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.
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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.
Hoffman LB, Schmeidler J, Lesser GT, Beeri MS, Purohit DP, Grossman HT, Haroutunian V.
Less Alzheimer disease neuropathology in medicated hypertensive than nonhypertensive persons.
Neurology. 2009 May 19;72(20):1720-6.
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.
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.
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