A commonly prescribed anti-hypertensive medication may reduce amyloid deposition in the brain, according to a paper published online September 10 in Archives of Neurology. To reach this conclusion, researchers led by Ihab Hajjar at the University of Southern California, Los Angeles, correlated medical and neuropathological data from almost 900 cognitively impaired elderly people who had suffered from hypertension before they died. Patients who had taken a particular class of hypertension drug, angiotensin receptor blockers (ARBs), did best on the assessment. They had significantly less amyloid pathology than people who were on other anti-hypertensives, or whose hypertension was not treated, the authors report. These people were also about a third less likely to have received a neuropathological diagnosis of Alzheimer’s disease than the other groups, and appeared to have been in better cognitive health. However, because these data are correlative and not prospective, they need to be interpreted with caution, scientists stressed. Hajjar and colleagues are now planning a prospective, five-year clinical trial to see if ARBs can improve cognitive outcomes.

Epidemiological data hint that they might just do that. Previously, researchers led by Benjamin Wolozin at Boston University, Massachusetts, had studied the U.S. Veterans Affairs database to show that in a large population of elderly men with cardiovascular disease, those taking ARBs had a lower incidence and slower progression of dementia than those on other anti-hypertensives (see ARF related news story on Li et al., 2010). Another human neuropathology study reported that people with high blood pressure who were on hypertension meds had about half the amyloid plaques in their brains as did non-hypertensive people, although this study did not break out classes of drugs (see Hoffman et al., 2009). Likewise, animal data indicate that at least some ARBs can slash Aβ pathology and improve learning (see ARF related news story; Danielyan et al., 2010).

Hajjar and colleagues hypothesized that treatment with ARBs might also reduce Aβ pathology in people. To test this idea, the authors used the National Alzheimer’s Coordinating Center (NACC) database, which collects clinical and neuropathological data from the 29 Alzheimer’s Disease Centers across the U.S. Their database includes detailed clinical data on more than 26,000 people and is freely available to researchers worldwide. For a detailed description of the NACC, see ARF related news story. From among about 1,300 people who had donated their brains for autopsy, Hajjar and colleagues analyzed the nearly 900 who had had hypertension and either cognitive impairment or abnormal pathology. About 15 percent of this population took ARBs, 20 percent were unmedicated for their hypertension, and the rest took other anti-hypertensives. The authors evaluated pathology by several criteria, including the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) score, Alzheimer's Disease and Related Disorders Association (ADRDA) score, and Braak and Braak staging. By all three measures, people who had taken ARBs had significantly less β amyloid pathology, with odds ratios of around 0.5.

“I was surprised by the strength of the effect,” Wolozin told Alzforum, noting that odds ratios of 0.5 for pathology data are “quite striking.” Wolozin was not involved in the current study, but said it agrees well with his own epidemiological findings. He pointed out that, in his study, the ARBs that penetrated the brain the best also had the greatest benefit for cognition. This suggests that the drugs might act directly on the brain.

How these drugs might lower β amyloid remains mysterious. The effect seems to be unrelated to their ability to control blood pressure, as other anti-hypertensives did not show it. Hajjar suggested the answer might lie in the drugs’ unique mechanism of action. ARBs block the hormone angiotensin II from binding to the angiotensin II receptor type 1 (AT1) on blood vessel walls. AT1 mediates vasoconstriction, which raises blood pressure. ARBs do not interfere with the binding of angiotensin II to the AT2 receptor. This receptor generally opposes the effects of AT1, causing blood vessels to dilate, lowering inflammation, and possibly increasing amyloid clearance, Hajjar said. By blocking AT1 while leaving the beneficial AT2 pathway intact, ARBs may improve the health of the brain. In contrast, a similar class of anti-hypertensives, angiotensin converting enzyme (ACE) inhibitors, prevents the maturation of angiotensin II and therefore inhibits both pathways.

Wolozin agreed the AT2 receptor pathway could be a key factor in the positive effects of ARBs. “ARBs increase blood flow to the brain,” he pointed out. More blood means more oxygen, which is good for the aging brain. Stressed brains have been shown to make more amyloid, he added. Indeed, several studies link hypoxia and vascular disease to a higher risk of dementia or faster cognitive decline (see, e.g., ARF related news story and ARF news story). Cardiovascular disease is a risk factor for dementia (see ARF related news story), though the data on hypertension are equivocal (see AlzRisk).

Hajjar and colleagues also saw a difference in cognition. People taking ARBs scored significantly better on several clinical measures, such as the Mini-Mental State Exam and the Global Clinical Dementia Rating scale, and were less likely to have a clinical diagnosis of AD than people on other anti-hypertensives or no medication. Hajjar cautioned, however, that this type of data is subject to selection bias. In theory, doctors could have prescribed ARBs to people with better cognition because of other health factors present in this population. One factor arguing against this idea, however, is that ARBs and ACE inhibitors tend to be prescribed to the same sort of patients, and ACE inhibitors had no effects on pathology in this study, Hajjar noted.

Commentators David Knopman at the Mayo Clinic in Rochester, Minnesota, and Deborah Blacker at Massachusetts General Hospital, Boston, agreed that selection bias could be a problem with this type of data. Blacker, who also oversees the AlzRisk database on Alzforum, noted that this is a particularly troublesome issue with neuropathology data, as few people agree to donate their brains after death. Therefore, autopsy data may not represent the whole population.

For his part, Knopman pointed out that the study looked at whether people took anti-hypertensive drugs, but included no information on dosage or duration of use. “It’s hard to interpret a beneficial effect of the medication when those things are unknown,” Knopman said. He considers the evidence to date too preliminary to recommend that physicians change how they prescribe anti-hypertensives. (Currently ARBs, which are newer and less studied than ACE inhibitors, are an alternative therapy for people who do not tolerate the latter.) It may make sense to look further at ARBs in a clinical trial setting, Knopman suggested. “The question is, Is there any value in giving them to people who are symptomatic?” he asked, pointing out that current thinking and recent clinical trials (see, e.g., ARF related news story and ARF news story) suggest that amyloid-targeting therapies may need to be initiated at presymptomatic stages to have a clinical benefit. ARBs might form a component of early-stage or preventive combination therapy in the future.

Hajjar believes that the drugs might help those already showing signs of impairment. In a small, one-year pilot trial, cognitively impaired people with hypertension who took ARBs improved their executive function and memory compared to people on other anti-hypertensives (see Hajjar et al., 2012). Based on these findings and the neuropathology data, Hajjar is beginning a five-year clinical trial in about 150 cognitively impaired people to see if ARBs can protect them from further decline. Hajjar will use structural MRI and arterial spin labeling (ASL) perfusion MRI to look for an effect of the drugs on structure and blood flow, respectively, in the brain. ASL-MRI acts as a surrogate measure of brain metabolism, similar to FDG-PET (see ARF related news story). Brain hypoperfusion as measured by ASL-MRI can predict cognitive decline (see Chao et al., 2010). Hajjar does not plan to include brain amyloid imaging in the trial. If ARBs prove to have a cognitive benefit, they might become part of the treatment regimen for older adults with hypertension, Hajjar suggested.

The AlzRisk meta-analysis of the current scientific literature on hypertension and dementia validates that high blood pressure, particularly in midlife, has been associated with a higher risk of dementia in some studies (see ARF related news story). The AlzRisk discussion noted that few studies have examined how treating hypertension affects AD risk.. “This [paper] adds a novel dimension” to the discussion of hypertension and AD, Blacker said.

Several clinical trials of other classes of anti-hypertensives are in the works, including a Phase 3 trial of the calcium channel blocker nilvadipine (see ARF related news story), and a pilot trial of the β blocker carvedilol (see ARF related news story), both of which also appear to lower β amyloid. Like ARBs, however, their effects on amyloid are believed to be independent of their ability to regulate blood pressure.—Madolyn Bowman Rogers.

Reference:
Hajjar I, Brown L, Mack WJ, Chui H. Impact of angiotensin receptor blockers on Alzheimer disease neuropathology in a large brain autopsy series. Arch Neurol. 2012 Sep 10:1-7. Abstract

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  1. This is a very interesting study suggesting the potential role of angiotensin receptor blockers (ARBs)/antihypertensive agents as potential disease-modifying agents in Alzheimer's disease amyloidosis. This evidence, based on postmortem brains of subjects with or without AD who were treated with ARBs and showed less amyloid deposition, is consistent with previous studies from our laboratory, suggesting that a certain ARB (valsartan) may beneficially influence AD-type neuropathology and cognitive deterioration (Wang et al., 2007). Our conclusion was that ARBs may act as a disease-modifying agent in AD. We hypothesized that ARBs could have been developed in primary and possibly secondary intervention, since disease-modifying activities were also seen at doses that were below the range for treatment of hypertension. Moreover, no hypotension side effects were found. This study by Hajjar et al. is consistent with our original study and new, ongoing preclinical and clinical studies testing the role of a series of antihypertensive agents as disease-modifying agents by assessing biomarkers of onset and progression of disease.

    References:

    . 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.

Comments on Primary Papers for this Article

  1. Of potential interest.

    View all comments by Takaomi Saido
  2. This paper by Ihab Hajjar and colleagues is an important addition to the growing body of evidence suggesting that a variety of treatments for cardiovascular and systemic diseases may have beneficial pleiotropic effects for Alzheimer’s disease (AD) and dementia. We reported the benefits of anti-hypertension therapy against the cardinal lesions of AD earlier (see Hoffman et al., 2009), but Hajjar and colleagues up the ante by reporting on almost a factor of 10 times as many cases, giving the study the power to identify the beneficial consequences of a specific class of anti-hypertension therapies, angiotensin receptor blockers (ARBs).

    Although this study was conducted as well as possible for an observational retrospective postmortem investigation, by its very nature it leaves many questions unanswered. The study was limited to evaluating the effects of anti-hypertension medications taken during the last few years of life. Increasing evidence suggests that the neuropathological lesions of AD begin accumulating in the brain years, if not decades, before the onset of AD symptoms, death, and autopsy. Losartan, the first ARB, was approved for treatment of hypertension in 1995. Since many persons with hypertension begin therapy with other agents, it is possible that the results reported represent the interactions of cumulative anti-hypertension treatment with a variety of agents and the clinical and sociodemographic features that led to the decision to treat with ARBs at the end of life. Of course, this and similar duration of treatment, compliance, disease severity, age of disease onset, etc., issues are characteristics of almost all postmortem studies of AD, and can only be resolved by prospective clinical trials. The study by Hajjar et al. provides a compelling rationale, not only for formal clinical investigations, but also for the study of the neurobiological mechanisms through which ARBs may reduce the burden of AD lesions and dementia.

    View all comments by Vahram (Harry) Haroutunian

References

News Citations

  1. In Veterans, Blood Pressure Meds Delay Dementia
  2. Anti-hypertensives for AD?—Remembrances of NSAIDs Past
  3. Does Brain Hypoxia Help Kick Off Alzheimer’s Pathology?
  4. Silent Vascular Disease May Hasten Dementia Progression
  5. Hypertension Begets Aβ, Begets Cardiovascular Damage
  6. Bapineuzumab Phase 3: Target Engagement, But No Benefit
  7. Phase 3 Solanezumab Trials "Fail"—Is There a Silver Lining?
  8. F18 PET Tracers, New MRI Method to Expand Reach of Brain Imaging
  9. AlzRisk Adds Fifth Factor to Database: Meta-Analysis of Hypertension
  10. Search for AD Drugs Turns to a Hypertension Medicine
  11. Stockholm: Therapeutics Roundup—Some New, Some Not So Much

Paper Citations

  1. . Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis. BMJ. 2010;340:b5465. PubMed.
  2. . Less Alzheimer disease neuropathology in medicated hypertensive than nonhypertensive persons. Neurology. 2009 May 19;72(20):1720-6. PubMed.
  3. . Protective effects of intranasal losartan in the APP/PS1 transgenic mouse model of Alzheimer disease. Rejuvenation Res. 2010 Apr-Jun;13(2-3):195-201. PubMed.
  4. . Effect of antihypertensive therapy on cognitive function in early executive cognitive impairment: a double-blind randomized clinical trial. Arch Intern Med. 2012 Mar 12;172(5):442-4. PubMed.
  5. . ASL perfusion MRI predicts cognitive decline and conversion from MCI to dementia. Alzheimer Dis Assoc Disord. 2010 Jan-Mar;24(1):19-27. PubMed.
  6. . Impact of Angiotensin Receptor Blockers on Alzheimer Disease Neuropathology in a Large Brain Autopsy Series. Arch Neurol. 2012 Sep 10;:1-7. PubMed.

Other Citations

  1. ARF related news story

External Citations

  1. National Alzheimer’s Coordinating Center
  2. AlzRisk
  3. pilot trial

Further Reading

Papers

  1. . Impact of Angiotensin Receptor Blockers on Alzheimer Disease Neuropathology in a Large Brain Autopsy Series. Arch Neurol. 2012 Sep 10;:1-7. PubMed.

News

  1. No Pressure, But Could Hypertension Medication Prevent AD?
  2. Hypertension Begets Aβ, Begets Cardiovascular Damage
  3. Anti-hypertensives for AD?—Remembrances of NSAIDs Past
  4. AlzRisk Adds Fifth Factor to Database: Meta-Analysis of Hypertension
  5. F18 PET Tracers, New MRI Method to Expand Reach of Brain Imaging
  6. Does Brain Hypoxia Help Kick Off Alzheimer’s Pathology?
  7. Silent Vascular Disease May Hasten Dementia Progression
  8. NACC News: Building a Frontotemporal Database, and More
  9. Stockholm: Therapeutics Roundup—Some New, Some Not So Much
  10. In Veterans, Blood Pressure Meds Delay Dementia
  11. Search for AD Drugs Turns to a Hypertension Medicine
  12. Phase 3 Solanezumab Trials "Fail"—Is There a Silver Lining?
  13. Bapineuzumab Phase 3: Target Engagement, But No Benefit

Primary Papers

  1. . Impact of Angiotensin Receptor Blockers on Alzheimer Disease Neuropathology in a Large Brain Autopsy Series. Arch Neurol. 2012 Sep 10;:1-7. PubMed.