hundred forty-nine studies across 26 countries were included. Qualitative synthesis found negative relationships between midlife hypertension and later life cognition in the domains of memory, executive function, and global cognition. Metanalytical evidence revealed midlife hypertension negatively impacts memory, executive function, and global cognition but had no observed effect on attention at midlife. Hypertension at midlife has a significant negative impact on cognition in mid-life and later life, namely memory, executive function, and global cognition.

High-normal systolic blood pressure in early midlife is a stronger risk factor for incident hypertension later in life for women than men

Abstract Background We have previously found that having high-normal blood pressure (BP) in early midlife is a stronger risk factor for incident hypertension later in life for women than for men. Whether this risk is related both to high-normal systolic and diastolic BP is not known. Purpose To explore whether there is a sex difference in risk of incident hypertension related to high-normal systolic and diastolic BP in early midlife. Methods In the community-based Hordaland Health Study, 1025 women and 703 men were examined at age 42 years (baseline) and re-examined after 26 years. Patients with hypertension at baseline were excluded. Attended BP was measured in triplets, and clinic BP taken as the average of the two last measurements. High-normal systolic BP was identified as systolic BP of 130-139 mmHg and high normal diastolic BP as diastolic BP 85-89 mmHg. Incident hypertension was identified as BP ≥140/90 mmHg or patient reported use of antihypertensive drugs on the follow-up visit. The associations of systolic and diastolic BP at baseline with incident hypertension at follow-up were explored in sex specific multivariable logistic regression analyses. Multivariable analysis looking at high-normal diastolic BP was adjusted for baseline BMI, systolic BP, high-normal diastolic BP , heart rate, physical activity, daily smoker, cholesterol, triglycerides. Multivariable analysis looking at high-normal systolic BP was adjusted for baseline BMI, diastolic BP, high normal systolic BP , heart rate, physical activity, daily smoker, cholesterol, triglyceride. Results are presented as odds ratios (OR), 95% confidence intervals (CI) and p-values. Results At baseline, average BP was 119/73 mmHg in women and 126/76 mmHg in men (p&amp;lt;0.001). A high-normal systolic BP was found in 16% of women and 35% of men (p&amp;lt; 0.001). A high-normal diastolic BP was found in 7% of women and 11% of men(p=0.008). After 26 years of follow-up, 39% of women and 45% of men had developed hypertension (p&amp;lt;0.05). In multivariable logistic regression analyses, high-normal systolic and diastolic BP at baseline predicted incident hypertension at follow up in both sexes (Table 1). High-normal systolic BP was a significantly stronger predictor for incident hypertension in women (OR 2.32, CI 1.5-3.5) with p&amp;lt;0.01 for sex interaction (Table 1). In men, high-normal diastolic BP at baseline, was the strongest predictor of incident hypertension (OR 2.1, 95% CI 1.2-3.7), but no sex-interaction was found for high-normal diastolic BP, possibly due to low numbers. Conclusions Having a high-normal systolic BP in early midlife is a greater risk for developing hypertension later in life for women than men.Table 1

Hypertension Trends and White Matter Brain Injury in the Offspring Framingham Heart Study Cohort.

Hypertension is the most potent stroke risk factor and is also related to cerebral small vessel disease. We studied the relation between mid-to-late-life hypertension trends and cerebral white matter injury in community-dwelling individuals from the FHS (Framingham Heart Study). FHS Offspring cohort participants with available mid-life and late-life blood pressure measurements and brain magnetic resonance imaging were included. Multiple regression analyses were used to relate hypertension trends (normotension-normotension [reference], normotension-hypertension, and hypertension-hypertension) to white matter injury metrics on diffusion tensor imaging (free water, fractional anisotropy, and peak skeletonized mean diffusivity) and Fluid Attenuated Inversion Recovery (white matter hyperintensity volume) by different blood pressure cutoffs (130/80, 140/90, and 150/90 mm Hg). We included 1018 participants (mean age 47.3±7.4 years at mid-life and 73.2±7.3 at late-life). At the 140/90 mm Hg cutoff, the hypertension-hypertension trend was associated with higher free water (β, 0.16 [95% CI, 0.03-0.30]; P=0.021) and peak skeletonized mean diffusivity (β, 0.15 [95% CI, 0.01-0.29]; P=0.033). At a 130/80 mm Hg cutoff, the hypertension-hypertension trend had significantly higher free water (β, 0.16 [95% CI, 0.01-0.30]; P=0.035); and the normotension-hypertension (β, 0.24 [95% CI, 0.03-0.44]; P=0.027) and hypertension-hypertension (β, 0.22 [95% CI, 0.04-0.41]; P=0.022) trends had significantly increased white matter hyperintensity volume. Exploratory stratified analysis showed effect modifications by APOE ɛ4 allele and age. Mid-to-late-life hypertension exposure is significantly associated with microstructural and to a lesser extent, visible white matter injury; the effects are observed at both conventional and lower blood pressure cutoffs and are associated with longer duration of hypertension.

Relationships between Late-Life Blood Pressure and Cerebral Microinfarcts in Octogenarians: An Observational Autopsy Study.

Mid-life high blood pressure (BP) is a risk factor for cerebral microinfarcts. Less is known about the relationship between late-life BP and cerebral microinfarcts, the examination of which is the objective of the current study. This case-control study analyzed data from 551 participants (94.6% aged ≥80 years; 58.6% women) in the Adult Changes in Thought (ACT) study who had autopsy data on microinfarcts and four values of systolic and diastolic blood pressure (SBP and DBP) before death. Using the average of four values, SBP was categorized using 10 mmHg intervals; a trend was defined as a ≥10 mmHg rise or fall from the first to fourth values (average gap of 6.5 years). Multivariable-adjusted regression models were used to examine the associations of BP and microinfarcts, adjusting for age, sex, last BP-to-death time, APOE genotype, and antihypertensive medication use. Microinfarcts were present in 274 (49.7%) participants; there were multiple in 51.8% of the participants, and they were located in cortical areas in 40.5%, subcortical areas in 29.6%, and both areas in 29.9% of the participants. All SBP categories (reference of 100-119 mmHg) and both SBP trends were associated with higher odds of both the presence and number of microinfarcts. The magnitude of these associations was numerically greater for subcortical than cortical microinfarcts. Similar associations were observed with DBP. These hypothesis-generating findings provide new information about the overall relationship between BP and cerebral microinfarcts in octogenarians.

Neuroimaging, clinical and life course correlates of normal-appearing white matter integrity in 70-year-olds.

We investigate associations between normal-appearing white matter microstructural integrity in cognitively normal ∼70-year-olds and concurrently measured brain health and cognition, demographics, genetics and life course cardiovascular health. Participants born in the same week in March 1946 (British 1946 birth cohort) underwent PET-MRI around age 70. Mean standardized normal-appearing white matter integrity metrics (fractional anisotropy, mean diffusivity, neurite density index and orientation dispersion index) were derived from diffusion MRI. Linear regression was used to test associations between normal-appearing white matter metrics and (i) concurrent measures, including whole brain volume, white matter hyperintensity volume, PET amyloid and cognition; (ii) the influence of demographic and genetic predictors, including sex, childhood cognition, education, socio-economic position and genetic risk for Alzheimer's disease (APOE-ɛ4); (iii) systolic and diastolic blood pressure and cardiovascular health (Framingham Heart Study Cardiovascular Risk Score) across adulthood. Sex interactions were tested. Statistical significance included false discovery rate correction (5%). Three hundred and sixty-two participants met inclusion criteria (mean age 70, 49% female). Higher white matter hyperintensity volume was associated with lower fractional anisotropy [b = -0.09 (95% confidence interval: -0.11, -0.06), P < 0.01], neurite density index [b = -0.17 (-0.22, -0.12), P < 0.01] and higher mean diffusivity [b = 0.14 (-0.10, -0.17), P < 0.01]; amyloid (in men) was associated with lower fractional anisotropy [b = -0.04 (-0.08, -0.01), P = 0.03)] and higher mean diffusivity [b = 0.06 (0.01, 0.11), P = 0.02]. Framingham Heart Study Cardiovascular Risk Score in later-life (age 69) was associated with normal-appearing white matter {lower fractional anisotropy [b = -0.06 (-0.09, -0.02) P < 0.01], neurite density index [b = -0.10 (-0.17, -0.03), P < 0.01] and higher mean diffusivity [b = 0.09 (0.04, 0.14), P < 0.01]}. Significant sex interactions (P < 0.05) emerged for midlife cardiovascular health (age 53) and normal-appearing white matter at 70: marginal effect plots demonstrated, in women only, normal-appearing white matter was associated with higher midlife Framingham Heart Study Cardiovascular Risk Score (lower fractional anisotropy and neurite density index), midlife systolic (lower fractional anisotropy, neurite density index and higher mean diffusivity) and diastolic (lower fractional anisotropy and neurite density index) blood pressure and greater blood pressure change between 43 and 53 years (lower fractional anisotropy and neurite density index), independently of white matter hyperintensity volume. In summary, poorer normal-appearing white matter microstructural integrity in ∼70-year-olds was associated with measures of cerebral small vessel disease, amyloid (in males) and later-life cardiovascular health, demonstrating how normal-appearing white matter can provide additional information to overt white matter disease. Our findings further show that greater 'midlife' cardiovascular risk and higher blood pressure were associated with poorer normal-appearing white matter microstructural integrity in females only, suggesting that women's brains may be more susceptible to the effects of midlife blood pressure and cardiovascular health.

Genetically Predicted Blood Pressure and Cognition in Midlife: A UK Biobank Study.

This UK Biobank study uses a mendelian randomization approach to mitigate the variability and confounding that has affected previous analyses of the relationship between measured blood pressure (BP) and cognition and thus delineate the true association between the two. Systolic BP (SBP) and diastolic BP polygenic risk scores (PRSs) were calculated using summary statistics from the International Consortium of Blood Pressure-Genome Wide Association Study (n=299 024). Adjusted nonlinear mixed-effects regression models were used, including a natural splines term for BP-PRS with outcomes of fluid intelligence, reaction time (RT), and composite attention score. Moderating effects of age, sex, and antihypertensive use were assessed in separate models. There were 448 575 participants (mean age, 56.3 years; age range, 37-72 years) included in the analysis after genetic and neurological disease exclusions. Genetic propensity for high SBP had an approximately linear association with worsened fluid intelligence (P=0.0018). This relationship was significantly moderated by age (P<0.0001). By contrast, genetic propensity for high and low SBP and diastolic BP predicted worse attention function (P=0.0099 and P=0.0019), with high PRSs predicting worse function than low PRSs. Genetic propensity for low SBP and diastolic BP was associated with considerably worse RTs, while for high SBP-PRSs, the RT plateaued (P<0.0001). The relationships between RT and the PRSs were significantly moderated by sex (P<0.0001) and antihypertensive use (P<0.0001). Genetic propensity for high and low BP impacts on midlife cognition in subtle ways and differentially affects cognitive domains. While a genetic propensity to low BP may preserve nontimed tests in midlife, it may come at a trade-off with worsened attention scores and RT.

Long-term blood pressure patterns in midlife and dementia in later life: Findings from the Framingham Heart Study.

Long-term blood pressure (BP) measures, such as visit-to-visit BP variability (BPV) and cumulative BP, are strong indicators of cardiovascular risks.This study modeled up to 20 years of BP patterns representative of midlife by using BPV and cumulative BP, then examined their associations with development of dementia in later life. For 3201 individuals from the Framingham Heart Study, multivariate logistic regression analyses were performed to examine the association between long-term BP patterns during midlife and the development of dementia (ages ≥65). After adjusting for covariates, every quartile increase in midlife cumulative BP was associated with a sequential increase in the risk of developing dementia (e.g., highest quartile of cumulative systolic blood pressure had approximately 2.5-fold increased risk of all-cause dementia). BPV was not significantly associated with dementia. Findings suggest that cumulative BP over the course of midlife predicts risk of dementia in later life. HIGHLIGHTS Long-term blood pressure (BP) patterns are strong indicators of vascular risks. Cumulative BP and BP variability (BPV) were used to reflect BP patterns across midlife. High cumulative BP in midlife is associated with increased dementia risk. Visit-to-visit BPV was not associated with the onset of dementia.

Educational Attainment and Dementia: Mediation by Mid-Life Vascular Risk Factors.

Lower education is associated with higher burden of vascular risk factors in mid-life and higher risk of dementia in late life. We aim to understand the causal mechanism through which vascular risk factors potentially mediate the relationship between education and dementia. In a cohort of 13,368 Black and White older adults in the Atherosclerosis Risk in Communities Study, we assessed the relationship between education (grade school, high school without graduation, high school graduate or equivalent, college, graduate/professional school) and dementia among all participants and among those with incident stroke. Cox models were adjusted for age, race-center (a variable stratified by race and field center), sex, apolipoprotein E (APOE) ε4 genotype, and family history of cardiovascular disease. Causal mediation models assessed mediation by mid-life systolic blood pressure, fasting blood glucose, body mass index, and smoking. More education was associated with 8 to 44% lower risk of dementia compared to grade school-level education in a dose-response pattern, while the relationship between education and post-stroke dementia was not statistically significant. Up to 25% of the association between education and dementia was mediated through mid-life vascular risk factors, with a smaller percentage mediated for lower levels of education. A substantial proportion of the relationship between education and dementia was mediated through mid-life vascular risk factors. However, risk factor modification is unlikely to fully address the large educational disparities in dementia risk. Prevention efforts must also address disparities in socioeconomic resources leading to divergent early-life education and other structural determinants of mid-life vascular risk factors. ANN NEUROL 2023;94:13-26.

Abstract 54: Newly Initiation of Antihypertensive Medication on Reduction of Incident Dementia: Emulation of Target Trials Based on the Health and Retirement Study

Background: Although antihypertensive medication use is associated with a lower risk of dementia in observational studies, such an effect is rarely found in randomized controlled trials (RCTs). As midlife high blood pressure is more predictive of incident dementia than hypertension in late life, so midlife hypertension may be the target for intervention. However, no such an RCT has been conducted to prevent incident dementia through reducing high blood pressure from midlife. Therefore, we aimed to emulate a target trial with an observational study design to estimate the effect of initiating antihypertensive medication from midlife on reducing incident dementia. Hypothesis: We assessed the hypothesis that newly initiating antihypertensive medication among midlife adults with hypertension reduces incident dementia. Methods: New-user design was used to emulate a target trial using data from the Health and Retirement Study from 1996 to 2018 with non-institutional dementia-free participants aged 45 to 65 years without taking antihypertensive medication in past two years. Participants with information of self-reported hypertension diagnosis and new use of antihypertensive medication, as well as no dementia based on algorithm were included in the analysis and represented group with/without initiating antihypertensive medication. An intention-to-treat approach was applied for analysis, and sequential emulation was used to increase the efficiency of intention-to-treat analysis. Proportional hazards models were applied to estimate the effect of initiating antihypertensive medication on incident dementia. Inverse probability of treatment and censoring weights were created to adjust for confounding and selection bias due to loss to follow-up, and death was considered as a competing event. Another emulated target trial with the same specifications was conducted among late-life adults aged 66 years or older for comparison. Results: A total of 3,151 non-unique participants (baseline mean age: 59.0 ± 4.0 years, 54.6% (n=1,719) women, 78.3% (n=2468) Whites, 71.4% (n=2,249) initiating antihypertensive medication) were included in the analysis. Initiating antihypertensive medication showed benefit in reducing incident dementia over a total of 22-year follow-up, with a reduction of risk by 19% (hazards ratio=0.81, 95% confidence interval: 0.66, 0.99). No significant reduction was observed for initiators of antihypertensive medication from late life. Conclusions: Initiating antihypertensive medication from midlife, but not from late life may reduce incident dementia. Future studies are warranted to estimate the effect of blood pressure lowering in midlife through other means of intervention in reducing incident dementia.