ARTICLE IN BRIEF
In a post-mortem analysis of brains from the Honolulu-Asia Aging Study, investigators found that people who had been treated with beta blockers alone showed fewer microinfarcts, less brain atrophy, and fewer brain lesions of the type linked to Alzheimer's disease.
Elderly people treated with beta blockers showed fewer signs of dementia at autopsy, but not just because the drugs reduced their blood pressure, according to a study that will be presented at the AAN annual meeting in San Diego later this month. Other antihypertensive drugs did not confer the same level of protection.
This initial phase of the study involved 2,285 participants in the Honolulu-Asia Aging Study (HAAS), a prospective, community-based study of Japanese-American men. The participants were aged 71-93 at baseline, and had hypertension without dementia when they entered. They were followed from 1991 through September 2010. During that time 854 of the men developed cognitive impairment, and 1,199 developed cognitive decline.
The researchers examined the brains of 774 autopsied men; 610 of whom had been treated with anti-hypertensive drugs; only 40 had been treated with beta blockers alone. After adjusting for age, diabetes, apolipoprotein E status, cognitive test scores, baseline blood pressure and midlife hypertension and treatment, the results showed that those treated with beta blockers alone showed fewer microinfarcts, less brain atrophy, and fewer brain lesions of the type linked to Alzheimer's disease. Those treated with beta blockers combined with other medications had fewer abnormalities than those not treated with beta blockers at all. However, the use of beta blockers alone was consistently associated with a lower risk of cognitive impairment developing during the final years of life.
“Beta-blocker use is associated with a lower risk of developing cognitive impairment and decline in elderly Japanese American men,” the authors concluded. [The investigators had not hypothesized this association before doing the analysis.]
“While other researchers have demonstrated that people treated for hypertension have better cognitive outcomes than untreated persons, and at least one analysis identified a benefit related to the use of angiotensin receptor-blocking agents, I am aware of no previous reports comparing the benefits of beta blocker meds with other meds for hypertension for any type of dementia,” said lead study author Lon White, MD, clinical professor of geriatric medicine at the Pacific Health Research Institute in Honolulu, who has been studying Alzheimer's disease for 30 years.
The use of beta blockers, which for decades were the preferred treatment for high blood pressure, has declined now that physicians can choose from about a dozen medications deemed more effective. Beta blockers block the action of adrenaline on the heart, slowing it down so it doesn't have to work as hard. Side effects can include fatigue, erectile dysfunction, depression, and insomnia. About 161 million prescriptions for beta blockers were written in 2011, making them the sixth most commonly prescribed drug in the U.S.
DATA ON ELEVATED BLOOD PRESSURE
Elevated blood pressure has long been known as a risk factor for Alzheimer's disease and cognitive impairment. A 2009 meta-analysis in the American Journal of Geriatric Pharmacotherapy reviewed 65 studies published between 1999 and 2008, and concluded that “antihypertensive medications — particularly ACE inhibitors and diuretics — may be helpful in reducing the risk for and progression of dementia.”
Also, a study by Chinese scientists published in 2011 in the Brain Research Bulletin noted that several longitudinal and cross-sectional epidemiological studies have shown that treatment with beta blockers specifically reduces the prevalence of Alzheimer's dementia and delays functional decline. Animal and in vitro studies, the authors noted, also have shown that beta-adrenergic receptors may reduce amyloid-beta production and inflammation.
The HAAS study, however, was the first to identify beta blockers specifically as superior to other anti-hypertensives at counteracting cognitive decline, although Dr. White emphasizes that the study based its results on brain lesions found at autopsy rather than clinical assessment of the men while alive.
“Our autopsy study did not use dementia as an endpoint,” he said. “One can only have that endpoint when a person is still alive. Instead, we looked for an association with the structural abnormalities found in the brain at death, focusing on abnormalities known to be the primary lesions responsible for dementia. We know that many people with such lesions were not demented. We regard the processes responsible for those lesions as necessary but not sufficient causes for the declines in cognitive functioning that define the clinical diseases.”
In an effort to explain the apparent superiority of beta blockers over other antihypertensives in protecting the brain from cognitive decline, Dr. White suggested that beta blockers might reduce stress on small blood vessels, reducing the risk of microinfarcts.
“Every type of treatment comes with its own mechanisms, advantages, and adverse associations,” he said. “Beta blockers influence the autonomic nervous system more than the others, which means they reduce heart rate, response to physical stress, the difference between systolic and diastolic pulse pressures, and other functions. We can only speculate if these influences, in association with simple correction of the blood pressure, provide specific benefits related to development of the brain lesions responsible for cognitive decline and dementia during life.”
EXPERTS WEIGH IN
Vladimir Hachinski, MD, DSc, Distinguished University Professor of neurology and epidemiology at the University of Western Ontario, who was not involved with the current study, suggested another possible mechanism.
“We know from the literature that propranolol, one of the prototypical beta blockers, increases brain blood flow at higher doses,” he said. “My hypothesis is that there's increased clearance of amyloid with increased blood flow. I think Dr. White could probably take a look and see whether the greatest clearance took place in those on the highest dose (of beta blockers).”
Dr. Hachinski also would like to see other investigators who use brain imaging to detect amyloid deposits in the brain to correlate blood pressure medications with amyloid deposits. “That way they could test my hypothesis that increased clearance is related to dosage,” he said.
Although the numbers involved in the study are small and the results surprising, Dr. Hachinski, who is a member of the Neurology Today editorial advisory board, considers the work fascinating. “They may be onto something important,” he said. “We shouldn't dismiss it simply because it's counterintuitive. The path to the truth is not usually predicted, so we should treat the result with respect. They're good scientists with a good track record of good data, so I wouldn't doubt the data, but it could be fluke of selection, or the variability could be greater because the numbers are small.”
Philip Gorelick, MD, medical director and vascular neurologist at the Hauenstein Neuroscience Center in Grand Rapids, MI, said previous publications have used the HAAS data to provide “pivotal information” linking hypertension in midlife to cognitive impairment and dementia, cerebral atrophy (especially hippocampal atrophy), and higher numbers of neuritic plaques and neurofibrillary tangles. However, beta blockers have never been studied extensively for the prevention or treatment of cognitive decline until this study, he added.
“Most of the focus for prevention of cognitive impairment or decline in the elderly in relation to blood pressure-lowering agents has been with angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, or long-acting calcium channel blockers,” he said. “The study is very interesting in that Alzheimer's disease changes were substantially eliminated by treatment with beta blockers. It is surprising, however, that the other blood pressure-lowering medications did not have a similar positive benefit.”
Dr. Gorelick does not expect the results to have substantial impact on clinical practice, but they will be important for “hypothesis generation” about how beta blockers might influence Alzheimer's neuropathology and therefore cognition in later life.
“Certainly lowering blood pressure reduces the risk of stroke,” he said. “However, other medications also lower blood pressure but were not associated with the same effect as beta blockers had in this study. It would be interesting to know which specific beta blockers were used to help determine if this was a class effect or one related to specific beta blocker medications.”
The study was funded by the National Institute on Aging; the National Heart, Lung, and Blood Institute; and by the Office of Research and Development, Medical Research Service of the Department of Veterans Affairs.