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 Sep;22(5):646-59.
PubMed.
Power et al. have done a thorough, systematic review and meta-analysis, according to the highest standards, on the association between hypertension and incident Alzheimer’s disease (AD). The results, however, are disappointing, since a clear association between hypertension and incident AD was not found. In the well-written discussion they address all potential sources of bias that could have contributed to these results.
They briefly address the possibility of misclassification of AD if, for example, hypertension leads to a greater likelihood of diagnosing vascular dementia or mixed dementia. Before concluding that there is no association between hypertension and dementia, the more fundamental problem of classification of old-age dementia, which is crucial for the interpretation of these epidemiological data, should be discussed. The distinction between AD and vascular dementia in old-age dementia is somewhat artificial, and the vast majority of patients suffer from mixed dementia. Excluding patients with a vascular component to the dementia probably contributed to the disappointing results of this meta-analysis, whereas from a pathophysiological point of view, these patients should have been included. In spite of the hypotheses underlying a potential link between hypertension and AD pathology (plaques and tangles), the association of hypertension with cerebrovascular disease and resulting cognitive decline is currently stronger.
Several randomized, controlled trials of hypertension treatment using the more pragmatic outcomes of cognitive decline or incident dementia instead of AD suggest a potential beneficial effect of hypertension treatment on cognitive decline, even in the very elderly over 80 years of age (Forette et al., 2002; Peters et al., 2008; reviewed in Ligthart et al., 2010). These results contrast with the current findings from epidemiological studies.
It would be of great clinical relevance if the current approach would be repeated with the more pragmatic outcome "dementia" instead of the specific nosological entity of AD. The new AlzRisk database could potentially be a good forum to mediate in this process. The results of Power et al. should be interpreted with the greatest caution, as the authors stress in their discussion. More epidemiological research, but certainly also more randomized, controlled trials of hypertension treatment to prevent cognitive decline and dementia in various populations, and with the more pragmatic outcome "incident dementia," are warranted and underway (Richard et al., 2009).
References:
Forette F, Seux ML, Staessen JA, Thijs L, Babarskiene MR, Babeanu S, Bossini A, Fagard R, Gil-Extremera B, Laks T, Kobalava Z, Sarti C, Tuomilehto J, Vanhanen H, Webster J, Yodfat Y, Birkenhäger WH, .
The prevention of dementia with antihypertensive treatment: new evidence from the Systolic Hypertension in Europe (Syst-Eur) study.
Arch Intern Med. 2002 Oct 14;162(18):2046-52.
PubMed.
Peters R, Beckett N, Forette F, Tuomilehto J, Clarke R, Ritchie C, Waldman A, Walton I, Poulter R, Ma S, Comsa M, Burch L, Fletcher A, Bulpitt C, .
Incident dementia and blood pressure lowering in the Hypertension in the Very Elderly Trial cognitive function assessment (HYVET-COG): a double-blind, placebo controlled trial.
Lancet Neurol. 2008 Aug;7(8):683-9.
PubMed.
Ligthart SA, Moll van Charante EP, Van Gool WA, Richard E.
Treatment of cardiovascular risk factors to prevent cognitive decline and dementia: a systematic review.
Vasc Health Risk Manag. 2010;6:775-85.
PubMed.
Richard E, Van den Heuvel E, Moll van Charante EP, Achthoven L, Vermeulen M, Bindels PJ, Van Gool WA.
Prevention of dementia by intensive vascular care (PreDIVA): a cluster-randomized trial in progress.
Alzheimer Dis Assoc Disord. 2009 Jul-Sep;23(3):198-204.
PubMed.
Power et al. have conducted a systematic review of studies of the associations of hypertension and incident Alzheimer's disease. Their bottom line is that their analysis does not offer either convincing support or refutation of the association. I applaud them for the huge amount of work that went into the review that itself will be of great aid to future researchers. My view is definite: that hypertension might be related to AD pathology or maybe not. The problem is that hypertension is a ubiquitous diagnosis these days. In our Mayo Clinic Study of Aging, a majority of subjects carry the diagnosis in their medical record. Undoubtedly, the chronicity and the severity make a big difference, but those features are very hard to quantify. Furthermore, there is convincing evidence that risks for AD due to hypertension are higher in middle age, or decades before dementia onset, and then slowly attenuate to the point that higher blood pressure actually looks protective in the older age group. This occurs for at least two reasons. First, orthostatic hypotension becomes more common with advancing age and is associated with a poor prognosis and with underlying degenerative disease of the brain. Second, cognitive impairment itself is associated with weight loss and other factors that might also cause blood pressure to drop as a person becomes symptomatic. Therefore, the timing of the baseline measurement of blood pressure relative to the onset of dementia is critical. It is certainly likely that many studies simply do not have the extended time of observation needed to demonstrate an association between hypertension and AD dementia.
Reply to comments by Edo Richard, David Knopman, and Ben Wolozin
We very much appreciate the careful attention to and appraisal of our systematic review and meta-analysis of prospective epidemiologic studies of blood pressure and risk of Alzheimer's disease (AD). Drs. Wolozin, Richard, and others raised concerns about the selection of studies for our meta-analysis and the appropriateness of evaluating AD rather than total dementia or cognitive decline as an outcome.
Dr. Wolozin and others maintained that the AlzRisk database should include data from additional cohorts. We’d like to clarify that we pre-specified the inclusion criteria for AlzRisk for all risk factors on the site, specifically, 1) the risk factor is studied in prospective relation to AD; 2) the report contains sufficient information to determine what covariates were included in analyses; 3) the analysis adjusts for at least age, gender, and education; 4) the report contains the effect estimates' 95 percent confidence intervals or corresponding P values, or sufficient information for us to compute them; and 5) the report includes results specific to AD (not just dementia). In addition, in order to perform meta-analysis, we require that there are at least four available studies where the exposure is defined sufficiently similarly to conduct a meta-analysis. If qualifying reports on blood pressure and AD from these sources appear in the future, we will most definitely add them to our database and update our meta-analyses.
Dr. Richard expressed the concern that limiting the meta-analysis to studies of AD may have excluded many of the cases with mixed or vascular dementias that could have been attributed in part to elevated blood pressure. Further, Dr. Richard proposed a review of “more pragmatic” outcomes such as total dementia and cognitive decline. While we agree that such an analysis would have been interesting, our goal was to evaluate blood pressure in relation to AD. This question was of interest because a relation between the two has been assumed, even though evidence linking blood pressure to AD pathology (e.g., amyloid-β and phosphorylated tau) is much weaker than evidence linking blood pressure to cerebrovascular pathology. Our analyses show that data from large-scale prospective epidemiologic studies of blood pressure and AD (in 20 distinct study populations) do not provide convincing evidence to support the hypothesis that higher blood pressure, at any point in the lifespan, increases AD risk. However, as we write in our accompanying paper in Epidemiology, preventing or treating hypertension can still benefit the public health, even where dementia is concerned. For example, systematic autopsy studies have shown that the presence of cerebrovascular pathology makes clinical dementia more likely for a given level of Alzheimer's pathology (Schneider et al., 2004). Thus, hypertension may substantially increase the burden of total dementia.
Intertwined AD and vascular pathologies in the CNS clearly frustrate the ability of epidemiologic studies to tie blood pressure to AD risk. In AlzRisk, when a paper includes results on both AD and total dementia, we record both sets of results on the site. Of the 20 populations noted above, 13 examined total dementia in addition to AD. Studies of two cohorts specifically defined their “total dementia” as AD and vascular dementia, and even without this definition, total dementia includes primarily these two diagnoses and mixed cases. Surprisingly, associations of measures of blood pressure with total dementia were not substantially stronger than corresponding associations with AD. Notably, the studies of total dementia are vulnerable to many of the same limitations found in studies of AD, including reverse causation, selection bias, misclassification of blood pressure, and misspecification of the shape of the association between blood pressure and dementia.
We agree that cognitive decline has several advantages as an outcome. For example, studies of cognitive decline in persons who are unlikely to have clinical dementia may be less prone to bias from reverse causation and differential selection. And, as Dr. Richard points out, cognitive decline may be especially practical in the context of clinical trials of blood pressure treatment. However, it seems unlikely that such studies could address the etiologic question about blood pressure and AD pathology. AlzRisk does not include studies of cognitive decline, but, in the detailed Discussion for each risk factor, we do consider findings from these studies when we interpret the epidemiologic results on AD.
Finally, we appreciate the insights of Dr. Knopman on the likely importance of timing. Given the blood pressure-lowering effects of frailty and cognitive decline, reverse causation could explain, in part, the “null” or protective findings in studies of the oldest participants. Studies of elevated blood pressure in midlife are less likely to suffer from bias due to reverse causation, but as of yet, these studies are frustratingly few.
References:
Schneider JA, Wilson RS, Bienias JL, Evans DA, Bennett DA.
Cerebral infarctions and the likelihood of dementia from Alzheimer disease pathology.
Neurology. 2004 Apr 13;62(7):1148-55.
PubMed.
Comments
Radboud University Medical Centre
Power et al. have done a thorough, systematic review and meta-analysis, according to the highest standards, on the association between hypertension and incident Alzheimer’s disease (AD). The results, however, are disappointing, since a clear association between hypertension and incident AD was not found. In the well-written discussion they address all potential sources of bias that could have contributed to these results.
They briefly address the possibility of misclassification of AD if, for example, hypertension leads to a greater likelihood of diagnosing vascular dementia or mixed dementia. Before concluding that there is no association between hypertension and dementia, the more fundamental problem of classification of old-age dementia, which is crucial for the interpretation of these epidemiological data, should be discussed. The distinction between AD and vascular dementia in old-age dementia is somewhat artificial, and the vast majority of patients suffer from mixed dementia. Excluding patients with a vascular component to the dementia probably contributed to the disappointing results of this meta-analysis, whereas from a pathophysiological point of view, these patients should have been included. In spite of the hypotheses underlying a potential link between hypertension and AD pathology (plaques and tangles), the association of hypertension with cerebrovascular disease and resulting cognitive decline is currently stronger.
Several randomized, controlled trials of hypertension treatment using the more pragmatic outcomes of cognitive decline or incident dementia instead of AD suggest a potential beneficial effect of hypertension treatment on cognitive decline, even in the very elderly over 80 years of age (Forette et al., 2002; Peters et al., 2008; reviewed in Ligthart et al., 2010). These results contrast with the current findings from epidemiological studies.
It would be of great clinical relevance if the current approach would be repeated with the more pragmatic outcome "dementia" instead of the specific nosological entity of AD. The new AlzRisk database could potentially be a good forum to mediate in this process. The results of Power et al. should be interpreted with the greatest caution, as the authors stress in their discussion. More epidemiological research, but certainly also more randomized, controlled trials of hypertension treatment to prevent cognitive decline and dementia in various populations, and with the more pragmatic outcome "incident dementia," are warranted and underway (Richard et al., 2009).
References:
Forette F, Seux ML, Staessen JA, Thijs L, Babarskiene MR, Babeanu S, Bossini A, Fagard R, Gil-Extremera B, Laks T, Kobalava Z, Sarti C, Tuomilehto J, Vanhanen H, Webster J, Yodfat Y, Birkenhäger WH, . The prevention of dementia with antihypertensive treatment: new evidence from the Systolic Hypertension in Europe (Syst-Eur) study. Arch Intern Med. 2002 Oct 14;162(18):2046-52. PubMed.
Peters R, Beckett N, Forette F, Tuomilehto J, Clarke R, Ritchie C, Waldman A, Walton I, Poulter R, Ma S, Comsa M, Burch L, Fletcher A, Bulpitt C, . Incident dementia and blood pressure lowering in the Hypertension in the Very Elderly Trial cognitive function assessment (HYVET-COG): a double-blind, placebo controlled trial. Lancet Neurol. 2008 Aug;7(8):683-9. PubMed.
Ligthart SA, Moll van Charante EP, Van Gool WA, Richard E. Treatment of cardiovascular risk factors to prevent cognitive decline and dementia: a systematic review. Vasc Health Risk Manag. 2010;6:775-85. PubMed.
Richard E, Van den Heuvel E, Moll van Charante EP, Achthoven L, Vermeulen M, Bindels PJ, Van Gool WA. Prevention of dementia by intensive vascular care (PreDIVA): a cluster-randomized trial in progress. Alzheimer Dis Assoc Disord. 2009 Jul-Sep;23(3):198-204. PubMed.
View all comments by Edo RichardMayo Clinic College of Medicine
Power et al. have conducted a systematic review of studies of the associations of hypertension and incident Alzheimer's disease. Their bottom line is that their analysis does not offer either convincing support or refutation of the association. I applaud them for the huge amount of work that went into the review that itself will be of great aid to future researchers. My view is definite: that hypertension might be related to AD pathology or maybe not. The problem is that hypertension is a ubiquitous diagnosis these days. In our Mayo Clinic Study of Aging, a majority of subjects carry the diagnosis in their medical record. Undoubtedly, the chronicity and the severity make a big difference, but those features are very hard to quantify. Furthermore, there is convincing evidence that risks for AD due to hypertension are higher in middle age, or decades before dementia onset, and then slowly attenuate to the point that higher blood pressure actually looks protective in the older age group. This occurs for at least two reasons. First, orthostatic hypotension becomes more common with advancing age and is associated with a poor prognosis and with underlying degenerative disease of the brain. Second, cognitive impairment itself is associated with weight loss and other factors that might also cause blood pressure to drop as a person becomes symptomatic. Therefore, the timing of the baseline measurement of blood pressure relative to the onset of dementia is critical. It is certainly likely that many studies simply do not have the extended time of observation needed to demonstrate an association between hypertension and AD dementia.
George Washington University
Reply to comments by Edo Richard, David Knopman, and Ben Wolozin
We very much appreciate the careful attention to and appraisal of our systematic review and meta-analysis of prospective epidemiologic studies of blood pressure and risk of Alzheimer's disease (AD). Drs. Wolozin, Richard, and others raised concerns about the selection of studies for our meta-analysis and the appropriateness of evaluating AD rather than total dementia or cognitive decline as an outcome.
Dr. Wolozin and others maintained that the AlzRisk database should include data from additional cohorts. We’d like to clarify that we pre-specified the inclusion criteria for AlzRisk for all risk factors on the site, specifically, 1) the risk factor is studied in prospective relation to AD; 2) the report contains sufficient information to determine what covariates were included in analyses; 3) the analysis adjusts for at least age, gender, and education; 4) the report contains the effect estimates' 95 percent confidence intervals or corresponding P values, or sufficient information for us to compute them; and 5) the report includes results specific to AD (not just dementia). In addition, in order to perform meta-analysis, we require that there are at least four available studies where the exposure is defined sufficiently similarly to conduct a meta-analysis. If qualifying reports on blood pressure and AD from these sources appear in the future, we will most definitely add them to our database and update our meta-analyses.
Dr. Richard expressed the concern that limiting the meta-analysis to studies of AD may have excluded many of the cases with mixed or vascular dementias that could have been attributed in part to elevated blood pressure. Further, Dr. Richard proposed a review of “more pragmatic” outcomes such as total dementia and cognitive decline. While we agree that such an analysis would have been interesting, our goal was to evaluate blood pressure in relation to AD. This question was of interest because a relation between the two has been assumed, even though evidence linking blood pressure to AD pathology (e.g., amyloid-β and phosphorylated tau) is much weaker than evidence linking blood pressure to cerebrovascular pathology. Our analyses show that data from large-scale prospective epidemiologic studies of blood pressure and AD (in 20 distinct study populations) do not provide convincing evidence to support the hypothesis that higher blood pressure, at any point in the lifespan, increases AD risk. However, as we write in our accompanying paper in Epidemiology, preventing or treating hypertension can still benefit the public health, even where dementia is concerned. For example, systematic autopsy studies have shown that the presence of cerebrovascular pathology makes clinical dementia more likely for a given level of Alzheimer's pathology (Schneider et al., 2004). Thus, hypertension may substantially increase the burden of total dementia.
Intertwined AD and vascular pathologies in the CNS clearly frustrate the ability of epidemiologic studies to tie blood pressure to AD risk. In AlzRisk, when a paper includes results on both AD and total dementia, we record both sets of results on the site. Of the 20 populations noted above, 13 examined total dementia in addition to AD. Studies of two cohorts specifically defined their “total dementia” as AD and vascular dementia, and even without this definition, total dementia includes primarily these two diagnoses and mixed cases. Surprisingly, associations of measures of blood pressure with total dementia were not substantially stronger than corresponding associations with AD. Notably, the studies of total dementia are vulnerable to many of the same limitations found in studies of AD, including reverse causation, selection bias, misclassification of blood pressure, and misspecification of the shape of the association between blood pressure and dementia.
We agree that cognitive decline has several advantages as an outcome. For example, studies of cognitive decline in persons who are unlikely to have clinical dementia may be less prone to bias from reverse causation and differential selection. And, as Dr. Richard points out, cognitive decline may be especially practical in the context of clinical trials of blood pressure treatment. However, it seems unlikely that such studies could address the etiologic question about blood pressure and AD pathology. AlzRisk does not include studies of cognitive decline, but, in the detailed Discussion for each risk factor, we do consider findings from these studies when we interpret the epidemiologic results on AD.
Finally, we appreciate the insights of Dr. Knopman on the likely importance of timing. Given the blood pressure-lowering effects of frailty and cognitive decline, reverse causation could explain, in part, the “null” or protective findings in studies of the oldest participants. Studies of elevated blood pressure in midlife are less likely to suffer from bias due to reverse causation, but as of yet, these studies are frustratingly few.
References:
Schneider JA, Wilson RS, Bienias JL, Evans DA, Bennett DA. Cerebral infarctions and the likelihood of dementia from Alzheimer disease pathology. Neurology. 2004 Apr 13;62(7):1148-55. PubMed.
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