To the Editor:
The conclusion of Power and colleagues1 (p.654) that “epidemiologic research does not provide clear evidence for a relationship between blood pressure and Alzheimer disease” is based on 18 prospective studies exploring this link. Although the meta-analysis results appear negative, there are several issues that make this conclusion problematic.
A number of studies used hypertension at baseline in their analyses, without considering whether future hypertension developed, or whether those who were hypertensive at baseline achieved control via medication. Such changes in blood pressure would lead to misclassification of “exposure” (measured hypertension), which usually, when nondifferential, lead to bias toward the null. Power et al advocate that future research should collect data on antihypertensive medication use and achieved control. We concur. Approximately 36% of patients taking antihypertensive medication have poor blood pressure control.2 Blood pressure measurements throughout follow-up are needed, along with analyses treating blood pressure as a time-dependent variable.
Another source of misclassification is self-reported hypertension. About half of the cited studies rely on self-report at baseline, rather than measured blood pressure. Self-report data are unreliable. Findings from the 2005–2006 National Health and Nutrition Examination Surveys indicated that only 78% of hypertensive adults were aware of their condition.2
Four studies used measured blood pressure as a continuous measure, and they were all negative. However, analyses using continuous blood pressure values assume that there is a linear dose-response between blood pressure and Alzheimer disease risk, a strong assumption. An alternative approach would be to consider standard categories of blood pressure, such as systolic pressures of ≥160 mm Hg, 140 to 160 mm Hg, and <140 mm Hg, which are free of assumptions of linearity. Such data are reported in Figures 5 and 6 of the paper. Considering Figure 5 (systolic blood pressure), 2 of the 6 studies show that Alzheimer disease risk increases with blood pressure category, whereas in the other 4 there is little trend or a negative trend. However, one of the latter studies did find a positive trend in persons 65–74 years of age (Adult Changes in Thought study3). Alzheimer disease risk appears higher for the 140–159-mm Hg group versus the <140-mm Hg group (RR = 1.5 [95% confidence interval = 0.8–2.7]) and for the ≥160-mm Hg group (1.4 [0.7–2.7]). There was no positive trend in the group aged ≥75 years. Another apparently negative study in Figure 5, the East Boston study,4 had very low power in the longer follow-up group, with only 41 cases divided between categories of <160 and ≥160 mm Hg. In Figure 6, 3 of 6 diastolic blood pressure studies showed some positive trends, especially the Honolulu Aging Study,5 where the untreated (57% of the population who might most be expected to show an effect) demonstrated a strong positive dose-response with RRs of 3.5 (1.3–9.5) for the 90–94-mm Hg group and RR = 4.5 (1.5–13.1) for the ≥95-mm Hg group, versus the 80–89-mm Hg group. Two of the negative studies, as Power and colleagues note, were restricted to subjects >75 years old, where the effect of prior high blood pressure might be less apparent, whereas a third one3 showed a generally positive trend in the age group 65–75 years. Hence, the story is unclear when considering studies with categorical results.
The authors1 cite research demonstrating an association between uncontrolled hypertension and increased neurofibrillary tangles and neuritic plaques.6–8 These intriguing findings point to one potential mechanism whereby hypertension could affect disease onset. Longitudinal studies of hypertension and measures of chronic inflammation, including serum interleukin-6 and C-reactive protein, might also elucidate mechanisms for cognitive decline and dementia.
In summary, a firm conclusion about a relationship, possibly age dependent, between hypertension and Alzheimer disease remains elusive. Future epidemiologic studies using measured blood pressure as a time-dependent variable, as well as studies exploring underlying mechanisms, are needed.
Department of Environmental and Occupational Health
School of Public Health
Allan I. Levey
Department of Neurology
Emory University School of Medicine
Felicia C. Goldstein
Department of Neurology
Emory University School of Medicine
1. Power MC, Weuve J, Gagne JJ, McQueen MB, Viswanathan A, Blacker D. The association between blood pressure and incident Alzheimer disease: a systematic review and meta-analysis. Epidemiology. 2011;22:646–659.
2. Ostchega Y, Yoon SS, Hughes J, Louis T. Hypertension awareness, treatment, and control-continued disparities in adults: United States, 2005–2006. NCHS Data Brief. 2008;1–8.
3. Li G, Rhew IC, Shofer JB. Age-varying association between blood pressure and risk of dementia in those aged 65 and older: a community-based prospective cohort study. J Am Geriatr Soc. 2007;55:1161–1167.
4. Morris MC, Scherr PA, Hebert LE, Glynn RJ, Bennett DA, Evans DA. Association of incident Alzheimer disease and blood pressure measured from 13 years before to 2 years after diagnosis in a large community study. Arch Neurol. 2001;58:1640–1646.
5. Launer LJ, Ross GW, Petrovitch H. Midlife blood pressure and dementia: the Honolulu-Asia aging study. Neurobiol Aging. 2000;21:49–55.
6. Petrovitch H, White LR, Izmirilian G. Midlife blood pressure and neuritic plaques, neurofibrillary tangles, and brain weight at death: the HAAS. Honolulu-Asia Aging Study. Neurobiol Aging. 2000;21:57–62.
7. Hoffman LB, Schmeidler J, Lesser GT. Less Alzheimer disease neuropathology in medicated hypertensive than nonhypertensive persons. Neurology. 2009;72:1720–1726.
8. Sparks DL, Scheff SW, Liu H, Landers TM, Coyne CM, Hunsaker JC III. Increased incidence of neurofibrillary tangles (NFT) in non-demented individuals with hypertension. J Neurol Sci. 1995;131:162–169.