Fifteen studies, covering 16 populations, reported associations with late-life measures of blood pressure,22,26,28–40 with 9 reporting on an association with “history of hypertension,”22,26,29,30,32,35,36,39 3 with “hypertension at enrollment,”31,33,40 3 with continuous measures of systolic or diastolic BP,28,37,38 and 3 with categories of systolic or diastolic BP.28,37,38 The summary relative risk among the 9 studies reporting on the association between “history of hypertension” and Alzheimer disease was 0.95 (95% CI = 0.78–1.17). Results were similar when we combined studies reporting on late-life “history of hypertension” and on late-life “hypertension at enrollment” to compute a single summary estimate (RRΣ = 0.95 [95% CI = 0.78–1.14]). The pooled estimate from those studies reporting on the association per 10-mm Hg increment in late-life systolic BP and incident Alzheimer disease was 0.95 (95% CI = 0.90–1.00), but there was no clear pattern in the associations corresponding to categories of late-life systolic BP (Fig. 5). The pooled estimate from those studies reporting on the association per 10 mm Hg increment in diastolic BP and incident Alzheimer disease was 0.93 (95% CI = 0.84–1.04), and studies reporting on the association between incident Alzheimer disease and categories of late-life diastolic BP also suggested decreased risk of Alzheimer disease with higher diastolic BP (Fig. 6).
This systematic review and meta-analysis of prospective epidemiologic research does not provide clear evidence for a relationship between blood pressure and Alzheimer disease. There was some suggestion of an age-dependent effect of blood pressure on Alzheimer disease, although the evidence is relatively weak: there is a suggestion that midlife diastolic, but not midlife systolic, hypertension in midlife may have an adverse effect on risk of incident Alzheimer disease and a suggestion that elevated late-life BP may actually be beneficial.
Alternately (or additionally), blood pressure may be related to Alzheimer disease progression, rather than initiation, through mechanisms involving beta-amyloid peptides. In mouse models of Alzheimer disease with mutations in the amyloid precursor protein or presenilin genes (which in humans lead to Alzheimer disease in an autosomal dominant manner and are associated with increased production of beta-amyloid peptides), regulation of cerebral blood flow is impaired, and episodes of hypotension or hypertension result in undesired fluctuations in cerebral blood flow that may contribute to neuronal dysfunction.58,59 Several studies have also observed greater brain atrophy (specifically hippocampal and cortical atrophy) with increased blood pressure in both nondemented and demented persons.60–64 The mechanisms underlying this association are unclear, but some evidence suggests that it could result from an effect of subcortical vascular pathology on cortical neuronal apoptosis (the process of programmed cell death) which, in exaggerated form, is thought to lead to brain atrophy.65
Systematic review and meta-analysis do not protect from bias and other challenges common to epidemiologic research, even when, as in this review, we only consider prospective epidemiologic studies. As such, we must consider whether observed results are indicative of the true causal relationship between BP and Alzheimer disease or whether they can be attributed to bias.
Selection bias, which can arise when study participation is incomplete and is related to both the exposure and the outcome of interest, can have a substantial impact in studies of older adults. Such studies enroll those who have survived into older adulthood and remain healthy enough to participate in a research study; over time, loss to follow-up related to declining health and death is common. For example, the majority of studies looking at the association between late-life BP and Alzheimer disease enrolled participants after age 65 years. If initial enrollment or continued participation once enrolled is related to blood pressure and to Alzheimer disease (or their strong correlates), estimates of the association between blood pressure and Alzheimer disease will be biased,66–70 and this bias will be reflected in our summary estimates. Reported loss to follow-up in the studies included in this review ranges from approximately 20% to 80%, indicating that there is ample potential for selection bias.
The potential for selection bias may be large because hypertension is an established risk factor for cardiovascular morbidity and mortality.71–73 Risk of cardiovascular disease appears to double with each 20-mm Hg increase in systolic BP or 10-mm Hg increase in diastolic BP in adults ages 40–69 years. The risk ratio associated with these increases in blood pressure is somewhat smaller in adults aged 70 and older. However, the blood-pressure-related risk in this older group remains considerable, especially viewed in terms of the risk difference, which may in fact be greater for the older group, among whom baseline risk is considerably higher.74 In addition, clinical trials demonstrate a robust benefit of antihypertensive medication use on coronary heart disease, congestive heart failure, stroke, other cardiovascular events, cardiovascular-related mortality, and all-cause mortality.75 Those with higher blood pressure would therefore be expected to have decreased participation due to increased cardiovascular mortality and morbidity, which would limit initial participation or continued follow-up.
Likewise, cognitive impairment itself (for which the most common cause is Alzheimer disease, whether full-blown dementia or milder syndromes) is an established risk factor for nonparticipation76 and mortality.77,78 Often defined as having a low Mini-Mental State Examination score or increased difficulty with activities of daily living, cognitive impairment appears to be associated specifically with loss to follow-up and drop-out due to death in longitudinal cohorts of older adults.79,80 In summary, it is reasonable to expect that persons with hypertension-associated morbidity or mortality and cognitive impairment would be the least likely to be enrolled in or successfully continue participation in a longitudinal cohort study. This pattern of selection would lead to an underestimation of the blood-pressure-Alzheimer disease relationship, which may account, at least in part, for the suggestion of an inverse association between late-life hypertension and Alzheimer disease. It also suggests that the true adverse association between midlife measures of hypertension and Alzheimer disease may be stronger than that observed in the literature.
In addition, other evidence supports the existence of bias due to selection effects. The age-dependent pattern observed in the current review, where the mean or minimum age at baseline predicts the direction of the association, has been observed for several other proposed Alzheimer disease risk factors that are in themselves significant predictors of mortality, including smoking70 and total cholesterol.81 Although we cannot exclude a true age-dependent association for each of these risk factors, the consistency of this pattern, in which the risk factor appears to have an adverse effect at younger ages and an inverse effect at older ages, suggests that there may be a common underlying source of bias.
Reverse causation may also account for the observed pattern of association. Given that the follow-up time for many of the studies of late-life hypertension and Alzheimer disease was less than 5 years and the time between onset of the disease process and diagnosis of Alzheimer disease is likely much longer,4 the suggestion of an inverse association between late-life blood pressure and Alzheimer disease probably does not reflect a true effect of blood pressure on Alzheimer disease initiation. Instead, the pathologic process of Alzheimer disease may influence BP regulation, leading to a decline in blood pressure during disease development and progression.12 However, reverse causation is less likely to account for the suggestion of an adverse effect of midlife blood pressure on Alzheimer disease risk given that the dementia typically developed 10 to 20 years after blood pressure assessment. This suggestion of an adverse effect of midlife blood pressure on Alzheimer disease risk may instead be due to a real effect of blood pressure on cognition. In late life, it is thought that persons with less compliant blood vessels may require higher blood pressure (particularly systolic blood pressure) to maintain adequate brain perfusion.82–87
Confounding may partially account for the current findings. Our eligibility criteria required all studies to report results adjusted for, at minimum, age and sex. Most studies also adjusted for education. Additional adjustment for covariates such as alcohol consumption, presence of apolipoprotein E4, and smoking status did not materially affect results of individual studies,21,27 and few established risk factors for Alzheimer disease are likely to be strong confounders. However, we cannot preclude the possibility of residual confounding or confounding by unknown factors, particularly other aspects of the metabolic syndrome or physical activity.88–91
Misclassification of blood pressure is likely, given that most studies relied on self-report or measured blood pressure at a single study visit, but this is probably not a significant source of bias. There are several factors that can introduce variability into blood pressure measurements. Factors related to the measurement process, including body size and cuff position, can introduce error.92 In addition, blood pressure exhibits natural variation, both within a day and from day to day, and in some people may be elevated primarily in medical settings (“white coat hypertension”).93 Despite these factors, James et al94 found that reproducibility of blood pressure measures in a clinical setting is high, both within a visit and across visits separated by 2 weeks, and clinical measures are highly correlated with measures taken outside of the clinical setting. In addition, the validity of blood pressure measurements is supported by their clear association with vascular mortality74 and other health endpoints.71 As such, the degree of misclassification of blood pressure is unlikely to render study effect estimates unreliable. Moreover, given that all studies included in this review were prospective, it is unlikely that misclassification of blood pressure was differential relative to ultimate Alzheimer disease status. Therefore, the direction of bias resulting from misclassification would be, most likely, toward the null, and might contribute to the overall null findings, although it is unlikely to account for the suggestion of either an adverse association between midlife blood pressure and Alzheimer disease or an inverse association between late life blood pressure and Alzheimer disease.
Misclassification of Alzheimer disease status may be differential based on history of hypertension or measured blood pressure because diagnosis of Alzheimer disease often uses cardiovascular risk factors such as hypertension—either explicitly or implicitly—to exclude people who are likely to have underlying vascular dementia or vascular cognitive impairment.95–98 If the presence of hypertension leads to a greater likelihood of diagnosing vascular dementia or a mixed dementia rather than Alzheimer disease, the effect of blood pressure on Alzheimer disease risk would be underestimated. This source of bias could contribute to the suggested inverse associations between measures of late-life blood pressure and Alzheimer disease, but cannot account for the suggestion of an adverse association between measures of midlife hypertension and Alzheimer disease. The magnitude of such a bias is difficult to quantify, and depends on the diagnostic criteria used and how they were implemented, which varied across studies. However, in one study,21 exclusion of Alzheimer disease cases with contributing cerebrovascular disease identified through CT scan did not appreciably change effect estimates, suggesting that the effect may not be large.
In summary, selection bias, reverse causation, and differential misclassification of Alzheimer disease status may contribute to the suggestion of an inverse association between late-life blood pressure and Alzheimer disease, but cannot account for the suggestion of an adverse relationship between midlife hypertension and Alzheimer disease. However, the possibility of a true relationship between late-life blood pressure and Alzheimer disease, mediated by an effect of blood pressure on Alzheimer disease progression, cannot be dismissed.
Even if the suggested adverse relationship between midlife hypertension and Alzheimer disease is confirmed, the overlap between vascular and Alzheimer disease pathology will make it difficult to infer a causal relationship between midlife hypertension and Alzheimer disease pathology. As noted earlier, increasing evidence shows that Alzheimer disease and vascular dementia often coexist,3,4 and midlife hypertension also appears to be a risk factor for vascular dementia21,25,27 and vascular cognitive impairment.99 In addition, autopsy studies have suggested that, for a given level of Alzheimer disease pathology, concurrent cerebrovascular pathology is associated with earlier onset of clinically significant symptoms of dementia,8–10 which would lead to earlier diagnosis. However, it is currently unknown whether these concurrent conditions act additively or synergistically. As such, it is difficult to distinguish whether blood pressure is an independent risk factor for both Alzheimer disease and vascular dementia or whether the association between blood pressure and Alzheimer disease is driven partly or primarily by the impact of blood pressure on vascular pathology.
The role of medication use must also be considered. If blood pressure is causally related to Alzheimer disease risk, treatment of hypertension may make it difficult to detect such an effect in the population, particularly in later birth cohorts where treatment of blood pressure has been more aggressive.100–102 In one study that considered the association between midlife blood pressure and Alzheimer disease, no association was apparent in the study population as a whole, but there was a suggestion of an association between midlife hypertension and Alzheimer disease in untreated persons.21 In a second study that considered the impact of late-life blood pressure on Alzheimer disease, risk of Alzheimer disease was much stronger in participants with drug-untreated hypertension compared with those with drug-treated hypertension.22 The potential modification of the association between blood pressure and Alzheimer disease by antihypertensive medication use has major public health importance and deserves further study.103
Our review and meta-analysis has several limitations. Although we have summarized the prospective epidemiologic literature, the reported associations may not reflect the true causal effect of blood pressure on Alzheimer disease risk due to the presence of selection bias, reverse causation, or misclassification, as discussed earlier in the text. As the current review is based on published work, we cannot exclude the possibility that publication bias influences our findings. However, if publication bias were important, we would expect to see much stronger findings than those we observed. Furthermore, the cohorts reporting on the BP-Alzheimer disease association include a majority of the current major Alzheimer disease cohort studies. Finally, our consideration of an age-dependent association between blood pressure and Alzheimer disease risk is limited due to the very small number of studies reporting on the association between midlife measures of blood pressure and Alzheimer disease and the disparate treatment of information about hypertension, systolic BP, and diastolic BP across studies.
To promote comparability across studies, we suggest that future studies report estimates of risk per 10-mm Hg increment in systolic BP and in diastolic BP, as well as estimates of risk across standard categories of blood pressure, such as those recommended by the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.71 Future epidemiologic research should focus on the influence of midlife measures of blood pressure on Alzheimer disease risk, as further work in older cohorts is unlikely to provide additional information given the intractable issues of selection and reverse causation. Furthermore, future epidemiologic research on the association between blood pressure and Alzheimer disease should report on the pattern of antihypertension medication use and achieved control; it should also consider the potential modifying effects of antihypertensive drug use, including aspects of duration, intensity, and achieved level of blood pressure control.
In addition, we advocate continued systematic review of epidemiologic findings in a centralized database. This analysis was conducted in parallel with a similar review undertaken for the AlzRisk centralized database (www.alzrisk.org), hosted by the Alzheimer Research Forum (www.alzforum.org), which attempts to systematically catalogue all prospective cohort data on nongenetic risk factors for Alzheimer disease. Data on the relationship between Alzheimer disease and several risk factors, including blood pressure, are currently available, with additional risk factors being added regularly. AlzRisk will be updated as new and updated studies become available over time; we anticipate a substantial volume of new data given the aging of existing, long-established cohort studies, and increasing interest in cognitive outcomes.
Finally, there may be value in collaboration to combine the data from these cohorts to conduct patient data-level analysis of this relationship. This would allow for a systematic exploration of the role of age of BP measurement, antihypertensive medication use, and other factors in the association between BP and Alzheimer disease.
The current epidemiologic literature is insufficient for a definitive conclusion about a causal relationship between blood pressure and Alzheimer disease. However, the benefits of midlife blood pressure control on cardiovascular outcomes are well established and justify current clinical recommendations.
Portions of this work also appear on the online database of Alzheimer disease epidemiology findings AlzRisk (www.alzrisk.org), hosted by the Alzheimer Research Forum (www.alzforum.org), and are reprinted with permission. We also thank Xiang Gao, Fumiaki Imamura, Sanae Kishimoto, Martin Lajous, and Peter Liang for their help in determining eligibility for non-English language articles, and Shanshan Li for extracting data from a non-English language article included in this review.
1.Stampfer MJ. Cardiovascular disease and Alzheimer's disease: common links. J Intern Med
2.Breteler MM. Vascular risk factors for Alzheimer's disease: an epidemiologic perspective. Neurobiol Aging
3.Zekry D, Hauw JJ, Gold G. Mixed dementia: epidemiology, diagnosis, and treatment. J Am Geriatr Soc
4.Schneider JA, Arvanitakis Z, Bang W, Bennett DA. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology
5.Prins ND, van Dijk EJ, den Heijer T, et al. Cerebral white matter lesions and the risk of dementia. Arch Neurol
6.Prins ND, van Dijk EJ, den Heijer T, et al. Cerebral small-vessel disease and decline in information processing speed, executive function and memory. Brain
. 2005;128(pt 9):2034–2041.
7.Diaz-Ruiz C, Wang J, Ksiezak-Reding H, et al. Role of hypertension in aggravating Abeta neuropathology of AD Type and tau-mediated motor impairment. Cardiovasc Psychiatry Neurol
8.Esiri MM, Nagy Z, Smith MZ, Barnetson L, Smith AD. Cerebrovascular disease and threshold for dementia in the early stages of Alzheimer's disease. Lancet
9.Schneider JA, Wilson RS, Bienias JL, Evans DA, Bennett DA. Cerebral infarctions and the likelihood of dementia from Alzheimer disease pathology. Neurology
10.Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA
11.Skoog I, Lernfelt B, Landahl S, et al. 15-year longitudinal study of blood pressure and dementia. Lancet
12.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
13.Purnell C, Gao S, Callahan CM, Hendrie HC. Cardiovascular risk factors and incident Alzheimer disease: a systematic review of the literature. Alzheimer Dis Assoc Disord
14.Kennelly SP, Lawlor BA, Kenny RA. Blood pressure and the risk for dementia: a double edged sword. Ageing Res Rev
15.Wacholder S, McLaughlin JK, Silverman DT, Mandel JS. Selection of controls in case-control studies. I. Principles. Am J Epidemiol
16.Qiu C, Winblad B, Fratiglioni L. The age-dependent relation of blood pressure to cognitive function and dementia. Lancet Neurol
17.Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of Observational Studies in Epidemiology (MOOSE) group. JAMA
18.Wells G, Shea B, O'Connell D, etc. The Newcastle-Ottawa scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses. Ottawa Health Research Institute; 2009.
19.Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst
20.DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials
21.Launer LJ, Ross GW, Petrovitch H, Masaki K, Foley D, White LR, Havlik RJ. Midlife blood pressure and dementia: the Honolulu-Asia aging study. Neurobiol Aging
22.Bermejo-Pareja F, Benito-Leon J, Louis ED, et al. Risk of incident dementia in drug-untreated arterial hypertension: a population-based study. J Alzheimers Dis
23.Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med
24.Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ
25.Chiang CJ, Yip PK, Wu SC, et al. Midlife risk factors for subtypes of dementia: a nested case-control study in Taiwan. Am J Geriatr Psychiatry
26.Hayden KM, Zandi PP, Lyketsos CG, et al. Vascular risk factors for incident Alzheimer disease and vascular dementia: the Cache County study. Alzheimer Dis Assoc Disord
27.Kivipelto M, Helkala EL, Laakso MP, et al. Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease. Ann Intern Med
28.Li G, Rhew IC, Shofer JB, Kukull WA, Breitner JC, Peskind E, Bowen JD, McCormick W, Teri L, Crane PK, Larson EB. 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
29.Lindsay J, Laurin D, Verreault R, et al. Risk factors for Alzheimer's disease: a prospective analysis from the Canadian Study of Health and Aging. Am J Epidemiol
30.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
31.Muller M, Tang MX, Schupf N, Manly JJ, Mayeux R, Luchsinger JA. Metabolic syndrome and dementia risk in a multiethnic elderly cohort. Dement Geriatr Cogn Disord
32.Ogunniyi A, Hall KS, Gureje O, et al. Risk factors for incident Alzheimer's disease in African Americans and Yoruba. Metab Brain Dis
33.Raffaitin C, Gin H, Empana JP, et al. Metabolic syndrome and risk for incident Alzheimer's disease or vascular dementia: the Three-City Study. Diabetes Care
34.Ruitenberg A, Skoog I, Ott A, et al. Blood pressure and risk of dementia: results from the Rotterdam study and the Gothenburg H-70 Study. Dement Geriatr Cogn Disord
35.Shah RC, Wilson RS, Bienias JL, Arvanitakis Z, Evans DA, Bennett DA. Relation of blood pressure to risk of incident Alzheimer's disease and change in global cognitive function in older persons. Neuroepidemiology
36.Tyas SL, Manfreda J, Strain LA, Montgomery PR. Risk factors for Alzheimer's disease: a population-based, longitudinal study in Manitoba, Canada. Int J Epidemiol
37.Verghese J, Lipton RB, Hall CB, Kuslansky G, Katz MJ. Low blood pressure and the risk of dementia in very old individuals. Neurology
38.Qiu C, Winblad B, Marengoni A, Klarin I, Fastbom J, Fratiglioni L. Heart failure and risk of dementia and Alzheimer disease: a population-based cohort study. Arch Intern Med
39.Qu QM, Qiao J, Han JF, et al. [The incidence of dementia among elderly people in Xi' an, China]. Zhonghua Liu Xing Bing Xue Za Zhi
40.Forti P, Pisacane N, Rietti E, et al. Metabolic syndrome and risk of dementia in older adults. J Am Geriatr Soc
41.de Leeuw FE, de Groot JC, Oudkerk M, et al. Hypertension and cerebral white matter lesions in a prospective cohort study. Brain
. 2002;125(pt 4):765–772.
42.Viswanathan A, Chabriat H. Cerebral microhemorrhage. Stroke
43.Kazui S, Levi CR, Jones EF, Quang L, Calafiore P, Donnan GA. Risk factors for lacunar stroke: a case-control transesophageal echocardiographic study. Neurology
44.Veldink JH, Scheltens P, Jonker C, Launer LJ. Progression of cerebral white matter hyper intensities on MRI is related to diastolic blood pressure. Neurology
45.Longstreth WT Jr, Bernick C, Manolio TA, Bryan N, Jungreis CA, Price TR. Lacunar infarcts defined by magnetic resonance imaging of 3660 elderly people: the Cardiovascular Health Study. Arch Neurol
46.Prabhakaran S, Wright CB, Yoshita M, et al. Prevalence and determinants of subclinical brain infarction: the Northern Manhattan Study. Neurology
47.Vermeer SE, Koudstaal PJ, Oudkerk M, Hofman A, Breteler MM. Prevalence and risk factors of silent brain infarcts in the population-based Rotterdam Scan Study. Stroke
48.Vernooij MW, van der Lugt A, Ikram MA, et al. Prevalence and risk factors of cerebral microbleeds: the Rotterdam Scan Study. Neurology
49.Petrovitch H, White LR, Izmirilian G, et al. Midlife blood pressure and neuritic plaques, neurofibrillary tangles, and brain weight at death: the HAAS.Honolulu-Asia aging Study. Neurobiol Aging
50.Hoffman LB, Schmeidler J, Lesser GT, et al. Less Alzheimer disease neuropathology in medicated hypertensive than nonhypertensive persons. Neurology
51.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
52.Iadecola C, Gorelick PB. Converging pathogenic mechanisms in vascular and neurodegenerative dementia. Stroke
53.Shi J, Yang SH, Stubley L, Day AL, Simpkins JW. Hypoperfusion induces overexpression of beta-amyloid precursor protein mRNA in a focal ischemic rodent model. Brain Res
54.Jin K, Mao XO, Eshoo MW, et al. Microarray analysis of hippocampal gene expression in global cerebral ischemia. Ann Neurol
55.Nihashi T, Inao S, Kajita Y, et al. Expression and distribution of beta amyloid precursor protein and beta amyloid peptide in reactive astrocytes after transient middle cerebral artery occlusion. Acta Neurochir (Wien)
56.Saido TC, Yokota M, Maruyama K, et al. Spatial resolution of the primary beta-amyloidogenic process induced in postischemic hippocampus. J Biol Chem
57.Weller RO, Yow HY, Preston SD, Mazanti I, Nicoll JA. Cerebrovascular disease is a major factor in the failure of elimination of Abeta from the aging human brain: implications for therapy of Alzheimer's disease. Ann N Y Acad Sci
58.Niwa K, Kazama K, Younkin L, Younkin SG, Carlson GA, Iadecola C. Cerebrovascular autoregulation is profoundly impaired in mice overexpressing amyloid precursor protein. Am J Physiol Heart Circ Physiol
59.Niwa K, Younkin L, Ebeling C, Turner SK, Westaway D, Younkin S, Ashe KH, Carlson GA, Iadecola C. Abeta 1–40-related reduction in functional hyperemia in mouse neocortex during somatosensory activation. Proc Natl Acad Sci U S A
60.den Heijer T, Launer LJ, Prins ND, et al. Association between blood pressure, white matter lesions, and atrophy of the medial temporal lobe. Neurology
61.Firbank MJ, Wiseman RM, Burton EJ, Saxby BK, O'Brien JT, Ford GA. Brain atrophy and white matter hyperintensity change in older adults and relationship to blood pressure. Brain atrophy, WMH change and blood pressure. J Neurol
62.Skoog I, Andreasson LA, Landahl S, Lernfelt B. A population-based study on blood pressure and brain atrophy in 85-year-olds. Hypertension
63.Jouvent E, Viswanathan A, Chabriat H. Cerebral atrophy in cerebrovascular disorders. J Neuroimaging
64.Korf ES, White LR, Scheltens P, Launer LJ. Midlife blood pressure and the risk of hippocampal atrophy: the Honolulu Asia Aging Study. Hypertension
65.Viswanathan A, Gray F, Bousser MG, Baudrimont M, Chabriat H. Cortical neuronal apoptosis in CADASIL. Stroke
66.Cole SR, Hernan MA. Fallibility in estimating direct effects. Int J Epidemiol
67.Robins JM, Greenland S. Identifiability and exchangeability for direct and indirect effects. Epidemiology
68.Greenland S. Quantifying biases in causal models: classical confounding vs collider-stratification bias. Epidemiology
69.Hernan MA, Hernandez-Diaz S, Robins JM. A structural approach to selection bias. Epidemiology
70.Hernan MA, Alonso A, Logroscino G. Cigarette smoking and dementia: potential selection bias in the elderly. Epidemiology
71.Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA
72.Miura K, Daviglus ML, Dyer AR, et al. Relationship of blood pressure to 25-year mortality due to coronary heart disease, cardiovascular diseases, and all causes in young adult men: the Chicago Heart Association Detection Project in Industry. Arch Intern Med
73.Psaty BM, Furberg CD, Kuller LH, et al. Association between blood pressure level and the risk of myocardial infarction, stroke, and total mortality: the cardiovascular health study. Arch Intern Med
74.Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet
75.Psaty BM, Lumley T, Furberg CD, et al. Health outcomes associated with various antihypertensive therapies used as first-line agents: a network meta-analysis. JAMA
76.Euser SM, Schram MT, Hofman A, Westendorp RG, Breteler MM. Measuring cognitive function with age: the influence of selection by health and survival. Epidemiology
77.Bassuk SS, Wypij D, Berkman LF. Cognitive impairment and mortality in the community-dwelling elderly. Am J Epidemiol
78.Ganguli M, Dodge HH, Shen C, Pandav RS, DeKosky ST. Alzheimer disease and mortality: a 15-year epidemiological study. Arch Neurol
79.Chatfield MD, Brayne CE, Matthews FE. A systematic literature review of attrition between waves in longitudinal studies in the elderly shows a consistent pattern of dropout between differing studies. J Clin Epidemiol
80.Matthews FE, Chatfield M, Freeman C, McCracken C, Brayne C. Attrition and bias in the MRC cognitive function and ageing study: an epidemiological investigation. BMC Public Health
81.Anstey KJ, Lipnicki DM, Low LF. Cholesterol as a risk factor for dementia and cognitive decline: a systematic review of prospective studies with meta-analysis. Am J Geriatr Psychiatry
82.Chabriat H, Pappata S, Ostergaard L, et al. Cerebral hemodynamics in CADASIL before and after acetazolamide challenge assessed with MRI bolus tracking. Stroke
83.Chao LL, Buckley ST, Kornak J, et al. ASL perfusion MRI predicts cognitive decline and conversion from MCI to dementia. Alzheimer Dis Assoc Disord
84.Fayed N, Davila J, Oliveros A Jr, Medrano J, Castillo J. Correlation of findings in advanced MR techniques with global severity scales in patients with some grade of cognitive impairment. Neurol Res
85.Jefferson AL, Himali JJ, Beiser AS, et al. Cardiac index is associated with brain aging: the Framingham Heart Study. Circulation
86.Luckhaus C, Cohnen M, Fluss MO, et al. The relation of regional cerebral perfusion and atrophy in mild cognitive impairment (MCI) and early Alzheimer's dementia. Psychiatry Res
87.Pappata S, Varrone A, Vicidomini C, et al. SPECT imaging of GABA(A)/benzodiazepine receptors and cerebral perfusion in mild cognitive impairment. Eur J Nucl Med Mol Imaging
88.Harrington M, Weuve J, Blacker D. Physical Activity
. The AlzRisk Database. Alzheimer Research Forum.
89.Profenno LA, Porsteinsson AP, Faraone SV. Meta-analysis of Alzheimer's disease risk with obesity, diabetes, and related disorders. Biol Psychiatry
90.Duron E, Hanon O. Vascular risk factors, cognitive decline, and dementia. Vasc Health Risk Manag
91.Weuve J, McQueen M, Blacker D. Diabetes.
The AlzRisk Database. Alzheimer Research Forum.
92.Pickering TG, Hall JE, Appel LJ, et al. Recommendations for blood pressure measurement in humans and experimental animals. Part 1: Blood pressure measurement in humans: a statement for professionals from the Subcomittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure. Hypertension
93.Pickering TG. Blood pressure variability and ambulatory monitoring. Curr Opin Nephrol Hypertens
94.James GD, Pickering TG, Yee LS, Harshfield GA, Riva S, Laragh JH. The reproducibility of average ambulatory, home, and clinic pressures. Hypertension
95.McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology
96.American Psychiatric Association. Diagnostic and statistical manual of mental disorders: DSM-IV. 1998;xxvii:xxvii, 886 p.
97.Wetterling T, Kanitz RD, Borgis KJ. Comparison of different diagnostic criteria for vascular dementia (ADDTC, DSM-IV, ICD-10, NINDS-AIREN). Stroke
98.Hachinski VC, Iliff LD, Zilhka E, et al. Cerebral blood flow in dementia. Arch Neurol
99.Barone FC, Rosenbaum DM, Zhou J, Crystal H. Vascular cognitive impairment: dementia biology and translational animal models. Curr Opin Investig Drugs
100.Hajjar I, Kotchen TA. Trends in prevalence, awareness, treatment, and control of hypertension in the United States, 1988–2000. JAMA
101.Antikainen RL, Moltchanov VA, Chukwuma C Sr, et al. Trends in the prevalence, awareness, treatment and control of hypertension: the WHO MONICA Project. Eur J Cardiovasc Prev Rehabil
102.Burt VL, Cutler JA, Higgins M, et al. Trends in the prevalence, awareness, treatment, and control of hypertension in the adult US population. Data from the health examination surveys, 1960 to 1991. Hypertension
103.Viswanathan A, Rocca WA, Tzourio C. Vascular risk factors and dementia: how to move forward? Neurology