24 June 2011. Does high blood pressure increase the risk of getting Alzheimer’s disease? Although several studies have highlighted hypertension as a potential AD risk factor, getting prominent play in the press, the epidemiologic evidence to date remains surprisingly weak. This is the conclusion of researchers led by Deborah Blacker at Massachusetts General Hospital, Boston, in a paper published online today in the journal Epidemiology. While their meta-analysis yielded inconclusive data, the authors point out that this may be due to the small number of studies that met inclusion criteria, as well as bias and other problems with the original data. They recommend further research in this area to make the data stronger and more comparable. The results also debut today in AlzRisk, the open online database hosted by Alzforum that curates and analyzes non-genetic risk factors for AD. The AlzRisk analysis is very similar but not identical to the Epidemiology paper. Hypertension is the fifth factor to be entered into AlzRisk, and marks a major expansion of the database. AlzRisk’s curators, led by Blacker and Jennifer Weuve at Rush University, Chicago, Illinois, plan to complete additional factors before the end of the year, and expect that scientists, journalists, and others interested in AD will find the database a useful resource.
Hypertension is of interest because it is treatable, many epidemiological studies have linked cardiovascular disease to dementia, and two previous reviews have found an association between high blood pressure and dementia (see Qiu et al., 2005; Kennelly et al., 2009). However, much of this link may be due not to blood pressure per se but to cerebrovascular pathology, which often coexists with AD and may contribute to cognitive impairment. First author Melinda Power and colleagues wanted to understand risk factors specifically for AD. To this end, they included only studies that reported results for AD dementia, and required that AD be diagnosed through clinical examination. This meant that a significant fraction of the literature on blood pressure and dementia had to be left out. Power and colleagues used stringent criteria for selecting the 18 studies they included in their meta-analysis. For example, data had to be from prospective cohort studies or nested case-control studies, include blood pressure as an exposure variable, provide confidence intervals, and adjust for age and sex. Several well-known stalwarts, such as the Atherosclerosis in Communities Study and the Cardiovascular Health Study, were excluded because they did not meet all the pre-specified inclusion criteria for the AlzRisk systematic reviews. Some researchers interviewed by ARF thought these omissions substantially weakened the review.
Counterintuitively, the meta-analysis showed that high blood pressure in late life was linked to a slightly lower risk of AD. This may be due to selection bias and other problems with the original data, the authors note. For example, people with either uncontrolled hypertension and/or AD are more likely to die or be too ill to participate in a study. People with both disorders may, therefore, drop out. Alternatively, the Alzheimer’s disease process itself might lower blood pressure, muddying the results. On the other hand, high blood pressure in middle age did seem to link to a higher risk of developing AD in late life. This finding was based on only four studies, however, and the data were not always consistent. The results highlight the need for further research in middle-aged populations, Power told ARF. An advantage of focusing on middle-aged populations is that they are likely to be free of the selection bias and disease effects that may confound results in the older groups. “I think it’s going to be surprising to the Alzheimer’s community that the evidence is as weak as it is,” Power noted.
The authors also recommend making improvements in data collection. Currently, different studies report blood pressure in varied ways, making it difficult to combine the data. The authors suggest reporting estimates of risk per 10-mm Hg increments in systolic and diastolic blood pressure, as well as using standard categories of blood pressure recommended by the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (see Chobanian et al., 2003). This would create standardized measures across studies, avoiding apples-to-oranges comparisons and allowing data to be more easily combined. Also, most studies do not show whether hypertension is being treated. This data should be collected and analyzed, Power told ARF. Controlling hypertension may alter AD risk, and this knowledge would have public health implications.
These types of inconsistencies are common in epidemiological research, creating difficulties for researchers who want to analyze studies and spot overall trends. The goal of the AlzRisk database is to make this job easier. AlzRisk aims to combine all available data on a given non-genetic risk factor into one searchable database and provide meta-analyses where feasible. By pulling out the same data elements from each study on a given risk factor, the reader can compare apples and apples in a way that is not feasible with, say, a PubMed search (see hypertension table). AlzRisk complements the AlzGene database, which collates all genetic risk factors for AD. Weuve manages the AlzRisk project and supervises its team of curators, who are mostly doctoral students and postdoctoral fellows at the Harvard School of Public Health.
AlzRisk fills a similar need to AlzGene, Weuve said, but pulling together epidemiologic studies presents more of a challenge than summarizing genetic data. “We are concerned about sources of bias, and we feel that those things require discussion. We are essentially writing a publishable paper with each risk factor,” Weuve noted. The strength of the database is its depth of analysis and documentation, Weuve told ARF. The other major advantage is that the database will be regularly updated to keep up with new findings in the literature. AlzRisk brings together and distills study findings on a particular risk factor to estimate the strength of its association with AD. Weuve suggested these summaries (see Current Understanding and Discussion) could be useful to scientists who are writing grants and need to cite research, as well as to epidemiologists who are designing new studies. Blacker, who is the principal investigator of the AlzRisk project, added, “We are trying to write the commentary at the Scientific American level, so that it will be useful to journalists, too.”
The database currently includes four factors that may modify AD risk: diabetes, physical activity, nutritional antioxidants, and inflammatory biomarkers. In addition to hypertension, the team expects to add several more factors this year and next, such as hormone replacement therapy, obesity, and head injury. “We select risk factors based on the volume of available study results, and also the clinical importance,” Weuve told ARF. Studies must meet strict criteria to be included. The database emphasizes large-scale prospective cohort studies, excluding cross-sectional research that simply compares characteristics of groups of people who have AD to those of groups who do not. “That design has so many problems that we eliminated it from consideration,” Weuve said. This limits the number of studies that can be considered.
As might be expected with such a complex topic, scientists in the field do not agree on the best approach for selecting studies. Benjamin Wolozin at Boston University, Massachusetts, would like AlzRisk to include more large, population-based datasets, such as those from Finland, Belgium, and Canada, as well as the Kaiser Permanente and Veterans Affairs databases in the U.S., because these datasets provide great statistical power. Edo Richard at the University of Amsterdam, The Netherlands, wrote to ARF that vascular dementias should be included in the hypertension analysis. “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,” he said (see full comment below). However, scientists contacted for this article agreed on the need for a centralized compendium of epidemiologic studies on AD. “In general, the approach of doing meta-analyses has been incredibly important,” Wolozin said. “As AlzRisk generates more data, I think it will be a very valuable resource.”—Madolyn Bowman Rogers.
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 Jun 23. Abstract