AlzRisk Adds Hypertension as Fifth Alzheimer’s Risk Factor

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.


How Alzheimer’s Progresses Through the Brain

Alzheimer’s disease symptoms result from physical changes in the brain. While the cause of these changes remains somewhat of a mystery and has yet to be thoroughly proven, researchers have a leading theory of how the Alzheimer’s disease progresses. Here’s an explanation, in brief.

In a healthy brain, certain chemical processes ensure the proper functioning of neurons. One is the processing of amyloid precursor protein (APP) that is attached to the outer membrane of nerve cells. An enzyme called alpha-secretase cuts off a section of the protein; then another enzyme, gamma-secretase, snips a second portion and releases APP from the cell’s membrane.

These APP fragments are then broken down and removed from the brain. Another process involves the microtubules, which carry nutrients through the nerve cells to keep them functioning normally. Tau protein helps to maintain the physical structure of microtubules.

The Plaques and Tangles of Alzheimer’s. But when these processes go awry, a different enzyme, beta-secretase, cuts shorter APP fragments from the nerve cell membrane. These smaller pieces are more resistant to breakdown and tend to clump together in toxic clusters called oligomers; eventually, the oligomers collect into larger beta-amyloid plaques that interfere with nerve cell functioning.

Within neurons, abnormal tau strands separate from the microtubules and cause the microtubules to fall apart, crippling the transport of nutrients and destroying nerve cells. Loose tau threads join together to form knotted strands inside neurons. Called neurofibrillary tangles, they cause further neuron destruction.

In the early stages of Alzheimer’s, plaques and tangles form in brain areas responsible for learning, thinking, and planning — in particular, the hippocampus. This is why forgetfulness, disorientation, and verbal repetition are often among the earliest signs of Alzheimer’s. As nerve cell destruction spreads, more brain areas are affected, especially the cerebral cortex, responsible for language, reasoning, and judgment. Speaking skills become impaired and emotional outbursts grow more frequent.

When large areas of nerve cells die off in the advanced Alzheimer’s stage, brain sections atrophy and the whole brain shrinks to as much as three quarters of its original size. People with Alzheimer’s lose most of their ability to communicate, walk, and care for themselves.


Plaque-blocking Compound May Aid Alzheimer’s Treatment

Researchers with the Institute for Memory Impairments and Neurological Disorders (UCI MIND) have discovered how a novel compound can reduce the accumulation of brain plaques seen in Alzheimer’s without the side effects produced by current drugs used for the chronic neurodegenerative disease.

In a study published online in the Annals of Neurology, neurobiologists Kim Green and Frank LaFerla found that the ST101 compound triggers a process that carves up amyloid precursor proteins into benign molecules. These precursor proteins, when intact, ultimately can form into beta-amyloid plaques, which are the hallmark lesions of Alzheimer’s and believed to be the primary cause of dementia. The researchers believe ST101 could be the basis of a drug therapy for people with mild Alzheimer’s symptoms.


Investment into Tau Research Grows

Meryl Comer: The mainstream research has been focused on beta amyloid.  Tau has always been there, but now there is a big controversy about where the progression comes, where does it really lie?  Take that debate on Dr. Gandy.

Dr. Gandy: Well certainly people with Alzheimer’s disease have two sorts of lesions in their brains, two sorts of clumps of protein.  Some of these clumps are in between nerve cells, and others are inside nerve cells.  The ones that are in between the nerve cells are called amyloid plaques.  The clumps that are inside the nerve cells, which are twisted, are called tangles or neurofibrillary tangles.  Now for many years we didn’t sort of know what the sequence of events was, but it is very clear now that all the genes that cause Alzheimer’s disease point to the buildup of amyloid. So it appears that Alzheimer’s disease amyloid comes first and tangles come next.  They may be extremely important in understanding why the nerve cell dies.  Now the disease that Dr. Troncoso mentioned, frontal temporal dementia, has also helped us to understand the relationship between plaques and tangles because in that disease the mutations that cause the genetic forms are in the protein called tau that builds up and causes tangles.  People with frontal temporal dementia get tangles, but they never get plaques, so in Alzheimer’s disease plagues can cause tangles, but in frontal temporal dementia tangles don’t cause plaques.

Meryl Comer: Well why is it so hard these days to get a grant from NIA around beta amyloid when you can get it for tau?

Alzheimer's Panel Discussion at Focuses on Tau Research

Dr. Gandy: Well so there is a specific reason for that that’s really evolved a lot in the last year.  There is a study that was reported this spring that showed using an antibody, a chemical aimed at the amyloid substance… that if people with mild Alzheimer’s disease received antibody infusions, anti-amyloid infusions, for a year and a half that the amyloid buildup in their brains would go down by about 25%.  They didn’t change at all clinically.  They didn’t get any better in terms of their cognitive function.  Why is that? Because we didn’t start early enough, because we didn’t treat long enough or because it’s actually another form of amyloid, not the plaques, but these floating clumps called oligomers?

Meryl Comer: You wanted to make a point, yes, doctor.

Dr. Troncoso: Yeah well, I think that there is a lot of debate between the amyloid and tau deposition, but I think one should not get stopped at that point of that argument because it’s perfectly possible that one of these abnormalities, let’s say amyloid may trigger the rest and there is more than amyloid and tau.  We haven’t spoken, but there is a very significant inflammatory, inflammation in the brain that once you have perhaps amyloid and tau trigger that event it becomes self-sufficient.  It actually may even promote more amyloid or more tau deposition, so I think that tau it may be as important as amyloid, but it may be later on in this progression of the disease. And if you could actually target each of these elements it probably would be beneficial. So I don’t see really a tremendous dichotomy, antagonism between looking at amyloid and tau.  I think that both are perfectly legitimate targets of research and one more perhaps disgression in terms of the dementia that is being seen in patients who have head trauma.  Most of that, the lesions that they have is of the tau type, so I think both of these targets amyloid and tau should be addressed.  There is no reason to eliminate one of them.

Dr. Gandy: There is the one experiment to mention that might also explain why the shift sort of toward tau.  A lot of what we’ve learned about Alzheimer’s disease is from mouse models.  Mice normally never ever get Alzheimer’s disease because their amyloid is different enough that it doesn’t clump and build up.  If we then put into a mouse the gene for amyloid and with a mutation that would cause it to build up and the gene for tau so that it will get tangles, then as that animal ages it will get buildup of plaques and tangles just like, similar to humans with Alzheimer’s disease.  They will then lose their ability to find their way around their cage or to find their way around a swim maze.  If you then treat them with a drug or substance that will decrease the levels of tau, will lower the tau down, the cognitive function comes back, so it’s possible to sort of render the amyloid inert if you can turn down the tau at least in the mouse model.


World Alzheimer’s Day

The theme for World Alzheimer’s Day™ 2011 is ‘Faces of dementia.’

In our materials and activities ADI and Alzheimer associations across the world will focus on the many issues surrounding the ‘Faces of dementia’. They will be asking if you recognize the face of dementia while paying tribute to those who represent the ‘Faces of dementia’ in all parts of the world and working tirelessly to promote increased support and care for people with dementia and their carers.

Every year on 21 September Alzheimer associations across the globe unite to recognise World Alzheimer’s Day and 2011 will be no exception with events taking place internationally. We are confident that the large numbers of people involved and the media coverage these events will gain can make a real difference for people with dementia, their families and carers worldwide.

Download the World Alzheimer’s Day 2011 poster PDF 195KB

Future of Dementia

In HBO’s groundbreaking The Alzheimer’s Project, the optimism is clear. Scientists proclaim, “We will slow this disease down one step at a time. We are going to see real treatments. Patients are going to benefit.”

With the unraveling of the human genome, research into the prevention and treatment of dementia has advanced light years. Current studies are investigating vaccines, genetic interventions, and hundreds of medications to conquer dementia. Their efforts bring hope to countless dementia patients and their families.

To learn more, visit The Alzheimer’s Project.

Alzheimer’s Project is a presentation of HBO Documentary Films and the National Institute on Aging at the National Institutes of Health in association with the Alzheimer’s Association®, Fidelity® Charitable Gift Fund, and Geoffrey Beene Gives Back® Alzheimer’s Initiative. The series’ producer is John Hoffman; the executive producers are Sheila Nevins and Maria Shriver.

Alzheimer’s Breakthrough Act

As the leading advocacy, research and support organization for Alzheimer’s disease, the Alzheimer’s Association® commends Reps. Christopher Smith (R-N.J.) and Edward Markey (D-Mass.) for their leadership in introducing the Alzheimer’s Breakthrough Act (H.R.1897) in the U.S. House of Representatives. The legislation will help strengthen and increase the federal commitment to Alzheimer’s research at the National Institutes of Health (NIH), the nation’s largest funder of biomedical research.

Alzheimer’s is the sixth-leading cause of death and the only cause of death among the top 10 causes in the United States without an identified way to prevent, cure or even slow its progression. Today, an estimated 5.4 million Americans are living with Alzheimer’s, and this number is expected to grow to as many as 16 million by mid-century without disease-modifying interventions.

“The discovery of effective treatments is the best hope to change the trajectory of Alzheimer’s. This legislation requires the NIH to assess and prioritize the scientific opportunities that exist and determine what funding levels are necessary to turn these opportunities into scientific breakthroughs,” said William Thies, chief medical and scientific officer of the Alzheimer’s Association. “The measure also ensures the NIH is encouraging public-private partnerships that spur robust innovative research and advancements in diagnostics, prevention and treatment.”

According to the Alzheimer’s Association’s 2011 Alzheimer’s Disease Facts and Figures report, total payments for health and long-term care services for people with Alzheimer’s and other dementias amount to $183 billion, with Medicare and Medicaid making up the overwhelming majority of these costs. In fact, for every $28,000 Medicare and Medicaid spend on care for individuals with Alzheimer’s and other dementias; the NIH spends only $100 on Alzheimer’s research.

This disproportion underscores the need for a greater commitment to Alzheimer’s research in order to find effective interventions that will reduce care costs. A treatment that delayed onset of Alzheimer’s by just five years could reduce the government’s spending on caring for those with the disease by 45 percent in 2050.

The leadership and dedication of Reps. Smith and Markey, who also serve as co-chairs of the Congressional Task Force on Alzheimer’s, should be applauded. The Association is also grateful to Reps. Mike Burgess (R-Texas) and Todd Platts (R-Pa.) for being original co-sponsors of the bill and urges all members of the U.S. House to support and pass this important legislation.

Alzheimer’s Association

The Alzheimer’s Association is the world’s leading voluntary health organization in Alzheimer care, support and research. Our mission is to eliminate Alzheimer’s disease through the advancement of research; to provide and enhance care and support for all affected; and to reduce the risk of dementia through the promotion of brain health. Our vision is a world without Alzheimer’s. For more information, visit