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Effect of Hypertension on Midlife Cognition May Be Detrimental in Women

Key findings

  • The objective of this study was to understand how sex differences in the timing of hypertension onset may contribute to early midlife risk of cognitive decline that may differ by sex
  • The 48 hypertensive participants performed worse overall on measures of attention, working memory, and associative memory than the 147 normotensive participants
  • Hypertensive men performed worse only on attention, whereas hypertensive women performed worse on attention, working memory, and associative memory
  • The sex-related performance advantages in normotensive participants were attenuated when comparing hypertensive women (or men) to normotensive or hypertensive men (or women)
  • Using sex-specific cutoffs in cognitive and neuropsychological assessments may improve the timely detection of early cognitive decline in people who have no evidence of outright dementia

On average, men develop hypertension approximately a decade before women, but the prevalence of hypertension in women surpasses that of men by age 75. Hypertension is an independent risk factor for Alzheimer's disease (AD) and vascular dementia. Women are more likely than men to develop AD, they're often diagnosed later than men, and their cognitive decline is often faster.

Researchers at Massachusetts General Hospital have determined midlife hypertension has a greater impact on cognition in women than men, which may explain why sex differences in the timing of hypertension onset contribute to sex differences in the risk of cognitive decline.

Hannah L. Shields, of the Department of Psychiatry, the Clinical Neuroscience Laboratory of Sex Differences in the Brain and the Innovation Center on Sex Differences in Medicine (ICON-X), Jill M. Goldstein, PhD, MPH, founder and executive director of ICON-X and the Helen T. Moerschner Endowed MGH Research Institute chair in Women's Health, and colleagues report in the Journal of Neuropsychology.


In previous research, offspring in the New England Family Study, a subsidiary of the Collaborative Perinatal Study, were followed for more than 28 years to investigate sex differences in their medical and psychiatric outcomes. For this study, 212 offspring, born between 1959 and 1966, were re-recruited at ages 45 to 55.

The participants were asked to complete clinical, cognitive, and neuropsychological assessments, including the:

  • Digit Span Forward and Digit Span Backward
  • Controlled Oral Word Fluency Test
  • American National Adult Reading Test
  • Selective Reminding Test
  • 12-item Face–Name Associative Memory Exam

Characteristics of the Cohort

195 participants (100 men and 95 women according to sex assigned at birth; mean age 50) had complete data and were included in the analysis. 48 participants (32 men, 16 women) self-reported a hypertension diagnosis and took at least one antihypertensive medication.

As expected at midlife, significantly more men than women had hypertension, but there was substantial variability among women. Neither age of diagnosis nor the number of years since diagnosis differed significantly between men and women.

Hypertension and Neuropsychological Performance

The principal findings were:

  • Hypertensive participants performed worse than normotensive participants on measures of attention and associative memory
  • Hypertension was associated with poor attention in both men and women, but in women, it was also associated with worse working and associative memory
  • Within the normotensive subgroup, women outperformed men on verbal and associative memory, and men performed better on attention
  • The female advantage on associative memory in normotensive participants was attenuated when comparing hypertensive women with both normotensive and hypertensive men
  • Similarly, the male advantage on attention in normotensive participants was attenuated when comparing hypertensive men with both normotensive and hypertensive women

Clinical Assessment and Intervention

In this study, hypertension did not impair performance to such a degree that indicates potential dementia. However, the subtle yet significant changes in hypertensive men and women demonstrate a loss of natural advantage, which may be an early sign of cognitive decline.

Since hypertensive women performed similarly to men, developing and consistently using sex-specific cutoffs on neuropsychological assessments is important. Otherwise, the diagnosis of cognitive impairment could be missed or delayed.

A better understanding of sex differences in how early midlife hypertension affects cognition might lead to early sex-selective treatments that could postpone or even prevent cognitive decline in those at the highest risk.

Learn more about the Psychiatric and Neurodevelopmental Genetics Unit

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In a large genome-wide genotype-by-sex analysis, Massachusetts General Hospital researchers found that significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within schizophrenia, major depressive disorder and bipolar disorder.


Jill M. Goldstein, PhD, and Jordan W. Smoller, MD, ScD, of the Department of Psychiatry, and colleagues have reported the first modest evidence of sex-dependent autosomal genetic effects across neuropsychiatric and behavioral traits.