Variation in blood pressure and long-term risk of dementia: A population-based cohort study

Autoři: Yuan Ma aff001;  Frank J. Wolters aff001;  Lori B. Chibnik aff002;  Silvan Licher aff001;  M. Arfan Ikram aff001;  Albert Hofman aff001;  M. Kamran Ikram aff001
Působiště autorů: Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands aff001;  Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America aff002;  Department of Neurology, Erasmus MC University Medical Center, Rotterdam, the Netherlands aff003
Vyšlo v časopise: Variation in blood pressure and long-term risk of dementia: A population-based cohort study. PLoS Med 16(11): e32767. doi:10.1371/journal.pmed.1002933
Kategorie: Research Article
doi: 10.1371/journal.pmed.1002933



Variation in blood pressure may relate to dementia risk via autonomic disturbance or hemodynamic mechanisms, but the long-term associations are unclear. We aimed to determine whether blood pressure variation over a period of years, considering both magnitude and direction, is associated with the risk of dementia.

Methods and findings

In a prospective cohort study ongoing since 1989 in the Netherlands, 5,273 dementia-free participants (58.1% women; mean [SD] age, 67.6 [8.0] years) were included. As of 2016, 1,059 dementia cases occurred during a median follow-up of 14.6 years. Absolute variation in systolic blood pressure (SBP) was assessed as the absolute difference in SBP divided by the mean over two sequential visits every 4.2 (median) years, with the first quantile set as the reference level. The direction was the rise or fall in SBP, with the third quantile set as the reference level. We estimated the risk of dementia in relation to SBP variation measured at different time windows (i.e., at least 0, 5, 10, and 15 years) prior to dementia diagnosis, with adjustments for age, sex, education, apolipoprotein E (APOE) genotype, vascular risk factors, and history of cardiovascular disease. We repeated the above analysis for variation in diastolic blood pressure (DBP).

A large SBP variation was associated with an increased dementia risk, which became more pronounced with longer intervals between the assessment of SBP variation and the diagnosis of dementia. The hazard ratio (HR) associated with large variation (the highest quintile) increased from 1.08 (95% confidence interval [CI] 0.88–1.34, P = 0.337) for risk within 5 years of SBP variation measurement to 3.13 (95% CI 2.05–4.77; P < 0.001) for risk after at least 15 years since the measurement of SBP variation. The increased long-term risk was associated with both large rises (HR for the highest quintile, 3.31 [95% CI 2.11–5.18], P < 0.001) and large falls in SBP (HR for the lowest quintile, 2.20 [95% CI 1.33–3.63], P = 0.002), whereas the higher short-term risk was only associated with large falls in SBP (HR, 1.21 [95% CI 1.00–1.48], P = 0.017). Similar findings were observed for variation in DBP. Despite our assessment of major confounders, potential residual confounding is possible, and the findings on blood pressure variability over periods of years may not be generalizable to variability over periods of days and other shorter periods.


Results of this study showed that a large blood pressure variation over a period of years was associated with an increased long-term risk of dementia. The association between blood pressure variation and dementia appears most pronounced when this variation occurred long before the diagnosis. An elevated long-term risk of dementia was observed with both a large rise and fall in blood pressure.

Klíčová slova:

Alzheimer's disease – Antihypertensives – Blood pressure – Body Mass Index – Cardiology – Cardiovascular diseases – Dementia – Vascular dementia


1. Livingston G, Sommerlad A, Orgeta V, Costafreda SG, Huntley J, Ames D, et al. Dementia prevention, intervention, and care. Lancet. 2017;390(10113):2673–734. doi: 10.1016/S0140-6736(17)31363-6 28735855

2. Nichols E, Szoeke CEI, Vollset SE, Abbasi N, Abd-Allah F, Abdela J, et al. Global, regional, and national burden of Alzheimer’s disease and other dementias, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019;18(1):88–106. doi: 10.1016/S1474-4422(18)30403-4 30497964

3. Norton S, Matthews FE, Barnes DE, Yaffe K, Brayne C. Potential for primary prevention of Alzheimer’s disease: an analysis of population-based data. Lancet Neurol. 2014;13(8):788–94. doi: 10.1016/S1474-4422(14)70136-X 25030513

4. Lawes CM, Vander Hoorn S, Rodgers A. Global burden of blood-pressure-related disease, 2001. Lancet. 2008;371(9623):1513–8. doi: 10.1016/S0140-6736(08)60655-8 18456100

5. Williamson JD, Pajewski NM, Auchus AP, Bryan RN, Chelune G, et al; Sprint Mind Investigators for the SPRINT Research Group. Effect of Intensive vs Standard Blood Pressure Control on Probable Dementia: A Randomized Clinical Trial. JAMA. 2019.

6. Qiu C, Winblad B, Fratiglioni L. The age-dependent relation of blood pressure to cognitive function and dementia. Lancet Neurol. 2005;4(8):487–99. doi: 10.1016/S1474-4422(05)70141-1 16033691

7. Rothwell PM. Limitations of the usual blood-pressure hypothesis and importance of variability, instability, and episodic hypertension. Lancet. 2010;375(9718):938–48. doi: 10.1016/S0140-6736(10)60309-1 20226991

8. Stevens SL, Wood S, Koshiaris C, Law K, Glasziou P, Stevens RJ, et al. Blood pressure variability and cardiovascular disease: systematic review and meta-analysis. BMJ. 2016;354:i4098.

9. Alperovitch A, Blachier M, Soumare A, Ritchie K, Dartigues JF, Richard-Harston S, et al. Blood pressure variability and risk of dementia in an elderly cohort, the Three-City Study. Alzheimers Dement. 2014;10(5 Suppl):S330–7. doi: 10.1016/j.jalz.2013.05.1777 23954028

10. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al. Toward defining the preclinical stages of Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):280–92. doi: 10.1016/j.jalz.2011.03.003 21514248

11. Nagai M, Dote K, Kato M, Sasaki S, Oda N, Kagawa E, et al. Visit-to-Visit Blood Pressure Variability and Alzheimer’s Disease: Links and Risks. J Alzheimers Dis. 2017;59(2):515–26. doi: 10.3233/JAD-161172 28598842

12. Ikram MA, Brusselle GGO, Murad SD, van Duijn CM, Franco OH, Goedegebure A, et al. The Rotterdam Study: 2018 update on objectives, design and main results. Eur J Epidemiol. 2017;32(9):807–50. doi: 10.1007/s10654-017-0321-4 29064009

13. Stamler J, Stamler R, Neaton JD. Blood pressure, systolic and diastolic, and cardiovascular risks. US population data. Arch Intern Med. 1993;153(5):598–615. doi: 10.1001/archinte.153.5.598 8439223

14. de Bruijn RF, Bos MJ, Portegies ML, Hofman A, Franco OH, Koudstaal PJ, et al. The potential for prevention of dementia across two decades: the prospective, population-based Rotterdam Study. BMC Med. 2015;13:132. doi: 10.1186/s12916-015-0377-5 26195085

15. Cole SR, Hernan MA. Constructing inverse probability weights for marginal structural models. Am J Epidemiol. 2008;168(6):656–64. doi: 10.1093/aje/kwn164 18682488

16. Durrleman S, Simon R. Flexible regression models with cubic splines. Stat Med. 1989;8(5):551–61. doi: 10.1002/sim.4780080504 2657958

17. Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D, et al. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J. 2006;27(21):2588–605. doi: 10.1093/eurheartj/ehl254 17000623

18. Austin PC, Lee DS, Fine JP. Introduction to the Analysis of Survival Data in the Presence of Competing Risks. Circulation. 2016;133(6):601–9. doi: 10.1161/CIRCULATIONAHA.115.017719 26858290

19. van Middelaar T, van Dalen JW, van Gool WA, van den Born BH, van Vught LA, Moll van Charante EP, et al. Visit-To-Visit Blood Pressure Variability and the Risk of Dementia in Older People. J Alzheimers Dis. 2018;62(2):727–35. doi: 10.3233/JAD-170757 29480175

20. VanderWeele TJ, Ding P. Sensitivity Analysis in Observational Research: Introducing the E-Value. Ann Intern Med. 2017;167(4):268–74. doi: 10.7326/M16-2607 28693043

21. Rothwell PM, Howard SC, Dolan E, O’Brien E, Dobson JE, Dahlof B, et al. Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension. Lancet. 2010;375(9718):895–905. doi: 10.1016/S0140-6736(10)60308-X 20226988

22. Sabayan B, Wijsman LW, Foster-Dingley JC, Stott DJ, Ford I, Buckley BM, et al. Association of visit-to-visit variability in blood pressure with cognitive function in old age: prospective cohort study. BMJ. 2013;347:f4600. doi: 10.1136/bmj.f4600 23900315

23. Franklin SS, Gustin W 4th, Wong ND, Larson MG, Weber MA, Kannel WB, et al. Hemodynamic patterns of age-related changes in blood pressure. The Framingham Heart Study. Circulation. 1997;96(1):308–15. doi: 10.1161/01.cir.96.1.308 9236450

24. Delgado J, Bowman K, Ble A, Masoli J, Han Y, Henley W, et al. Blood Pressure Trajectories in the 20 Years Before Death. JAMA Intern Med. 2018;178(1):93–9. doi: 10.1001/jamainternmed.2017.7023 29204655

25. Tilvis RS, Hakala S-M. Determinants and significance of declining blood pressure in old age. A prospective birth cohort study. Eur Heart J. 1998;19(12):1872–8. doi: 10.1053/euhj.1998.1232 9886731

26. McGrath ER, Beiser AS, DeCarli C, Plourde KL, Vasan RS, Greenberg SM, et al. Blood pressure from mid- to late life and risk of incident dementia. Neurology. 2017;89(24):2447–54. doi: 10.1212/WNL.0000000000004741 29117954

27. Stewart R, Xue Q-L, Masaki K, Petrovitch H, Ross GW, White LR, et al. Change in blood pressure and incident dementia: a 32-year prospective study. Hypertension. 2009;54(2):233–40. doi: 10.1161/HYPERTENSIONAHA.109.128744 19564551

28. Qiu C, von Strauss E, Winblad B, Fratiglioni L. Decline in blood pressure over time and risk of dementia: a longitudinal study from the Kungsholmen project. Stroke. 2004;35(8):1810–5. doi: 10.1161/01.STR.0000133128.42462.ef 15232128

29. Launer LJ, Ross GW, Petrovitch H, Masaki K, Foley D, White LR, et al. Midlife blood pressure and dementia: the Honolulu–Asia aging study. Neurobiol Aging. 2000;21(1):49–55. doi: 10.1016/s0197-4580(00)00096-8 10794848

30. Oishi E, Ohara T, Sakata S, Fukuhara M, Hata J, Yoshida D, et al. Day-to-Day Blood Pressure Variability and Risk of Dementia in a General Japanese Elderly Population: The Hisayama Study. Circulation. 2017;136(6):516–25. doi: 10.1161/CIRCULATIONAHA.116.025667 28784822

31. Kronish IM, Lynch AI, Oparil S, Whittle J, Davis BR, Simpson LM, et al. The Association Between Antihypertensive Medication Nonadherence and Visit-to-Visit Variability of Blood Pressure: Findings From the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Hypertension. 2016;68(1):39–45. doi: 10.1161/HYPERTENSIONAHA.115.06960 27217410

32. Mitchell GF, van Buchem MA, Sigurdsson S, Gotal JD, Jonsdottir MK, Kjartansson O, et al. Arterial stiffness, pressure and flow pulsatility and brain structure and function: the Age, Gene/Environment Susceptibility—Reykjavik study. Brain. 2011;134(Pt 11):3398–407. doi: 10.1093/brain/awr253 22075523

33. Xu TY, Staessen JA, Wei FF, Xu J, Li FH, Fan WX, et al. Blood flow pattern in the middle cerebral artery in relation to indices of arterial stiffness in the systemic circulation. Am J Hypertens. 2012;25(3):319–24. doi: 10.1038/ajh.2011.223 22113170

34. Bos D, Wolters FJ, Darweesh SKL, Vernooij MW, de Wolf F, Ikram MA, et al. Cerebral small vessel disease and the risk of dementia: A systematic review and meta-analysis of population-based evidence. Alzheimers Dement. 2018;14(11):1482–92. doi: 10.1016/j.jalz.2018.04.007 29792871

35. Eto M, Toba K, Akishita M, Kozaki K, Watanabe T, Kim S, et al. Reduced endothelial vasomotor function and enhanced neointimal formation after vascular injury in a rat model of blood pressure lability. Hypertens Res. 2003;26(12):991–8. 14717342

36. Abbott NJ, Ronnback L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci. 2006;7(1):41–53. doi: 10.1038/nrn1824 16371949

37. Toth P, Tarantini S, Csiszar A, Ungvari Z. Functional vascular contributions to cognitive impairment and dementia: mechanisms and consequences of cerebral autoregulatory dysfunction, endothelial impairment, and neurovascular uncoupling in aging. Am J Physiol Heart Circ Physiol. 2017;312(1):H1–h20. doi: 10.1152/ajpheart.00581.2016 27793855

38. Wolters FJ, Zonneveld HI, Hofman A, van der Lugt A, Koudstaal PJ, Vernooij MW, et al. Cerebral Perfusion and the Risk of Dementia: A Population-Based Study. Circulation. 2017;136(8):719–28. doi: 10.1161/CIRCULATIONAHA.117.027448 28588075

39. Convertino VA, Rickards CA, Ryan KL. Autonomic mechanisms associated with heart rate and vasoconstrictor reserves. Clin Auton Res. 2012;22(3):123–30. doi: 10.1007/s10286-011-0151-5 22083580

40. Webb AJS, Fischer U, Mehta Z, Rothwell PM. Effects of antihypertensive-drug class on interindividual variation in blood pressure and risk of stroke: a systematic review and meta-analysis. Lancet. 2010;375(9718):906–15. doi: 10.1016/S0140-6736(10)60235-8 20226989

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