. Female sex, early-onset hypertension, and risk of dementia. Neurology. 2017 Oct 4; PubMed.


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  1. This is an interesting paper. There are several reasons why there might be a sex difference in the relationship between midlife hypertension and risk of dementia, i.e., higher rates in women. First, the paper purports to document that their method of ascertainment of dementia has been validated. However, the reference provided in the paper (#19) has no relationship to the current study using the Kaiser Permanente database and refers to a personal communication as the validation for the evaluation of dementia in a study done in members of a health program in Seattle. A further reference from that paper is to a publication on the accuracy of Medicare claims data to identify Alzheimer's disease in the Journal of Clinical Epidemiology by Taylor, et al. That paper shows that Medicare claims data, using all types of Medicare claims records, including hospital records, physician records, and so-called institutional records over a three- to five-year period, identified about 80 percent of all of the dementia cases that were in the CERAD registry. However, the CERAD registry by definition was a registry of patients seen and evaluated in tertiary care facilities at major teaching hospitals and AD centers in the late 1990s, and these patients were most likely to have been referred from clinical services within these centers and therefore much more likely to have dementia diagnoses on their hospital records. Furthermore, CERAD likely reported their diagnoses of dementia to the primary care physician. Thus, there still may be a substantial underreporting of dementia in this paper. The likelihood of a dementia diagnosis being on a hospital record is a function of the number of times an individual is seen by a physician or in hospital care. Women have a higher level of morbidity and hospitalizations than men and it is possible, therefore, that the diagnosis of dementia was more likely identified among women as compared to men. Therefore, there may be a substantial bias in using the database for their study.

    Men have a higher mortality, especially in relationship to hypertension and atherosclerosis, and may have died prior to the diagnosis of dementia appearing on their hospital record or other records. The time between the dementia diagnosis and death after the diagnosis of dementia will, in part, determine the likelihood that the dementia diagnosis will appear on a medical record and be included in this study, and since men have a higher mortality or possibly shorter length of time with their dementia, the diagnosis may not be included in their records. I would suspect that this is the most likely explanation for this sex difference, i.e., a bias associated with likelihood of dementia appearing on the medical records.

    The second and interesting possibility is that the association may be a function of use of sex steroid hormones, i.e., estrogens and progesterone, in women. The cohort that they describe probably included large numbers of women who were using estrogen or estrogen plus progesterone prior to the results of the Women's Health Initiative (WHI), etc. In the WHI, the use of estrogens or estrogen plus progesterone was associated with an increased risk of stroke and also with an increased risk of dementia. Furthermore, studies have shown that estrogen and progesterone therapy, as well as estrogens alone, are associated with an increased risk of hypertension. Thus, it is possible that the midlife hypertension plus the use of estrogens or estrogens plus progesterone may have been associated with a further increase in the risk of dementia. It would be very interesting for the group to analyze their data among the women in relationship to prior use of estrogens and progesterone, midlife hypertension, and risk of dementia. Was the higher risk of dementia primarily found among women who were estrogen and estrogen plus progesterone users and those who were nonusers had a lower risk of dementia or risk similar to that of men?

    A third and final possibility is that they have previously reported from this same cohort (Whitmer et al., 2008) that central obesity in midlife is associated with an increased risk of dementia independent of diabetes and cardiovascular comorbidities. Fifty percent of adults have central obesity. Central obesity is a major risk factor for hypertension and is also a risk factor for diabetes, and previous studies from the group have also suggested that diabetes is related to dementia. Older women tend to be more obese than men, although men generally have more central obesity at younger ages while women tend to get more central obesity postmenopausally. It is possible that the interaction between obesity, development of hypertension, and diabetes may have differential effects in men and women and account for the observed association of dementia with hypertension only primarily in the women.

    Unfortunately, there are no solid clinical trial data substantiating that reduction of blood pressure, especially in middle age or even in older ages, is associated with any substantial decrease in the risk of dementia, and certainly no data on whether there is a differential effect between men and women. Such data from clinical trials as well as better evaluation of the underlying pathology, i.e., amount of vascular disease in the brain, small vessel disease, etc., would be critically important to further understand the relationship between midlife blood pressure and dementia risk, and especially the sex difference.


    . Central obesity and increased risk of dementia more than three decades later. Neurology. 2008 Sep 30;71(14):1057-64. Epub 2008 Mar 26 PubMed.

    View all comments by Lewis H. Kuller

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  1. High Blood Pressure in Younger Adults: Dementia Risk Only in Women?