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Research Letter |

Association Between Angiotensin Receptor Blockers and Longitudinal Decline in Tau in Mild Cognitive Impairment FREE

Ihab Hajjar, MD1,2; Allan Levey, MD, PhD2,3
[+] Author Affiliations
1Department of Medicine, Emory University, Atlanta, Georgia
2Department of Neurology, Emory University, Atlanta, Georgia
3Emory Alzheimer’s Disease Research Center, Emory University, Atlanta, Georgia
JAMA Neurol. 2015;72(9):1069-1070. doi:10.1001/jamaneurol.2015.1001.
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Published online

We have previously shown that angiotensin receptor blocker (ARB) use is associated with improved cognitive function in those with mild cognitive impairment (MCI) and with lower amyloid and tau content on autopsy studies.1,2 The impact of ARBs on cerebrospinal fluid (CSF) amyloid and tau biomarkers is unknown. We analyzed data from the longitudinal Alzheimer’s Disease Neuroimaging Initiative to assess the impact of ARB use on CSF amyloid and tau markers.

The Alzheimer’s Disease Neuroimaging Initiative is a longitudinal study of clinical, biochemical, and neuroimaging data collected from participants with normal cognition, MCI, or dementia enrolled from 59 centers in the United States. Lumbar punctures were performed using standardized protocols and biomarker measurements were conducted at the University of Pennsylvania. Amyloid-β (Aβ) 1-42 peptide, total tau (tau), and tau phosphorylated at the threonine 181 (p-tau) were measured using the multiplex xMAP Luminex platform with Innogenetics immunoassay.3

Antihypertensive medication information was coded into 1 of 5 classes (ARBs, angiotensin-converting enzyme inhibitors, diuretics, β-blockers, and calcium channel blockers). Those receiving multiple classes were categorized into each class separately. Blood pressure was measured at baseline and follow-up. Participants were hypertensive if their blood pressure was 140/90 mm Hg or greater or were receiving antihypertensive medication. Because switching class during the follow-up period was possible, our independent variable was the use of ARBs during at least 1 visit prior to the CSF measurement and our comparison groups were those treated with other antihypertensive classes or those with untreated hypertension (additional comparisons were done including participants without hypertension). Mixed models with repeated measures were used. Our parsimonious models included age, sex, systolic blood pressure, and baseline measure for corresponding marker (adding additional covariates did not alter the results or improve the model-fit statistics). We included those with 2, 3, or 4 CSF collections and conducted analyses in normal cognitive control individuals, patients with MCI, and those with dementia.

The study protocol was approved by each participating institution’s institutional review board, and participants provided written informed consent.

Our sample included 319 individuals: 45% with hypertension, 8% taking ARBs, 47% with MCI, 30% healthy control individuals, and 23% with Alzheimer disease. The mean (SD) age was 73 (7.5) years, 56% were women, and the range of the number of visits was 2 to 4 (Table). In those with MCI, after adjusting for the covariates and baseline marker measure, use of ARBs during at least 1 visit prior to lumbar puncture was associated with a decrease in both total tau (P = .002) and p-tau (P = .01) but not Aβ (P = .12) relative to those treated with non-ARB classes and untreated hypertension (Figure). In normal cognitive control individuals, ARB use was associated with lower decline in Aβ (P = .03) but no impact on tau markers (P = .30 for tau and P = .71 for p-tau). In Alzheimer disease, ARB use was not associated with any changes (all P > .05). The results did not change when we included normotension in the comparison group.

Table Graphic Jump LocationTable.  Baseline Characteristics in the ADNI Cohort by Exposure to ARBs
Place holder to copy figure label and caption
Figure.
Progression of Total and Phosphorylated Tau (P-tau) by Exposure to Angiotensin Receptor Blockers (ARBs) in Those With Mild Cognitive Impairment in the Alzheimer’s Disease Neuroimaging Initiative Cohort

Values are least square means adjusted for age, sex, systolic blood pressure, and the baseline measures of tau and p-tau, respectively. Patient totals were as follows: baseline = 319, year 1 = 317, year 2 = 144, and year 3 = 80. P values are for trend/change over the follow-up obtained from the ARB-by-time parameter.

aP < .05 for the difference between ARB and no ARB within that follow-up visit per year.

Graphic Jump Location

The use of ARB in those with MCI may be associated with longitudinal declines in tau and p-tau. These data extend our previous favorable ARB findings. Tau markers, more so than Aβ, correlate with the severity of clinical symptoms.4 This may provide an explanation of why ARBs may specifically impact symptoms in MCI. Although not investigated in our report, previous animal studies have suggested that ARBs inhibit glycogen synthase kinase, which is involved in tau production and neurodegeneration.5,6 This may offer an underlying biological plausibility for this observation. Despite the limitation of our small sample size and small number of individuals taking ARBs, our study offers further evidence of a favorable effect of ARBs on brain markers of Alzheimer disease in the predementia stages. Clinical trials are needed to further confirm these effects.

Corresponding Author: Ihab Hajjar, MD, Departments of Medicine and Neurology, 1841 Clifton Rd NE, 5th Floor, Atlanta, GA 30329 (ihajjar@emory.edu).

Author Contributions: Dr Hajjar had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Hajjar.

Acquisition, analysis, or interpretation of data: Both authors.

Drafting of the manuscript: Hajjar.

Critical revision of the manuscript for important intellectual content: Both authors.

Statistical analysis: Hajjar.

Obtained funding: Hajjar.

Conflict of Interest Disclosures: The Alzheimer’s Disease Neuroimaging Initiative is funded by contributions from the following: Araclon Biotech, BioClinica Inc, Biogen Idec Inc, Bristol-Myers Squibb Co, Eisai Inc, Elan Pharmaceuticals Inc, Eli Lilly and Co, EuroImmun, F Hoffmann–La Roche Ltd and its affiliated company Genentech Inc, Fujirebio, GE Healthcare, IXICO Ltd, Janssen Alzheimer Immunotherapy Research & Development LLC, Johnson & Johnson Pharmaceutical Research & Development LLC, Medpace Inc, Merck & Co Inc, Meso Scale Diagnostics LLC, NeuroRx Research, Neurotrack Technologies, Novartis Pharmaceuticals Corp, Pfizer Inc, Piramal Imaging, Servier, Synarc Inc, and Takeda Pharmaceutical Co. No other disclosures were reported.

Funding/Support: Dr Hajjar is funded by the National Institute on Aging (R01AG042127) and Dr Levey is funded by the Emory Alzheimer’s Disease Research Center (P50 AG025688). The Alzheimer’s Disease Neuroimaging Initiative is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, the Alzheimer’s Association, and the Alzheimer’s Drug Discovery Foundation. The Canadian Institutes of Health Research provides funding to support Alzheimer’s Disease Neuroimaging Initiative clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (http://www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Disease Cooperative Study at the University of California, San Diego. Alzheimer’s Disease Neuroimaging Initiative data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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;69(12):1632-1638.
PubMed   |  Link to Article
Hajjar  I, Hart  M, Chen  YL,  et al.  Effect of antihypertensive therapy on cognitive function in early executive cognitive impairment: a double-blind randomized clinical trial. Arch Intern Med. 2012;172(5):442-444.
PubMed   |  Link to Article
Shaw  LM, Vanderstichele  H, Knapik-Czajka  M,  et al; Alzheimer’s Disease Neuroimaging Initiative.  Qualification of the analytical and clinical performance of CSF biomarker analyses in ADNI. Acta Neuropathol. 2011;121(5):597-609.
PubMed   |  Link to Article
Bierer  LM, Hof  PR, Purohit  DP,  et al.  Neocortical neurofibrillary tangles correlate with dementia severity in Alzheimer’s disease. Arch Neurol. 1995;52(1):81-88.
PubMed   |  Link to Article
Wang  JZ, Wu  Q, Smith  A, Grundke-Iqbal  I, Iqbal  K.  Tau is phosphorylated by GSK-3 at several sites found in Alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by A-kinase. FEBS Lett. 1998;436(1):28-34.
PubMed   |  Link to Article
Agarwal  D, Dange  RB, Raizada  MK, Francis  J.  Angiotensin II causes imbalance between pro- and anti-inflammatory cytokines by modulating GSK-3β in neuronal culture. Br J Pharmacol. 2013;169(4):860-874.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure.
Progression of Total and Phosphorylated Tau (P-tau) by Exposure to Angiotensin Receptor Blockers (ARBs) in Those With Mild Cognitive Impairment in the Alzheimer’s Disease Neuroimaging Initiative Cohort

Values are least square means adjusted for age, sex, systolic blood pressure, and the baseline measures of tau and p-tau, respectively. Patient totals were as follows: baseline = 319, year 1 = 317, year 2 = 144, and year 3 = 80. P values are for trend/change over the follow-up obtained from the ARB-by-time parameter.

aP < .05 for the difference between ARB and no ARB within that follow-up visit per year.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable.  Baseline Characteristics in the ADNI Cohort by Exposure to ARBs

References

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;69(12):1632-1638.
PubMed   |  Link to Article
Hajjar  I, Hart  M, Chen  YL,  et al.  Effect of antihypertensive therapy on cognitive function in early executive cognitive impairment: a double-blind randomized clinical trial. Arch Intern Med. 2012;172(5):442-444.
PubMed   |  Link to Article
Shaw  LM, Vanderstichele  H, Knapik-Czajka  M,  et al; Alzheimer’s Disease Neuroimaging Initiative.  Qualification of the analytical and clinical performance of CSF biomarker analyses in ADNI. Acta Neuropathol. 2011;121(5):597-609.
PubMed   |  Link to Article
Bierer  LM, Hof  PR, Purohit  DP,  et al.  Neocortical neurofibrillary tangles correlate with dementia severity in Alzheimer’s disease. Arch Neurol. 1995;52(1):81-88.
PubMed   |  Link to Article
Wang  JZ, Wu  Q, Smith  A, Grundke-Iqbal  I, Iqbal  K.  Tau is phosphorylated by GSK-3 at several sites found in Alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by A-kinase. FEBS Lett. 1998;436(1):28-34.
PubMed   |  Link to Article
Agarwal  D, Dange  RB, Raizada  MK, Francis  J.  Angiotensin II causes imbalance between pro- and anti-inflammatory cytokines by modulating GSK-3β in neuronal culture. Br J Pharmacol. 2013;169(4):860-874.
PubMed   |  Link to Article

Correspondence

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