26 Jan 2010

In an organ as highly vascular as the brain, optimal performance depends on keeping the plumbing shipshape, so it may come as no surprise that the risk factors for heart disease and dementia overlap considerably. High cholesterol, high blood pressure, and diabetes at mid-life all increase the chances of both cardiovascular and Alzheimer disease years later. Even while the mechanistic links between the heart’s and the brain’s health remain murky, factors like high blood pressure are attractive from a prevention perspective because—unlike amyloid—they can be modified with currently available medications and lifestyle modifications. Indeed, several studies have raised the prospect that medications that lower blood pressure might reduce the incidence of dementia (for a recent review, see Piguet and Garner, 2010).

This idea gets both a boost and refinement from a new epidemiological study that finds the use of a specific class of blood pressure medications, the angiotensin receptor blockers (ARBs), to be associated with a lower incidence of AD, fewer nursing home admissions, and fewer deaths compared to other treatments for hypertension. The work, from Benjamin Wolozin and colleagues at Boston University Medical School, Massachusetts, involved more than 800,000 participants in the U.S. Veterans Affairs database who were treated for cardiovascular disease. The results suggest that ARBs are more effective at forestalling dementia than other blood pressure medications, including angiotensin converting enzyme (ACE) inhibitors.

ACE inhibitors were previously associated with slowing of cognitive decline in older adults with hypertension (Sink et al., 2009). Wolozin’s new data, published on January 12 in the British Medical Journal online, indicates that the combination of ARBs and ACE inhibitors works even better.

ARBs and ACE inhibitors both interfere with the action of the angiotensin II peptide, but in different ways. ACE inhibitors prevent production of the active peptide, while ARBs antagonize the type 1 angiotensin II receptor. ACE inhibitors are considered more effective at controlling blood pressure, and are the primary drug choice for hypertension. Both classes of medicine have been shown to protect cognitive function (reviewed in Kehoe et al., 2009).

To compare the effects of different medications, first author Nien Chen Li analyzed information on heart patients divided into three groups: those who took any angiotensin receptor blockers, those who took the ACE inhibitor lisinopril, and those who used other cardiovascular drugs. The scientists then tabulated the incidence of AD and dementia over four years of follow-up. Compared to patients taking the ACE inhibitor or other cardiovascular drugs, veterans who had taken ARBs had a 16 to 24 percent lower risk of developing AD or dementia. In addition, the effect of four different commonly used ARBs on dementia incidence showed a dose response.

What about progression among people who already had AD or dementia? As a proxy for progression, Li and coworkers looked at nursing home admissions and death. Among ARB users, the researchers saw a 50 percent reduction in nursing home admissions compared to the cardiovascular comparator group, and a 17 percent reduction in deaths. Lisinopril use was also associated with a reduction in dementia incidence and nursing home admissions, but to a lesser degree than the ARBs. However, the two drugs together gave the most dramatic effects. Compared to ACE inhibitor use alone, combination treatment gave a 55 percent reduction in the incidence of AD, and a 67 percent reduction in nursing home admissions.

One drawback of the study is that the patient database is predominantly male, raising the question of whether the results will generalize. Confirmatory studies are underway, Wolozin told ARF, in a large database covering a mixed gender population in California. That study, led by coauthor Rachel Whitmer, is showing promising results using similar methods, he said.

The use of nursing home admissions to track progression is a novel aspect of the study, Wolozin told ARF. “In the VA system and other large population databases, we don’t have cognitive measures to go on. This study gives us insight into both a way of looking at progression in these large databases and also some promising effects,” he said.

The measure may also give researchers a way to test ARBs in the clinic. “The classic problem we’ve had in epidemiology is that people do studies of incidence, but it’s too expensive to do a trial on incidence without a lot of strong data,” Wolozin says. “In this case, we also looked at nursing home admission, which means we should be able to take patients with moderate dementia and do a prospective clinical trial using nursing home admission as an outcome.” In the meantime, Wolozin reports that he is working with the National Alzheimer’s Coordinating Center to see if data from other trials can parse out the effects of any of these medications on cognitive function.

How might the ARBs work differently? There have been some suggestions that at least one ARB, valsartan, can reduce Aβ production and pathology in mice (see ARF related news story on Wang et al., 2007). However, in the Wolozin study, anti-amyloid effects are not likely to explain the findings in the majority of people who used ARBs other than valsartan. Wolozin favors the idea, gleaned from human and animal studies of the effects of ARBs on cognition, that blocking the AT1 receptor has a beneficial effect in the brain independent of blood pressure control. People with AD and hypertension sustain a double whammy, where loss of blood flow and infarcts compromise neurons that then are more sensitive to the toxic effects of Aβ. ARBs may help on both counts, by reducing infarcts and improving blood supply, as well as making neurons more resilient to amyloid, he speculates.

While ARBs may have additional effects, there is no question that controlling high blood pressure is important to preserving brain health. Two additional recent studies give reason for hope that reducing hypertension and other cardiovascular risk factors can effectively spare brain tissue from damage. Both studies focus on white matter lesions, spots of hyperintensity visible on MRI. It is not clear exactly what the lesions are, but they accumulate with age. Their presence has been shown to be associated with a worse course of cognitive decline in AD (Brickman et al., 2008), and their progression tracks with development of cognitive impairment (Silbert et al., 2009). The first new paper reports epidemiological data from researchers at the Women’s Health Initiative that appeared in the December Journal of Clinical Hypertension. Lewis Kuller and colleagues of the University of Pittsburgh in Pennsylvania looked at white matter abnormalities as a function of blood pressure control in 1,424 women. They found that women with high blood pressure at baseline and those with poorly controlled high blood pressure had the most white matter lesions. They conclude, “The evidence to date supports tight control of BP levels, especially beginning at younger and middle age, as a possible and perhaps the only way to prevent dementia.”

A brief report published January 7 in Stroke describes a prospective clinical study on the impact of a heart-healthy intervention of medication and lifestyle changes to slow the progression of white matter lesions in patients with AD. In the study, from Edo Richard and colleagues at the University of Amsterdam in the Netherlands, 65 patients with early AD and cerebrovascular lesions were randomized to standard care or a special regimen of vascular care. This included lifestyle interventions (weight loss, improved diet, more exercise, ending smoking), treatment of hypertension with drugs other than ACE inhibitors or ARBs, and of hypercholesterolemia where present, and a supplement of aspirin, pyridoxine, and folic acid. After two years, a follow-up MRI showed that the white matter lesions of the vascular care group had progressed less. The trial was part of a larger study of 123 people that yielded no difference in cognitive or functional decline between the vascular care group and standard care (Richard et al., 2009). From that, the investigators conclude that while the intervention was successful in slowing the progress of brain lesions, efforts may need to start even earlier to be clinically meaningful. This would not be the first time that a treatment was able to successfully change a biomarker, yet fell short of meeting the larger goal, in this case preserving cognitive health.—Pat McCaffrey

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References

News Citations

1. Anti-hypertensives for AD?—Remembrances of NSAIDs Past 27 Oct 2007

Paper Citations

1. Piguet O, Garner B. Vascular pharmacotherapy and dementia. Curr Vasc Pharmacol. 2010 Jan;8(1):44-50. PubMed.
2. Sink KM, Leng X, Williamson J, Kritchevsky SB, Yaffe K, Kuller L, Yasar S, Atkinson H, Robbins M, Psaty B, Goff DC. Angiotensin-converting enzyme inhibitors and cognitive decline in older adults with hypertension: results from the Cardiovascular Health Study. Arch Intern Med. 2009 Jul 13;169(13):1195-202. PubMed.
3. Kehoe PG, Miners S, Love S. Angiotensins in Alzheimer's disease - friend or foe?. Trends Neurosci. 2009 Dec;32(12):619-28. PubMed.
4. Wang J, Ho L, Chen L, Zhao Z, Zhao W, Qian X, Humala N, Seror I, Bartholomew S, Rosendorff C, Pasinetti GM. Valsartan lowers brain beta-amyloid protein levels and improves spatial learning in a mouse model of Alzheimer disease. J Clin Invest. 2007 Nov;117(11):3393-402. PubMed.
5. Brickman AM, Honig LS, Scarmeas N, Tatarina O, Sanders L, Albert MS, Brandt J, Blacker D, Stern Y. Measuring cerebral atrophy and white matter hyperintensity burden to predict the rate of cognitive decline in Alzheimer disease. Arch Neurol. 2008 Sep;65(9):1202-8. PubMed.
6. Silbert LC, Howieson DB, Dodge H, Kaye JA. Cognitive impairment risk: white matter hyperintensity progression matters. Neurology. 2009 Jul 14;73(2):120-5. PubMed.
7. Richard E, Kuiper R, Dijkgraaf MG, Van Gool WA, . Vascular care in patients with Alzheimer's disease with cerebrovascular lesions-a randomized clinical trial. J Am Geriatr Soc. 2009 May;57(5):797-805. PubMed.

Further Reading

News

1. Anti-hypertensives for AD?—Remembrances of NSAIDs Past 27 Oct 2007